Alfort dexta i.v.

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALFORT DEXA I.V. (ALFORT DEXA I.V.)

Composition:

Active substance: dexketoprofen trometamol;

1 ml of injection solution contains dexketoprofen trometamol 36.9 mg, equivalent to dexketoprofen 25 mg;

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

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: clear, colorless, homogeneous solution.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. Dexketoprofen. ATC code M01A E17.

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 reducing the synthesis of prostaglandins by inhibiting the activity of cyclooxygenase. 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

Dexketoprofen trometamol has been shown to inhibit the activity of both cyclooxygenase-1 and cyclooxygenase-2 in laboratory animals and 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 after intramuscular and intravenous administration in patients with moderate to severe pain has been studied in various pain conditions 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 analgesia after administration of 50 mg of dexketoprofen trometamol is typically 8 hours. Clinical studies have shown that the use of dexketoprofen trometamol allows a significant reduction in opioid dosage when used concomitantly for postoperative pain management. In patients receiving morphine via a patient-controlled analgesia device for postoperative pain, co-administration of dexketoprofen trometamol resulted in a significantly lower morphine requirement (by 30–45%) compared to patients receiving placebo.

Pharmacokinetics

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 plasma 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 the absence of drug accumulation.

Biological Transformation and Elimination

The 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 the absence of in vivo conversion 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, although no statistically significant differences in maximum concentration (Cmax) or time to reach it (Tmax) were observed. The mean elimination half-life increased (by up to 48%), and the total body clearance decreased.

Preclinical Safety Data

Standard preclinical studies—including pharmacological safety, genotoxicity, and immunopharmacology assessments—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 exposure levels 14–18 times higher than those observed at the maximum recommended human dose. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen may lead to embryonic or fetal death in animals, either directly by affecting embryonic/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 not appropriate, such as in postoperative pain, renal colic, and lumbago (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 substances of similar action, 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 (Child-Pugh score 10–15 points);
• hemorrhagic diathesis and other coagulation disorders;
• in cases of pronounced dehydration (due to vomiting, diarrhea, or insufficient fluid intake);
• third trimester of pregnancy or breastfeeding period.

Due to the ethanol content in Alfort Dexa I.V., the drug is contraindicated for neuroaxial (intrathecal or epidural) administration.

Interaction with other medicinal products and other forms of interaction

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

• other NSAIDs (including selective cyclooxygenase-2 inhibitors), as well as high-dose salicylates (≥ 3 g/day). Concomitant use of multiple NSAIDs increases the risk of gastrointestinal ulceration and gastrointestinal bleeding due to their mutually potentiating effects;
• anticoagulants: NSAIDs enhance the effect of anticoagulants such as 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 medical 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 medical supervision with careful monitoring of relevant laboratory parameters;
• corticosteroids: increased risk of gastrointestinal ulceration or gastrointestinal bleeding;
• lithium (reports exist for several NSAIDs): NSAIDs increase lithium blood levels, potentially leading to toxicity (due to reduced renal excretion of lithium). Therefore, lithium blood levels should be monitored at the initiation of dexketoprofen treatment, during dose adjustments, or upon discontinuation;
• 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 increased 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 efficacy 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): 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. Treatment should be closely supervised by a physician, even in cases of mild renal impairment or in elderly patients;
• 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. A blood test and reticulocyte count should be performed 1–2 weeks after initiating NSAID therapy;
• sulfonylurea agents: NSAIDs may enhance the hypoglycemic effect of these agents by displacing them from plasma protein binding sites.

Potential interactions should be considered when using the following agents:

• beta-blockers: NSAIDs may reduce their antihypertensive effect by inhibiting prostaglandin synthesis;
• cyclosporine and tacrolimus: possible increased 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 due to prostaglandin synthetase inhibitors. Limited data suggest that concomitant administration of NSAIDs on the same day as prostaglandin does not adversely affect mifepristone or prostaglandin efficacy regarding cervical ripening or contractility, nor does it reduce the clinical efficacy of medical abortion regimens;
• quinolone antibiotics: animal studies have shown 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 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

General

The medicinal product should be used with caution in patients with a history of allergic conditions. Concomitant use of this drug with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Gastrointestinal safety

Gastrointestinal bleeding, ulceration, or perforation, sometimes fatal, have been reported with NSAIDs at any stage of treatment, regardless of the presence of prior symptoms or 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, 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 disease 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 complications during treatment, particularly gastrointestinal bleeding. NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (e.g., 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 gastroprotective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

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), SSRIs, or antiplatelet agents like 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 receiving diuretics or those at risk of hypovolemia. Adequate fluid intake should be maintained during treatment 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 inhibitors of prostaglandin synthesis, 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. As with 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 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 prior episodes of heart failure (the drug increases the risk of heart failure), 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 thrombotic events (e.g., myocardial infarction or stroke). Data to exclude this risk with dexketoprofen 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 (e.g., arterial hypertension, hyperlipidemia, diabetes, smoking).

Cases of Kounis syndrome have been reported in patients receiving dexketoprofen. Kounis syndrome is defined as cardiovascular symptoms arising from 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 low-dose low-molecular-weight heparin 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 (e.g., warfarin, other coumarins, or heparins) should be under close medical supervision. Cardiovascular function disturbances occur most frequently in elderly patients.

Skin reactions

There have been reports of very rare cases of serious skin reactions (some fatal) associated 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, Alfort Dexta I.V. should be discontinued.

Masking symptoms of underlying infections

Alfort Dexta I.V. may mask symptoms of infections, 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 Alfort Dexta I.V. 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 inherited 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 rarely, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. If early signs of severe hypersensitivity reactions occur after taking Alfort Dexta I.V., treatment should be discontinued. Any necessary treatment in such cases 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 in the context of varicella. Data to exclude a role of NSAIDs in exacerbating this infectious process are lacking. Therefore, dexketoprofen trometamol is not recommended in cases of varicella.

Alfort Dexta I.V. should be administered with caution to 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 some cases, activation of infectious processes localized in soft tissues 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.

Each vial of Alfort Dexta I.V. 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., liver disease, epilepsy). The medicinal product contains less than 1 mmol sodium (23 mg) per dose and is practically sodium-free.

Use during pregnancy or breastfeeding

The use of Alfort Dexta I.V. 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 inhibiting prostaglandin synthesis in early pregnancy increases the risk of miscarriage and fetal congenital heart defects and abdominal wall defects. The absolute risk of cardiovascular malformations increases from <1% to approximately 1.5%. The risk 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 higher embryofetal mortality. Additionally, in animals treated with prostaglandin synthesis inhibitors during organogenesis, increased frequency 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 treatment initiation and is usually reversible upon discontinuation. 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 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 effective dose for the shortest possible duration should be used. Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered if exposure occurs 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 may cause:

Risks for the fetus:

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

Risks for 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 prolonged labor.

Breastfeeding

There are no data on the passage of dexketoprofen into breast milk. Alfort Dexta I.V. is contraindicated during breastfeeding.

Fertility

Like all other NSAIDs, dexketoprofen trometamol may reduce female fertility and therefore is not recommended for women attempting to conceive. Women experiencing infertility or undergoing fertility investigations should consider discontinuing the drug.

Ability to affect reaction speed when driving or operating machinery

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

Dosage and Administration

Adults

The recommended dose is 50 mg every 8–12 hours. If necessary, a repeat 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 be used only during the period of acute pain (no longer than 2 days). Patients should be switched to oral analgesics as soon as possible. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. 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, with a maximum daily dose of 50 mg in patients with mild renal impairment.

Hepatic impairment

For patients with mild or moderate hepatic impairment (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 disease (10–15 points on the Child-Pugh scale).

Renal impairment

For 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).

Intramuscular administration

The injection solution should be administered slowly and deeply into the muscle.

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 should be prepared under aseptic conditions, avoiding exposure to natural daylight. The prepared solution must be clear and transparent. The infusion should be administered over 10–30 minutes. Avoid exposure of the prepared solution to natural daylight.

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.

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

Intravenous injection (bolus administration)

If necessary, the contents of one ampoule (2 mL of injection solution) may 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.

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

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

The drug should only be mixed 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 adsorption of the active substance was observed when diluted solutions of the drug were stored in plastic bags or delivery devices made of ethylene-vinyl acetate, propionate cellulose, low-density polyethylene, or polyvinyl chloride.

The drug is intended for single use only; any unused portion of the solution should be discarded. The solution should be visually inspected before administration to ensure clarity and colorlessness. The drug must not be used if mechanical particles are observed.

Children

The drug should not be used in children (under 18 years of age) 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, according to clinical trial data, are considered at least possible in relation to dexketoprofen trometamol, as well as adverse reactions reported after marketing authorization of the drug.

Gastrointestinal disorders were observed most frequently.

Peptic ulceration, perforation, or gastrointestinal bleeding, sometimes fatal, especially in elderly patients, may occur. 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 has been observed less frequently. Edema, arterial hypertension, and heart failure, which may be associated with the use of NSAIDs, have also been reported. As with other NSAIDs, the following adverse reactions may occur: aseptic meningitis, which generally occurs in patients with systemic lupus erythematosus or mixed connective tissue disorders, and blood-related reactions (purpura, aplastic and hemolytic anemia, rarely agranulocytosis and bone marrow hypoplasia). Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), are possible.

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

Reporting 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. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

After dilution according to the instructions for medical use, the diluted solution has been shown to be chemically stable for 24 hours when stored at 25 °C, provided it is adequately protected from sunlight.

From a microbiological standpoint, the product should be used immediately. If not used immediately, the duration and conditions of storage after dilution and prior to use are the responsibility of the user. Generally, these should not exceed 24 hours at 2–8 °C, except in cases where dilution was performed under controlled and validated aseptic conditions.

Storage conditions

Store at a temperature not exceeding 25 °C in a place inaccessible to children. Keep in the original packaging to protect from light. Storage conditions after dilution are specified in the section “Shelf life”.

Incompatibilities

The drug 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 forms.

Diluted infusion solutions prepared as described in the section “Intravenous infusions” must not be mixed with promethazine or pentazocine.

Packaging

2 mL in a vial; 3 or 6 vials in a cassette in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Idol Ilac Doluluk San. ve Tic. A.Ş.

Manufacturer’s address and location of operations

Davutpasa Cad. Jebelialibey Sok. No 20, Topkapi Zeytinburnu/Istanbul, Turkey.

Marketing authorization holder

Delta Medical Promotions AG.

Address of the marketing authorization holder

Ottenbachstrasse 26, Zurich CH–8001, Switzerland.