Myaldex

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

Composition:

Active substance: dexketoprofen trometamol;

1 ml of injection solution contains 25 mg of dexketoprofen (in the form of dexketoprofen trometamol);

Excipients: ethanol 96%, sodium chloride, sodium hydroxide and/or hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives.

ATC code M01A E17.

Pharmacological Properties

Pharmacodynamics

Dexketoprofen trometamol is a propionic acid salt that exerts 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 reducing the synthesis of prostaglandins by inhibiting 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

An inhibitory effect of dexketoprofen trometamol on the activity of cyclooxygenase-1 and cyclooxygenase-2 has 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 a pronounced analgesic effect. The analgesic effect of dexketoprofen trometamol following intramuscular or intravenous administration in patients with moderate to severe pain intensity 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. The analgesic effect of the drug begins rapidly and reaches its maximum within the first 45 minutes. The duration of analgesic action after administration of 50 mg dexketoprofen trometamol usually lasts 8 hours. Administration of the drug Myaldex 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 management were also given dexketoprofen trometamol, they required significantly less morphine (by 30–45%) compared to patients receiving placebo.

Pharmacokinetics

Absorption

After intramuscular administration of dexketoprofen trometamol, maximum concentration (Cmax) 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 medicinal products with a high degree of plasma protein binding (99%), the volume of distribution of dexketoprofen averages 0.25 L/kg. The half-distribution time is approximately 0.35 hours, and the elimination half-life is 1–2.7 hours.

Pharmacokinetic studies with repeated administration of the drug demonstrated that AUC and Cmax after the last intramuscular or intravenous dose did not differ from those observed 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.

Elderly patients

After administration of single and multiple doses, the extent of drug 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 increased (by up to 48%), and the total clearance decreased.

Preclinical safety data

Standard preclinical studies—pharmacological safety, genotoxicity, and immunopharmacology—did not reveal any special hazard for humans. Chronic toxicity studies in animals identified the no-observed-adverse-effect level (NOAEL), which was twice 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 tract 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 lead to embryo or fetal death in animals due to a direct effect on its development or indirectly due to maternal gastrointestinal tract damage.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to dexketoprofen or to other nonsteroidal anti-inflammatory drugs (NSAIDs), or to excipients of the medicinal product.

• Patients in whom administration of drugs of similar action, such as 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.

• History of gastrointestinal bleeding or perforation related to the use of NSAIDs.

• Active peptic ulcer/gastrointestinal bleeding, or history of gastrointestinal bleeding, ulcers, or perforations.

• Chronic dyspepsia.

• Gastrointestinal bleeding, other active bleeding, or coagulation disorders.

• Crohn’s disease or ulcerative colitis.

• Severe heart failure.

• Moderate or severe renal impairment (creatinine clearance ˂ 59 mL/min).

• Severe hepatic impairment (Child-Pugh score 10–15 points).

• Hemorrhagic diathesis or other coagulation disorders.

• Marked dehydration (due to vomiting, diarrhea, or insufficient fluid intake).

• Third trimester of pregnancy and breastfeeding period.

• Use for neuroaxial (intrathecal or epidural) administration (due to ethanol content).

Interaction with other medicinal products and other forms of interaction.

Concomitant use of the following medicinal products with NSAIDs is not recommended:

• Other NSAIDs (including selective cyclooxygenase-2 inhibitors), including high-dose salicylates (≥ 3 g per day). Concurrent use of multiple NSAIDs increases the risk of gastrointestinal ulcers and gastrointestinal bleeding due to their mutually potentiating effects.

• Anticoagulants: NSAIDs enhance the effect of anticoagulants, such as warfarin, due to high plasma protein binding of dexketoprofen, as well as due to inhibition of platelet function and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be performed under strict medical supervision with monitoring of appropriate laboratory parameters.

• Heparin: 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 strict medical supervision with monitoring of appropriate laboratory parameters.

• Corticosteroids: increased risk of gastrointestinal ulcers and gastrointestinal bleeding.

• Lithium (reports with 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 start of dexketoprofen treatment, during dose adjustments, and upon discontinuation of the drug.

• High-dose methotrexate (≥ 15 mg per week): due to reduced renal clearance of methotrexate under the influence of NSAIDs, its overall negative effect on the blood system is enhanced.

• Hydantoin derivatives and sulfonamides: possible increase in toxicity of these substances.

Concomitant use of the following medicinal products with NSAIDs requires caution:

• Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. Dexketoprofen reduces the effectiveness of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydration or elderly patients), concomitant use of drugs that inhibit cyclooxygenase with ACE inhibitors or angiotensin II receptor antagonists 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 the influence of NSAIDs, 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 close medical supervision.

• Pentoxifylline: risk of bleeding. Monitoring should be intensified, and bleeding time should be checked more frequently.

• 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 counts should be performed within 1–2 weeks after starting NSAID treatment.

• Sulfonylurea derivatives: NSAIDs can enhance the hypoglycemic effect of these drugs by displacing them from plasma protein binding sites.

Possible interactions should be considered when using the following medicinal products:

• Beta-blockers: NSAIDs may reduce their antihypertensive effect by inhibiting prostaglandin synthesis.

• Cyclosporine and tacrolimus: possible increase in nephrotoxicity due to the effect of NSAIDs on renal prostaglandins. Renal function should be monitored during combination therapy.

• Thrombolytic agents: increased risk of bleeding.

• Antiplatelet agents and selective serotonin reuptake inhibitors: increased risk of gastrointestinal bleeding.

• Probenecid: possible increase in dexketoprofen plasma concentration, likely due to inhibition of 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 concurrent 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 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: plasma urea nitrogen and creatinine concentrations may increase when used concomitantly with NSAIDs; therefore, renal function should be monitored to assess the potential impact of combined use.

• Deferasirox: risk of increased gastrointestinal toxicity when used concomitantly with NSAIDs. 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), NSAIDs should be avoided for two days before and two days after pemetrexed administration.

Special precautions for use.

The medicinal product Mialdex should be used with caution in patients with a history of allergic reactions.

Concomitant use of the drug with other NSAIDs, including cyclooxygenase-2 inhibitors, should be avoided. Adverse reactions may be minimized by using the lowest effective dose for the shortest duration necessary to improve the condition.

Digestive system

Gastrointestinal bleeding, ulceration, or perforation, in some cases fatal, have been observed during treatment with all NSAIDs at various stages, regardless of the presence of warning symptoms or a history of serious gastrointestinal pathology. If gastrointestinal bleeding develops, 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 have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, sometimes with fatal outcomes. Treatment in such patients should be initiated with the lowest possible dose. NSAIDs should be prescribed with caution in patients with gastrointestinal disorders in their medical history (e.g., ulcerative colitis, Crohn’s disease), as there is a risk of exacerbation. Before initiating treatment with dexketoprofen trometamol in patients with a history of esophagitis, gastritis, and/or peptic ulcer, it should be ensured that these conditions are in remission. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored for possible complications during treatment, particularly gastrointestinal bleeding.

For such patients and those taking low-dose acetylsalicylic acid or other drugs increasing the risk of gastrointestinal adverse reactions, combination therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) may be appropriate.

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

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

Cardiovascular system and cerebral circulation

Patients with arterial hypertension and/or mild to moderate congestive heart failure should be under close medical supervision due to the possible fluid retention and development of peripheral edema.

According to available clinical and epidemiological data, the use of certain NSAIDs, especially at high doses and over prolonged periods, is associated with a slight increase in the risk of thrombotic events such as myocardial infarction or stroke. Whether this also applies to dexketoprofen trometamol is unknown.

Dexketoprofen trometamol should be used only after careful assessment of the patient’s condition in cases of uncontrolled arterial hypertension, congestive heart failure, confirmed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. The same applies before initiating long-term treatment in patients with risk factors for cardiovascular diseases (arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

Particular caution is required when treating patients with a history of heart disease, especially those with previous episodes of heart failure, as the risk of heart failure may increase during treatment.

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, with no effect on coagulation parameters observed. However, patients taking dexketoprofen trometamol concurrently with agents affecting hemostasis, such as warfarin, other coumarin derivatives, or heparins, should be under close medical supervision. Most cardiovascular adverse events occur in elderly patients.

Skin reactions

Rare cases of serious skin reactions (some with fatal outcomes) have been reported during NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk occurs at the beginning of treatment, with most cases developing within the first month. If a skin rash, signs of mucosal involvement, or other symptoms of hypersensitivity occur, dexketoprofen should be discontinued.

Renal function impairment

The drug should be prescribed with caution in patients with impaired renal function, as NSAIDs may cause deterioration of kidney function, fluid retention, and peripheral 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 all NSAIDs, the drug may increase plasma urea and creatinine levels. 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. Most renal function disturbances occur in elderly patients.

Hepatic function impairment

The medicinal product should be prescribed with caution in patients with hepatic impairment. Like other NSAIDs, the drug may cause transient and slight increases in certain liver function tests, as well as significant elevations in AST and ALT levels. Treatment should be discontinued if such increases occur. Most hepatic function disturbances occur in elderly patients.

Other information

Particular caution should be exercised when prescribing the drug 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 should be performed.

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

Patients suffering from asthma in combination 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, particularly in patients allergic to acetylsalicylic acid or NSAIDs.

The medicinal product Mialdex 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. During NSAID therapy, exacerbation of soft tissue infections has been reported. Therefore, if symptoms of bacterial infection appear or worsen during treatment with Mialdex, patients are advised to seek immediate medical attention.

Severe infectious complications of the skin and soft tissues may occur during varicella. To date, no data are available to exclude the role of NSAIDs in exacerbating this infectious process. Therefore, dexketoprofen is not recommended during varicella.

Like all other NSAIDs, dexketoprofen trometamol may reduce female fertility and therefore is not recommended for women planning pregnancy. For women experiencing fertility problems or undergoing infertility evaluation, discontinuation of the drug may be advisable. Administration during the first and second trimesters of pregnancy may be considered if clearly necessary.

One ampoule of the drug contains 200 mg of ethanol. The drug may have a negative effect on individuals suffering from alcoholism. The ethanol content should be taken into account when using the drug during the first and second trimesters of pregnancy, in children, and in patients at risk (e.g., liver disease, epilepsy).

Like other NSAIDs, dexketoprofen trometamol may mask symptoms of infectious disease, potentially delaying appropriate treatment and worsening the course of illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Mialdex is used for fever or pain relief during infection, monitoring of the infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

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

Use during pregnancy or breastfeeding.

Use of the drug during the third trimester of pregnancy and during breastfeeding is contraindicated.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. According to epidemiological studies, the use of prostaglandin synthesis inhibitors during early pregnancy increases the risk of miscarriage and congenital heart defects and abdominal wall defects in the fetus. Specifically, the absolute risk of cardiovascular malformations 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 higher embryofetal mortality. Additionally, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of fetal developmental abnormalities, including cardiovascular malformations, has been observed. However, animal studies with dexketoprofen trometamol did not reveal reproductive toxicity. Starting from the 20th week of pregnancy, the use of dexketoprofen trometamol may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after treatment initiation and is usually reversible upon discontinuation. Mialdrex should not be prescribed during the first and second trimesters of pregnancy except in cases of extreme necessity. If dexketoprofen trometamol is used in women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the treatment duration as short as possible. Fetal oligohydramnios monitoring should be considered after several days of dexketoprofen trometamol exposure starting from the 20th week of pregnancy. Mialdrex should be discontinued if oligohydramnios is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks for the fetus:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction (see above);

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

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

Therefore, dexketoprofen trometamol is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Period of breastfeeding

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

Fertility

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

Ability to influence reaction rate when driving or operating machinery.

Dizziness, visual disturbances, or somnolence may occur during dexketoprofen 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.

Adults. The recommended dose is 50 mg administered at intervals of 8–12 hours. If necessary, the dose may be repeated after 6 hours. The maximum daily dose should not exceed 150 mg. The drug is intended for short-term use 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. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to relieve 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 the physiological decline in renal function, a lower dose is recommended: maximum daily dose – 50 mg in cases of mild renal impairment.

Hepatic impairment. For 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 severe hepatic impairment (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 moderate to severe renal impairment (creatinine clearance < 59 mL/min).

Method of 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 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 should be clear. The infusion should be administered intravenously slowly over 10–30 minutes. Exposure of the prepared solution to natural daylight must be avoided.

Mialdex, 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.

Mialdex 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 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.

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

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

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

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

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

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section "Special Precautions").

Children.

The use of the drug in children has not been studied; therefore, dexketoprofen should not be prescribed to patients in this age group.

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 should be initiated immediately according to the patient’s condition. Trometamol salt of dexketoprofen is eliminated from the body by dialysis.

Adverse reactions.

The table below lists the adverse reactions observed with dexketoprofen trometamol, classified by organ systems and frequency of occurrence.

Gastrointestinal disorders were observed most frequently.

The development of peptic ulcer, perforation, or gastrointestinal bleeding, sometimes with fatal outcome, is possible, especially in elderly patients. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, vomiting with blood, 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 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, particularly at high doses and over prolonged periods, is associated with a small increased risk of thrombotic events such as myocardial infarction and stroke.

Reporting suspected adverse reactions

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

Shelf life.

3 years.

Storage conditions.

Store in the original packaging, protected from light and inaccessible to children. After reconstitution, the solution should be stored for up to 24 hours at 2–8°C in a place protected from light.

Incompatibilities.

Dexketoprofen trometamol 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 "Dosage and administration" must not be mixed with promethazine or pentazocine.

Packaging.

2 ml in a vial, 5 vials in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LABORATORIOS NORMON, S.A.

Manufacturer's address and location of operations.

Ronda de Valdecarrizo, 6, Tres Cantos 28760 (Madrid), Spain