De-span®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DE-SPAN® (DE-SPAN)

Composition:

Active substance: dexketoprofen;

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

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

Pharmaceutical form. Injectable solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

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

Pharmacological Properties.

Pharmacodynamics.

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

Mechanism of action.

The mechanism of action of NSAIDs is based on the reduction of prostaglandin synthesis through inhibition of cyclooxygenase activity. Specifically, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2α, PGD2, as well as prostacyclin PGI2 and thromboxanes TxА2 and TxВ2 are formed. Additionally, 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 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 action of dexketoprofen trometamol following intramuscular and intravenous administration in patients with moderate to severe pain has been studied in various painful conditions associated with surgical procedures (orthopedic and gynecological surgeries, abdominal operations), musculoskeletal disorders (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 shown that the use of dexketoprofen trometamol allows a significant reduction in opioid dosage when used concomitantly to manage postoperative pain. In patients receiving morphine via a patient-controlled analgesia device for postoperative pain relief, co-administration of dexketoprofen trometamol resulted in a significantly lower morphine requirement (by 30–45%) compared to patients receiving placebo.

Pharmacokinetics.

After intramuscular administration of dexketoprofen trometamol to humans, maximum plasma 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. Pharmacokinetic studies of repeated administration have shown that AUC and Cmax (mean maximum value) after the last intramuscular or intravenous dose do not differ from those after single administration, indicating absence of drug accumulation.

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 dosing demonstrated that Cmax and AUC after the last intramuscular or intravenous administration 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 interconversion to the R-(–) optical isomer in humans.

Elderly patients.

After administration of single and multiple doses, the extent of exposure in healthy elderly 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 (Cmax) or time to reach Cmax were observed. The mean elimination half-life was prolonged (by up to 48%), and total clearance was reduced.

Preclinical safety data.

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

Like all NSAIDs, dexketoprofen may lead to embryonic or fetal death in animals, either directly by affecting embryofetal development or indirectly via adverse effects on the gastrointestinal tract of the mother.

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 back pain (spinal pain).

Contraindications.

• Hypersensitivity to dexketoprofen, to any other nonsteroidal anti-inflammatory drug (NSAID), or to excipients of the medicinal product;
• contraindicated in patients in whom agents of similar action, such as acetylsalicylic acid or other NSAIDs, provoke attacks of bronchial asthma, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria, or angioedema;
• contraindicated in patients who developed photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates;
• gastrointestinal bleeding or perforation in history related to previous NSAID therapy;
• active peptic ulcer / gastrointestinal bleeding or history of gastrointestinal bleeding, ulcers, or perforations;
• chronic dyspepsia;
• active gastrointestinal bleeding, other 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;
• pronounced dehydration (due to vomiting, diarrhea, or insufficient fluid intake);
• third trimester of pregnancy and breastfeeding period;
• do not 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 agents with NSAIDs is not recommended:

• other NSAIDs (including selective cyclooxygenase-2 inhibitors), including salicylates in high doses (≥ 3 g/day). Concurrent use of multiple NSAIDs increases the risk of gastrointestinal ulceration and gastrointestinal bleeding due to mutual enhancement of effects;
• anticoagulants: NSAIDs enhance the effect of anticoagulants such as warfarin due to high plasma protein binding of dexketoprofen, as well as platelet function inhibition and damage to gastric and duodenal mucosa. If concomitant use is necessary, it should be performed under strict medical supervision and appropriate laboratory monitoring;
• heparins: increased risk of bleeding (due to platelet function inhibition and damage to gastric and duodenal mucosa). If concomitant use is necessary, it should be performed under medical supervision with careful monitoring of appropriate laboratory parameters;
• corticosteroids: increased risk of gastrointestinal ulceration and gastrointestinal bleeding;
• lithium (reports with several NSAIDs): NSAIDs increase lithium blood levels, potentially leading to toxicity (reduced renal excretion of lithium). Therefore, lithium blood levels should be monitored at the initiation of dexketoprofen therapy, during dose adjustments, and 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 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 renal impairment (e.g., dehydration or 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 under NSAID therapy enhances its overall negative effect on the blood system. During the first weeks of concomitant use, weekly blood tests are required. Even with mild renal impairment and in elderly patients, treatment should be 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 effect on erythrocytes due to impact on reticulocytes, leading to severe anemia after one week of NSAID use. Blood test and reticulocyte count 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:

• β-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 (SSRIs): increased risk of gastrointestinal bleeding;
• probenecid: possible increase in dexketoprofen plasma concentration, likely due to inhibition of renal tubular secretion and glucuronide conjugation of the drug, requiring dose adjustment of dexketoprofen;
• cardiac glycosides: NSAIDs may increase glycoside plasma concentrations;
• mifepristone: theoretically, there is a risk of altered mifepristone efficacy under the influence of prostaglandin synthetase inhibitors. Limited data suggest that co-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 agents;
• quinolone antibiotics: animal studies indicate that high-dose quinolone derivatives in combination with NSAIDs increase the risk of seizures;
• tenofovir: when used concomitantly with NSAIDs, plasma urea nitrogen and creatinine concentrations may increase; 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 concomitantly with deferasirox;
• pemetrexed: concomitant use with NSAIDs may reduce pemetrexed elimination; therefore, particular caution is required when using NSAIDs at high doses. Patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min) should avoid concomitant use of pemetrexed and NSAIDs for two days before and two days after pemetrexed administration.

Special precautions.

The medicinal product should be used with caution in patients with a history of allergic conditions. Concomitant use of the 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 all NSAIDs at various stages of treatment, regardless of the presence of preceding symptoms or a history of serious gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, particularly in patients with a history of peptic ulcer, especially complicated by bleeding or perforation, and in elderly patients.

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

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

The drug should be prescribed with caution to patients concurrently using agents that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents 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 all NSAIDs, the drug may increase plasma concentrations of blood urea nitrogen and creatinine. Similar to other prostaglandin synthesis inhibitors, its use may be associated with renal adverse reactions, including glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Renal function disturbances occur most frequently in elderly patients.

Hepatic safety.

The medicinal product should be used with caution in patients with impaired liver function. As with other NSAIDs, the drug may cause transient and mild elevations in certain liver function tests, as well as marked increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity. If such elevations occur, treatment 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 should be under close medical supervision. Particular caution is required when treating patients with a history of heart disease, especially prior episodes of heart failure (the risk of heart failure increases during treatment), as NSAIDs may cause fluid retention and edema. Clinical and epidemiological data suggest a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) with some NSAIDs, particularly at high doses and during prolonged use. Data to exclude such risk with dexketoprofen are insufficient. Therefore, dexketoprofen should be prescribed only after careful assessment in patients with uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Similarly careful evaluation is required before initiating long-term treatment in patients with cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

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 receiving dexketoprofen trometamol concurrently with agents affecting hemostasis (e.g., warfarin, other coumarins, or heparins) should be closely monitored. 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 NSAIDs, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk occurs early in treatment, with most cases appearing within the first month. If skin rashes, signs of mucosal involvement, or other symptoms of hypersensitivity occur, the medicinal product DE-SPAN® should be discontinued.

Masking symptoms of underlying infections.

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

Other information.

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

• hereditary disorders of porphyrin metabolism (e.g., acute intermittent porphyria);
• 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.

In very rare cases, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. Treatment should be discontinued at the first signs of severe hypersensitivity reactions following DE-SPAN® administration. Depending on symptoms, any necessary treatment should be administered under medical supervision.

Patients with 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, particularly in patients allergic to acetylsalicylic acid or NSAIDs.

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

DE-SPAN® should be prescribed with caution in patients with blood 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, there have been reports of exacerbation of soft tissue infections during NSAID use. Therefore, if symptoms of bacterial infection appear or worsen during treatment, patients are advised to seek immediate medical attention.

Each ampoule of the medicinal product DE-SPAN® contains 200 mg of ethanol, equivalent to 5 mL of beer or 2.08 mL of wine per dose. The product 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 medicinal product contains less than 1 mmol of sodium (23 mg) per dose and is therefore considered practically sodium-free.

Use during pregnancy or breastfeeding.

The use of the medicinal product DE-SPAN® 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 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 considered to increase with higher drug doses and longer treatment duration. In animal studies, prostaglandin synthesis inhibitors have caused increased pre- and post-implantation losses and higher embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of fetal developmental abnormalities, including cardiovascular anomalies, has been observed. However, animal studies with dexketoprofen trometamol did not reveal toxicity to reproductive organs.

From the 20th week of pregnancy, the use of DE-SPAN® may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. There are also reports of arterial duct constriction after second-trimester treatment, which in most cases resolved after stopping 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, the lowest effective dose for the shortest possible duration should be used.

After several days of DE-SPAN® exposure starting from the 20th gestational week, oligohydramnios and arterial duct constriction should be considered in prenatal monitoring. If oligohydramnios or arterial duct constriction is detected, DE-SPAN® should be discontinued.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• cardiopulmonary toxic syndrome (premature constriction/closure of the arterial duct and pulmonary hypertension);
• impaired renal function (see above), which may progress to renal failure and oligohydramnios;

Risks at the end of pregnancy for mother and child:

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

Breastfeeding.

There are no data on the passage of dexketoprofen into breast milk. The medicinal product DE-SPAN® 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. If a woman experiences difficulties in conceiving or undergoes infertility investigations, discontinuation of the drug should be considered.

Ability to influence reaction speed when driving or operating machinery.

Dizziness, visual disturbances, or somnolence may occur during treatment with DE-SPAN®. 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

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

Adults.

The recommended dose is 50 mg every 8–12 hours. If necessary, the next dose may be administered after 6 hours. The maximum daily dose should not exceed 150 mg. The drug is intended for short-term use and should only be administered during episodes of acute pain (no longer than 2 days). Patients should be switched to oral analgesics as soon as possible. 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 physiological decline in renal function, a lower dose is recommended; the maximum daily dose should be 50 mg in patients with 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 patients with severe hepatic impairment (10–15 points on the Child–Pugh scale).

Renal Impairment.

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

Children (including adolescents).

The drug should not be used in children (including adolescents) due to lack of data on efficacy and safety.

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 must be prepared under aseptic conditions and protected from exposure to natural daylight. The final solution must be clear and transparent. The infusion should be administered over 10–30 minutes.

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

Intravenous 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.

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

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

The drug should only be mixed with the medicinal products listed above.

After drawing the drug from the ampoule, it should be administered immediately when used intramuscularly or as an intravenous bolus.

No changes in active substance concentration due to adsorption have been 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.

DESPAN® is intended for single use only; any unused portion of the prepared solution must be discarded. Prior to administration, ensure that the solution is clear and colorless. The solution must not be used if it contains particulate matter.

Children.

The drug should not be used in children (including 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 by system organ class and frequency, which are considered at least possible in relation to dexketoprofen trometamol based on clinical trial data, as well as adverse reactions reported after marketing authorization.

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, 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 associated with 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), are also possible.

According to the results of clinical trials and epidemiological data, the use of certain NSAIDs, particularly at high doses and over prolonged periods, may slightly increase the risk of arterial thrombotic events such as myocardial infarction and stroke.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is of great importance. 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 through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging. After dilution, the solution should be stored for up to 24 hours at 2–8 °C in a light-protected place. Keep out of reach of children.

Incompatibility.

DE-SPAN® must not be mixed in small volumes (e.g., in a syringe) with dopamine, promethazine, pentazocine, pethidine, or hydroxyzine solutions, as precipitation may occur.

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

Packaging.

2 ml in ampoules, pack of 5 (5×1) or 10 (5×2) or 10 (10×1) in cassettes in a cardboard box.

Prescription status.

Prescription only.

Manufacturers.

Private Joint-Stock Company "Lekhym-Kharkiv" (responsible for manufacturing and batch control/testing, excluding batch release).

LLC NPF "MIKROKHEM" (responsible for batch release, excluding batch control/testing).

Manufacturers' addresses and locations of their operations.

Ukraine, 61115, Kharkiv region, Kharkiv, Severin Pototskogo St., 36.

Ukraine, 93000, Luhansk region, Rubizhne, Lenina St., 33.

Marketing Authorization Holder.

LLC NPF "MIKROKHEM".

Address of the Marketing Authorization Holder.

Ukraine, 01013, Kyiv, Budynstustriyi St., 5.

You can report an adverse event associated with the use of this medicinal product by calling +38(050) 309-83-54 (24/7).

INSTRUCTION

for medical use of the medicinal product

DE-SPAN®

(DE-SPAN)

Composition:

Active substance: dexketoprofen;

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

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

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

Mechanism of action.

The mechanism of action of NSAIDs is based on the reduction of prostaglandin synthesis through inhibition of cyclooxygenase activity. Specifically, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2α, PGD2, as well as prostacyclin PGI2 and thromboxanes TxА2 and TxВ2 are formed. In addition, inhibition of prostaglandin synthesis may 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 exerts pronounced analgesic effects. The analgesic effect of dexketoprofen trometamol administered intramuscularly or intravenously to 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 analgesic action after administration of 50 mg of dexketoprofen trometamol is generally 8 hours. Clinical studies have shown that the use of dexketoprofen trometamol allows a significant reduction in opioid dosage when used concomitantly to manage postoperative pain. In patients receiving morphine via a patient-controlled analgesia device for postoperative pain relief, co-administration of dexketoprofen trometamol resulted in a significantly lower morphine requirement (by 30–45%) compared to patients receiving placebo.

Pharmacokinetics.

After intramuscular administration of dexketoprofen trometamol to humans, maximum plasma 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. Pharmacokinetic studies of repeated administration have shown that AUC and Cmax (mean maximum value) after the last intramuscular or intravenous dose do not differ from those after single administration, indicating the absence of drug accumulation.

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 drug administration demonstrated that Cmax and AUC after the last intramuscular or intravenous dose did not differ from those after single administration, indicating no accumulation of the drug.

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 the absence of interconversion of the drug 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 (Cmax) or time to reach Cmax were observed. The mean elimination half-life was prolonged (by up to 48%), and total clearance was reduced.

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 a no-observed-adverse-effect level (NOAEL) that was 2 times higher than the recommended human dose. 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 effects occurred at doses where drug exposure was 14–18 times higher than at the maximum recommended human dose. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen may cause embryonic or fetal death in animals, either directly by affecting embryonic/fetal development or indirectly via adverse effects on the gastrointestinal tract of the maternal organism.

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 back pain (lumbago).

Contraindications.

• Hypersensitivity to dexketoprofen, to any other nonsteroidal anti-inflammatory drug (NSAID), or to excipients of the medicinal product;
• contraindicated in patients in whom agents of similar action, such as acetylsalicylic acid or other NSAIDs, provoke attacks of bronchial asthma, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria, or angioedema;
• contraindicated in patients who have experienced photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates;
• gastrointestinal bleeding or perforation in history related to previous NSAID therapy;
• active peptic ulcer/gastrointestinal bleeding or history of gastrointestinal bleeding, ulcers, or perforations;
• chronic dyspepsia;
• active gastrointestinal bleeding, other 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;
• marked dehydration (due to vomiting, diarrhea, or insufficient fluid intake);
• third trimester of pregnancy and breastfeeding period;
• do not 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 agents with NSAIDs is not recommended:

• other NSAIDs (including selective cyclooxygenase-2 inhibitors), including salicylates in high doses (≥ 3 g/day). Concurrent use of multiple NSAIDs increases the risk of gastrointestinal ulceration and gastrointestinal bleeding due to mutual enhancement of their effects;
• anticoagulants: NSAIDs enhance the effect of anticoagulants, such as warfarin, due to high plasma protein binding of dexketoprofen, as well as 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 and with appropriate laboratory monitoring;
• 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 appropriate laboratory parameters;
• corticosteroids: increased risk of gastrointestinal ulceration and gastrointestinal bleeding;
• lithium (reports with several NSAIDs): NSAIDs increase lithium blood levels, potentially leading to toxicity (reduced renal excretion of lithium). Therefore, lithium blood levels should be monitored at the start of dexketoprofen treatment, during dose adjustment, or upon discontinuation;
• high-dose methotrexate (≥ 15 mg weekly): due to reduced renal clearance of methotrexate under NSAID therapy, its overall hematological toxicity is enhanced;
• hydantoin derivatives and sulfonamides: possible increase in toxicity of these agents.

Concomitant use of the following agents with NSAIDs requires caution:

• diuretics, angiotensin-converting enzyme (ACE) inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists. Dexketoprofen reduces the effectiveness of diuretics and other antihypertensive agents. In some patients with renal impairment (e.g., dehydration or 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 (< 15 mg weekly): due to reduced renal clearance of methotrexate under NSAID therapy, its overall hematological toxicity is enhanced. During the first weeks of concomitant use, weekly blood tests are required. Treatment should be closely supervised in elderly patients or those with even mild renal impairment;
• pentoxifylline: risk of bleeding. Increased monitoring and more frequent assessment of bleeding time are required;
• zidovudine: risk of increased toxic effects on erythrocytes due to effects on reticulocytes, leading to severe anemia after 1 week of NSAID use. Blood tests and reticulocyte count should be performed within 1–2 weeks after starting 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:

• β-blockers: NSAIDs may reduce their antihypertensive effect by inhibiting 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 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 agents;
• quinolone antibiotics: animal studies indicate that high-dose quinolone derivatives combined with NSAIDs may increase the risk of seizures;
• tenofovir: concomitant use with NSAIDs may increase plasma urea nitrogen and creatinine concentrations; 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. Patients with mild to moderate renal impairment (creatinine clearance 45–79 ml/min) should avoid concomitant use of pemetrexed and NSAIDs for two days before and two days after pemetrexed administration.

Special precautions.

The medicinal product should be used with caution in patients with a history of allergic conditions. Concomitant use of the 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 all NSAIDs at various stages of treatment, regardless of the presence of preceding symptoms or a history of serious gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, particularly in patients with a history of peptic ulcer, especially complicated by bleeding or perforation, and in elderly patients.

Elderly patients have an increased frequency of NSAID-related adverse reactions, particularly gastrointestinal bleeding and perforation, sometimes fatal. Treatment in such patients should be initiated with the lowest possible dose. Before starting treatment with dexketoprofen trometamol, patients with a history of esophagitis, gastritis, and/or peptic ulcer should be evaluated to ensure these conditions are in remission. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored for possible complications during treatment, especially gastrointestinal bleeding. NSAIDs should be used cautiously in patients with a history of gastrointestinal diseases (e.g., ulcerative colitis, Crohn’s disease) due to the risk of exacerbation. For such patients and those taking low-dose acetylsalicylic acid or other agents increasing gastrointestinal adverse risk, combination therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

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

The drug should be prescribed with caution to patients concurrently using agents that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents 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 all NSAIDs, the drug may increase blood urea nitrogen and plasma creatinine concentrations. Similar to other prostaglandin synthesis inhibitors, its use may be associated with renal adverse reactions, including glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Renal function disturbances occur most frequently in elderly patients.

Hepatic safety.

The medicinal product should be used with caution in patients with impaired liver function. Similar to other NSAIDs, the drug may cause transient and mild elevations in certain liver function tests, as well as marked increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity. If such increases occur, treatment 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 should be under close medical supervision. Particular caution is required in patients with a history of heart disease, especially previous episodes of heart failure (the risk of heart failure increases during treatment), as NSAIDs may cause fluid retention and edema. Clinical and epidemiological data suggest a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) with some NSAIDs, particularly at high doses and during prolonged use. Data are insufficient to exclude this risk with dexketoprofen. Therefore, dexketoprofen should be prescribed only after careful assessment in patients with uncontrolled hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. A similarly careful evaluation should be performed before initiating long-term treatment in patients with cardiovascular risk factors (e.g., 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 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 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 NSAIDs, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk occurs early in treatment, with most cases appearing within the first month. If skin rashes, signs of mucosal involvement, or other hypersensitivity symptoms occur, the medicinal product DE-SPAN® should be discontinued.

Masking symptoms of underlying infections.

DE-SPAN® may mask symptoms of infections, potentially delaying diagnosis and timely treatment, thereby worsening infection outcomes. Such cases have been observed in bacterial pneumonia and bacterial complications of varicella. When DE-SPAN® 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);
• 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. Treatment should be discontinued at the first signs of severe hypersensitivity reactions after taking DE-SPAN®. Depending on symptoms, any necessary treatment should be administered under medical supervision.

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

Severe skin and soft tissue infections may develop during varicella. Data excluding a role of NSAIDs in exacerbating this infection are lacking. Therefore, the use of DE-SPAN® is not recommended in varicella.

DE-SPAN® should be prescribed with caution in patients with blood disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

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

Each ampoule of the medicinal product DE-SPAN® contains 200 mg of ethanol, equivalent to 5 mL of beer or 2.08 mL of wine per dose. The product may adversely affect individuals with alcoholism. 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 medicinal product contains less than 1 mmol sodium (23 mg) per dose and is therefore considered practically sodium-free.

Use during pregnancy or breastfeeding.

The use of the medicinal product DE-SPAN® is contraindicated during the third trimester of pregnancy and during breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological studies indicate that using drugs that inhibit prostaglandin synthesis in early pregnancy increases the risk of miscarriage and congenital heart defects and abdominal wall defects in the fetus. The absolute risk of cardiovascular anomalies increases from <1% to approximately 1.5%. The risk is considered 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. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of fetal malformations, including cardiovascular anomalies, was observed. However, animal studies with dexketoprofen trometamol did not reveal reproductive organ toxicity.

From the 20th week of pregnancy, the use of DE-SPAN® may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after starting treatment and is usually reversible upon discontinuation. There are also reports of arterial duct constriction after second-trimester treatment, which typically resolves after stopping 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, the lowest effective dose for the shortest possible duration should be used.

After several days of DE-SPAN® use starting from the 20th gestational week, oligohydramnios and arterial duct constriction should be considered during prenatal monitoring. If oligohydramnios or arterial duct constriction is detected, DE-SPAN® should be discontinued.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• cardiopulmonary toxic syndrome (premature constriction/closure of the arterial duct and pulmonary hypertension);
• impaired renal function (see above), potentially progressing to renal failure and oligohydramnios;

Risks at the end of pregnancy for mother and child:

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

Breastfeeding.

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

Fertility.

Like all other NSAIDs, dexketoprofen trometamol may reduce female fertility and is therefore not recommended for women planning pregnancy. If a woman experiences fertility problems or undergoes infertility evaluation, discontinuation of the drug should be considered.

Ability to affect reaction speed when driving or operating machinery.

Dizziness, visual disturbances, or somnolence may occur during treatment with DE-SPAN®. 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

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

Adults.

The recommended dose is 50 mg every 8–12 hours. If necessary, the next dose may be administered after 6 hours. The maximum daily dose should not exceed 150 mg. The drug is intended for short-term use only and should be administered 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 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 physiological decline in renal function, a lower dose is recommended; the maximum daily dose should be 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).

Children (including adolescents).

The drug should not be used in children (including adolescents) due to lack of data on efficacy and safety.

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 one 2 mL ampoule should be diluted in 30–100 mL of 0.9% sodium chloride solution, glucose solution, or Ringer’s lactate solution. The infusion solution should be prepared under aseptic conditions and protected from exposure to natural daylight. The final solution must be clear and free from particles. The infusion should be administered over 10–30 minutes.

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

Intravenous Bolus Injection.

If necessary, the contents of one ampoule (2 mL of injection solution) may be administered intravenously slowly over at least 15 seconds.

The drug may be mixed in small volumes (e.g., in a syringe) with injection solutions of heparin, lidocaine, morphine, and theophylline.

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

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

The drug should only be mixed with the agents listed above.

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

No significant loss of active substance due to adsorption has been observed during storage of diluted solutions in polyethylene bags or in administration devices made of ethylene-vinyl acetate, cellulose propionate, low-density polyethylene, or polyvinyl chloride.

DE-SPAN® 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. Do not use solutions containing particulate matter.

Children.

The drug should not be used in children (including adolescents) due to lack of data on efficacy and safety.

Overdose.

Symptoms of overdose are unknown. Similar medicinal products may cause gastrointestinal disorders (nausea, 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 system organ class 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 after marketing authorization of the drug.

Gastrointestinal disorders were observed most frequently.

Peptic ulceration, perforation, or gastrointestinal bleeding, sometimes with fatal outcomes, may occur, particularly in elderly patients. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis, and Crohn's disease may develop during treatment. Gastritis has been reported less frequently. Edema, arterial hypertension, and heart failure, which may be associated with the use of NSAIDs, have also been observed. As with other NSAIDs, the following adverse reactions are possible: aseptic meningitis, which generally occurs in patients with systemic lupus erythematosus or mixed connective tissue diseases, and blood-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), may also occur.

According to clinical trial results and epidemiological data, the use of certain NSAIDs, particularly at high doses and over prolonged periods, is associated with a small increase in the risk of thrombotic events such as myocardial infarction and stroke.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging. After dilution, the solution should be stored for up to 24 hours at 2–8 °C, protected from light. Keep out of reach of children.

Incompatibilities.

DE-SPAN® must not be mixed in small volumes (e.g., in a syringe) with dopamine, promethazine, pentazocine, meperidine, or hydroxyzine solutions, as precipitation may occur.

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

Packaging.

2 ml in ampoules, pack of 5 (5×1) or 10 (5×2) or 10 (10×1) in cassettes, in a cardboard box.

Prescription status.

Prescription only.

Manufacturers.

JSC "Halychpharm" (responsible for manufacturing and batch control/testing, excluding batch release).

LLC NVP "MIKROKHEM" (responsible for batch release, excluding batch control/testing).

Manufacturers' addresses.

6/8 Opryshkivska St., Lviv, 79024, Ukraine.

5 Budynstustriyi St., Kyiv, 01013, Ukraine.

Marketing authorization holder.

LLC NVP "MIKROKHEM".

Address of the marketing authorization holder.

5 Budynstustriyi St., Kyiv, 01013, Ukraine.

You can report any adverse event associated with this medicinal product by calling +38 (050) 309-83-54 (available 24/7).