Rotalfen

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

Composition:

Active substance: dexketoprofen;

1 ampoule (2 mL) of solution contains dexketoprofen (as dexketoprofen trometamol) 50 mg;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.
Non-steroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. Dexketoprofen. 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).

The mechanism of action of NSAIDs is based on reducing the synthesis of prostaglandins by inhibiting 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 dexketoprofen. Inhibitory effects on the activity of both cyclooxygenase-1 and cyclooxygenase-2 have been demonstrated in laboratory animals and in humans.

Clinical studies in various types of pain have demonstrated that dexketoprofen has pronounced analgesic activity. Its analgesic effect after intramuscular and intravenous administration in patients with moderate to severe pain has been studied in various pain conditions associated with surgical procedures (orthopedic and gynecological surgeries, abdominal surgeries), as well as musculoskeletal pain (acute low back pain) and renal colic. In these studies, the analgesic effect began rapidly and reached its maximum within the first 45 minutes. The duration of analgesic action after administration of 50 mg of dexketoprofen is typically 8 hours. The use of dexketoprofen allows a significant reduction in opioid dosage when used concomitantly to manage postoperative pain. Patients receiving morphine (via a patient-controlled analgesia device) and dexketoprofen required significantly less morphine (by 30–45%) compared to patients receiving placebo.

Pharmacokinetics

Absorption

After intramuscular administration of dexketoprofen, 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, the area under the concentration-time curve (AUC) is dose-proportional. Pharmacokinetic studies with repeated dosing 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 dexketoprofen 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.

Metabolism

Dexketoprofen metabolism occurs mainly via glucuronide conjugation, followed by renal excretion. After administration, only the S-(+) optical isomer is detected in urine, indicating absence of interconversion of the drug to the R-(-) optical isomer in humans.

Excretion

The elimination half-life (T1/2) of dexketoprofen is 1–2.7 hours.

Elderly Patients

After administration of single and multiple doses, the extent of exposure to dexketoprofen 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 T1/2 was prolonged (by up to 48%), and total clearance was reduced.

Preclinical Safety Data

Standard preclinical studies—evaluating pharmacological safety, genotoxicity, and immunopharmacology—did not reveal any specific hazard for humans. Chronic toxicity studies in animals identified the no-observed-adverse-effect level (NOAEL) of dexketoprofen as being 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 lesions such as erosions. These effects occurred at doses where dexketoprofen 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 embryonic/fetal 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 dexketoprofen is inappropriate, for example, in postoperative pain, renal colic, and lumbar pain.

Contraindications.

• Hypersensitivity to dexketoprofen, to any other nonsteroidal anti-inflammatory drug (NSAID), or to excipients of the medicinal product.
• Asthma attacks, bronchospasm, acute rhinitis, nasal polyps, urticaria, or angioedema associated with previous use of drugs of similar action, e.g., acetylsalicylic acid or other NSAIDs.
• Photoallergic or phototoxic reactions associated with prior use of ketoprofen or other fibrates.
• History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.
• Active peptic ulcer/gastrointestinal bleeding, or history of gastrointestinal bleeding, ulcers, or perforations.
• Chronic dyspepsia.
• Crohn’s disease or ulcerative colitis.
• Active gastrointestinal bleeding, other active bleeding, or increased bleeding tendency.
• Hemorrhagic diathesis and other coagulation disorders.
• Severe heart failure.
• Moderate to severe renal impairment (creatinine clearance ≤59 mL/min).
• Severe hepatic impairment (Child-Pugh score 10–15 points).
• Marked dehydration (due to vomiting, diarrhea, or insufficient fluid intake).
• Third trimester of pregnancy.
• Breastfeeding period.
• Neuraxial (intrathecal or epidural) administration of the medicinal product (due to ethanol content).

Interaction with other medicinal products and other forms of interaction.

Concomitant use of dexketoprofen with the following agents is not recommended.

• Other NSAIDs (including selective cyclooxygenase-2 inhibitors), including salicylates in high doses (≥ 3 g/day): concomitant use of dexketoprofen with these agents increases the risk of gastrointestinal ulceration and gastrointestinal bleeding due to their mutually enhancing effects.

• Anticoagulants: concomitant use with dexketoprofen enhances the effect of anticoagulants, e.g., warfarin (due to high plasma protein binding of dexketoprofen, inhibition of platelet function, and damage to gastric and duodenal mucosa). If concomitant use is necessary, careful physician monitoring and laboratory tests are required.

• Heparins: concomitant use of dexketoprofen with these agents increases the risk of bleeding (due to inhibition of platelet function and damage to gastric and duodenal mucosa by dexketoprofen). If concomitant use is necessary, careful physician monitoring and laboratory tests are required.

• Corticosteroids: concomitant use of dexketoprofen with these agents increases the risk of gastrointestinal ulceration or gastrointestinal bleeding.

• Lithium: concomitant use with NSAIDs (reported for several NSAIDs) increases plasma lithium levels, potentially leading to toxicity (reduced renal excretion of lithium). Plasma lithium levels should be monitored at the beginning of dexketoprofen treatment, during dose adjustments, or upon discontinuation.

• High-dose methotrexate (≥ 15 mg/week): concomitant use with dexketoprofen reduces renal clearance of methotrexate and generally enhances its adverse effects on the blood system.

• Hydantoin derivatives and sulfonamides: concomitant use with dexketoprofen enhances the toxicity of these agents.

Concomitant use of dexketoprofen with the following agents should be done with caution.

• Diuretics, angiotensin-converting enzyme (ACE) inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists: concomitant use with dexketoprofen reduces the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydration or elderly patients), concomitant use of cyclooxygenase inhibitors (including dexketoprofen) with ACE inhibitors, angiotensin II receptor antagonists, or aminoglycoside antibiotics may worsen renal function, which is usually reversible. When using these agents concomitantly, ensure the patient is not dehydrated and monitor renal function at the beginning of treatment.
• Low-dose methotrexate (< 15 mg/week): concomitant use with dexketoprofen reduces renal clearance of methotrexate and generally enhances its adverse effects on the blood system. Blood tests should be performed weekly during the first weeks of concomitant use. Close physician monitoring is required for patients with even mild renal impairment or elderly patients.
• Pentoxifylline: concomitant use of dexketoprofen with pentoxifylline increases the risk of bleeding. Enhanced monitoring and more frequent bleeding time tests are required when these agents are used together.
• Zidovudine: concomitant use of dexketoprofen with zidovudine increases the risk of toxic effects on erythrocytes due to effects on reticulocytes, leading to severe anemia after one week of NSAID use. Blood tests and reticulocyte counts should be performed after 1–2 weeks of concomitant use.
• Sulfonylurea agents: concomitant use with dexketoprofen enhances the hypoglycemic effect of these agents due to displacement of sulfonylureas from plasma protein binding sites.

When using dexketoprofen concomitantly with the following agents, potential interactions should be considered.

• Beta-blockers: concomitant use with dexketoprofen may reduce the antihypertensive effect of beta-blockers (due to inhibition of prostaglandin synthesis).
• Cyclosporine, tacrolimus: concomitant use with dexketoprofen may increase nephrotoxicity of these agents (due to the effect of dexketoprofen on renal prostaglandins). Renal function should be monitored when these agents are used together.
• Thrombolytic agents: concomitant use of dexketoprofen with these agents increases the risk of bleeding.
• Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): concomitant use of dexketoprofen with these agents increases the risk of gastrointestinal bleeding.
• Probenecid: concomitant use with probenecid may increase plasma levels of dexketoprofen, likely due to inhibition of its renal tubular secretion and glucuronidation. Dose adjustment of dexketoprofen may be necessary.
• Cardiac glycosides: concomitant use with dexketoprofen may increase plasma levels of glycosides.
• Mifepristone: theoretically, there is a risk of altered efficacy of mifepristone under the influence of prostaglandin synthetase inhibitors. Limited data suggest that concomitant use of NSAIDs on the same day as prostaglandin does not adversely affect the efficacy of mifepristone or prostaglandin regarding cervical ripening or contractility, nor does it reduce the clinical efficacy of medical abortion regimens.
• Quinolone antibiotics: animal studies indicate that concomitant use of high-dose quinolones with NSAIDs increases the risk of seizures.
• Tenofovir: concomitant use with dexketoprofen may increase blood urea nitrogen and creatinine levels. Renal function should be monitored when these agents are used together.
• Deferasirox: concomitant use of dexketoprofen with deferasirox may increase the risk of gastrointestinal toxicity. Close patient monitoring is required.
• Pemetrexed: concomitant use with dexketoprofen may reduce pemetrexed elimination. Particular caution is required when using these agents together (especially with high-dose dexketoprofen). In patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min), concomitant use of pemetrexed and dexketoprofen should be avoided for 2 days before and 2 days after pemetrexed administration.

Special precautions for use.

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

Concomitant use of the medicinal product with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Adverse reactions of the medicinal product can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms.

Gastrointestinal effects

Gastrointestinal bleeding, ulceration, or perforation, in some cases fatal, have been observed with all NSAIDs at various stages of treatment, regardless of the presence of warning symptoms or a history of serious gastrointestinal pathology.

If gastrointestinal bleeding or ulceration occurs, administration of the medicinal product should be discontinued.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation, and in elderly patients.

Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, sometimes fatal. Treatment of such patients should be initiated with the lowest possible dose of the medicinal product.

As with all NSAIDs, patients with a history of esophagitis, gastritis, and/or peptic ulcer disease should ensure these conditions are in remission before starting treatment.

During treatment with the medicinal product, patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored for possible complications, particularly gastrointestinal bleeding.

The medicinal product should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn's disease), as there is a risk of exacerbation. NSAID use may trigger relapses of non-specific ulcerative colitis and Crohn's disease in patients in remission. 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 inform their physician of any unusual gastrointestinal symptoms, including gastrointestinal bleeding, particularly during the initial stages of treatment.

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

Renal effects

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 medicinal product should be used with caution in patients concurrently taking diuretics or in those at risk of hypovolemia.

During treatment with the medicinal product, patients should receive adequate fluid intake to avoid dehydration, which may exacerbate renal toxicity.

Like all NSAIDs, dexketoprofen 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, leading to glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Renal function disturbances occur most frequently in elderly patients.

Hepatic effects

The medicinal product should be used with caution in patients with impaired liver function. Like other NSAIDs, dexketoprofen may cause transient and minor elevations in some liver function parameters, as well as marked increases in AST and ALT activity. If such increases occur, the medicinal product should be discontinued.

Hepatic function disturbances occur most frequently in elderly patients.

Cardiovascular and cerebral circulation effects

Patients with hypertension and/or mild to moderate heart failure should be under close medical supervision during treatment with the medicinal product.

The medicinal product should be used with particular caution in patients with a history of heart disease, particularly previous episodes of heart failure (as dexketoprofen increases the risk of heart failure development), since fluid retention and edema may occur during NSAID treatment. Clinical and epidemiological data suggest a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) with some NSAIDs (especially at high doses and prolonged use). Data to exclude such risk with dexketoprofen are insufficient.

The medicinal product may be used only after careful assessment in patients with uncontrolled hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Similarly careful assessment is required before initiating long-term treatment in patients with cardiovascular risk factors (such as hypertension, hyperlipidemia, diabetes, smoking).

Non-selective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. Concomitant use of dexketoprofen and prophylactic doses of low-molecular-weight heparin in the postoperative period has been studied in clinical trials, and no effect on coagulation parameters was observed.

However, patients taking agents affecting hemostasis (e.g., warfarin, other coumarins, or heparins) should be under close medical supervision during treatment with the medicinal product. Cardiovascular system disturbances occur most frequently in elderly patients.

Skin effects

During NSAID use, there have been reports of very rare cases of serious skin reactions (some fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk is likely during the initial stages of treatment, with most cases occurring within the first month of therapy. If skin rashes, signs of mucosal involvement, or other hypersensitivity symptoms appear, the medicinal product should be discontinued.

Masking symptoms of underlying infections

Dexketoprofen may mask symptoms of infections, potentially interfering with diagnosis and timely treatment, thereby worsening infection outcomes. Such cases have been observed in bacterial pneumonia and bacterial complications of varicella. When the medicinal product is used 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 warnings

The medicinal product should be used with particular caution in patients with hereditary porphyrin metabolism disorders (e.g., acute intermittent porphyria), dehydration, or immediately after major surgical procedures.

With prolonged use of the medicinal product, liver and kidney function and blood cell counts should be monitored regularly.

During dexketoprofen use, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed very rarely. If early signs of severe hypersensitivity reactions occur, the medicinal product should be discontinued. Depending on symptoms, any necessary treatment should be administered under medical supervision.

Patients suffering from asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyps are at higher risk of allergy to acetylsalicylic acid and/or NSAIDs than other patients. Use of the medicinal product may trigger asthma attacks or bronchospasm, especially in patients allergic to acetylsalicylic acid or NSAIDs.

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

The medicinal product should be used with caution in patients with coagulation disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

Like other NSAIDs, dexketoprofen may mask symptoms of infectious diseases during its use. In isolated cases, NSAID use has been associated with activation of soft tissue infections. If bacterial infection symptoms develop or worsen, immediate medical attention is required.

Each ampoule of the medicinal product contains 12.35 vol.% ethanol, i.e., up to 200 mg per dose, equivalent to 5 ml of beer or 2.08 ml of wine per dose. The medicinal product may have adverse effects in individuals suffering from alcoholism. Ethanol content should be considered when using the product in pregnant women, breastfeeding women, children, and patients at risk (e.g., with liver disease or epilepsy).

The medicinal product contains less than 1 mmol sodium (23 mg) per dose and is therefore practically sodium-free.

Use during pregnancy or breastfeeding.

The medicinal product 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, use of drugs inhibiting prostaglandin synthesis during early pregnancy increases the risk of miscarriage, 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 doses of dexketoprofen and longer duration of therapy. In animal studies, prostaglandin synthesis inhibitors caused increased pre- and post-implantation losses and increased embryofetal mortality. In addition, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the frequency of fetal developmental abnormalities, including cardiovascular anomalies, increased. However, animal studies with dexketoprofen trometamol did not reveal toxicity to reproductive organs.

From the 20th week of pregnancy, dexketoprofen use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of the medicinal product.

During the first and second trimesters of pregnancy, dexketoprofen should not be prescribed except in cases of extreme necessity.

When using the medicinal product in women planning pregnancy or during the first and second trimesters of pregnancy, the lowest possible effective dose should be used for the shortest possible duration.

Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after exposure to dexketoprofen for several days starting from the 20th gestational week. The medicinal product should be discontinued if oligohydramnios is detected.

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

Risks for the fetus:

• Cardio-pulmonary toxic syndrome (with closure of the arterial duct and pulmonary hypertension);
• Impaired renal function, potentially progressing to renal failure with oligohydramnios (see above);

Risks for mother and child near the end of pregnancy:

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

Breastfeeding period

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

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

During dexketoprofen use, dizziness, visual disturbances, or somnolence may occur. In such cases, ability to react quickly, orient in traffic situations, and drive vehicles or operate machinery may be impaired.

Method of Administration and Dosage

Dosage

Adults

The recommended dose is 50 mg every 8–12 hours.

If necessary, a repeat dose may be administered after 6 hours.

The maximum daily dose should not exceed 150 mg.

The medicinal product is intended for short-term use 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, if feasible.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

For moderate to severe postoperative pain, the medicinal product may be used as indicated at the same recommended doses in combination with opioid analgesics.

Elderly Patients

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

Patients with 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 use of the medicinal product is contraindicated in patients with moderate or severe renal impairment (creatinine clearance <59 mL/min).

Patients with Hepatic Impairment

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

Method of Administration

Intramuscular Injection

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

Intravenous Infusion

The contents of the ampoule (2 mL of injection solution) should be diluted in 30–100 mL of 0.9% sodium chloride solution, glucose solution, or Ringer’s lactate solution.

The infusion solution must be prepared under aseptic conditions and protected from exposure to natural daylight. The prepared solution should be clear and transparent.

The infusion should be administered intravenously over 10–30 minutes at a slow rate.

The prepared solution must be protected from exposure to natural daylight.

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

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

Intravenous Injection (Bolus Administration)

The contents of the ampoule (2 mL of injection solution) should be administered intravenously slowly over at least 15 seconds.

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

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

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

The medicinal product may only be mixed with the medicinal products listed above.

After intramuscular or intravenous bolus administration, the medicinal product should be administered immediately after being drawn from the ampoule. The solution for intravenous infusion should be used immediately after preparation.

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

The medicinal product is intended for single use only; any unused portion of the prepared solution should be discarded.

Before administration, the solution should be visually inspected to ensure it is clear and colorless. The solution must not be used if it contains particulate matter.

Children

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

Overdose

Symptoms of overdose are unknown. Similar medicinal products may cause gastrointestinal disturbances (vomiting, anorexia, abdominal pain) and nervous system effects (drowsiness, dizziness, disorientation, headache).

In case of accidental overdose, symptomatic treatment appropriate to the patient's condition should be initiated immediately. Dexketoprofen can be removed from the body by dialysis.

Adverse Reactions

The adverse reactions listed below are classified by organ systems and frequency of occurrence, for which a causal relationship to dexketoprofen, based on available clinical data, is considered at least possible, as well as adverse reactions reported during the post-marketing period. Frequency categories: common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Blood and lymphatic system disorders:

Uncommon – anaemia; very rare – neutropenia, thrombocytopenia.

Immune system disorders:

Rare – laryngeal edema; very rare – anaphylactic reactions, including anaphylactic shock.

Metabolism and nutrition disorders:

Rare – hyperglycemia, hypoglycemia, hypertriglyceridemia, anorexia, loss of appetite.

Psychiatric disorders:

Uncommon – insomnia, anxiety.

Nervous system disorders:

Uncommon – headache, dizziness, somnolence; rare – paresthesia, syncope.

Eye disorders:

Uncommon – blurred vision.

Ear and labyrinth disorders:

Uncommon – vertigo; rare – tinnitus.

Cardiac disorders:

Uncommon – palpitations; rare – extrasystoles, tachycardia.

Vascular disorders:

Uncommon – arterial hypotension, flushing; rare – arterial hypertension, thrombophlebitis of superficial veins.

Respiratory, thoracic and mediastinal disorders:

Rare – bradypnea; very rare – bronchospasm, dyspnea.

Gastrointestinal disorders:

Common – nausea, vomiting; uncommon – abdominal pain, dyspepsia, diarrhea, constipation, vomiting with blood, dry mouth; rare – peptic ulcer, gastrointestinal bleeding or perforation; very rare – pancreatitis.

Hepatobiliary disorders:

Rare – hepatocellular pathology.

Skin and subcutaneous tissue disorders:

Uncommon – dermatitis, pruritus, rash, increased sweating; rare – urticaria, acne; very rare – Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), angioneurotic edema, facial swelling, photosensitization.

Musculoskeletal and connective tissue disorders:

Rare – muscle rigidity, joint stiffness, muscle cramps, back pain.

Renal and urinary disorders:

Rare – acute renal failure, polyuria, renal pain, ketonuria, proteinuria; very rare – nephritis, nephrotic syndrome.

Reproductive system and breast disorders:

Rare – menstrual disorders, prostate function disorders.

General disorders and administration site conditions:

Common – injection site pain, injection site reactions including inflammation, hematoma, bleeding; uncommon – chills, fatigue, pain, chills, asthenia, malaise; rare – tremor, peripheral edema.

Investigations:

Rare – abnormalities in liver function tests.

Gastrointestinal disorders were the most frequently observed.

Peptic ulceration, gastrointestinal perforation or bleeding, sometimes fatal, especially in elderly patients, may occur.

Based on available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, vomiting with blood, ulcerative stomatitis, exacerbation of colitis, Crohn’s disease may occur during dexketoprofen treatment. Gastritis is observed less frequently.

Edema, arterial hypertension, and heart failure may also occur, which may be associated with the use of NSAIDs.

As with other NSAIDs, aseptic meningitis (usually in patients with systemic lupus erythematosus or mixed connective tissue diseases), and blood disorders (purpura, aplastic and hemolytic anemia, rarely agranulocytosis and bone marrow hypoplasia) may occur. Bullous reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis (very rare), are also possible.

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store in the original packaging, protected from light, at a temperature not exceeding 25 °C, and out of the reach of children.

Incompatibilities

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

The diluted infusion solution, prepared as described in the section "Intravenous infusions", must not be mixed with promethazine or pentazocine.

Packaging

2 ml in a vial; 5 or 6 vials in a blister pack; 1 or 2 blister packs in a cardboard box.

Prescription status

Prescription only.

Manufacturer

WORLD MEDICINE ILAC SAN. VE TIC. A.S.
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and place of business

COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey