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

Composition:

Active substance: dexketoprofen;

1 ampoule (2 ml) contains 73.8 mg of dexketoprofen trometamol, equivalent to 50 mg of dexketoprofen;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.

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

Pharmacological Properties.

Pharmacodynamics.

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

Mechanism of action.

The mechanism of action of NSAIDs is based on reducing the synthesis of prostaglandins by inhibiting 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.

Pharmacodynamics.

An inhibitory effect of dexketoprofen on the activity of cyclooxygenase-1 and cyclooxygenase-2 has been demonstrated in laboratory animals and in humans.

Clinical efficacy and safety.

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

Pharmacokinetics.

After intramuscular administration of dexketoprofen, its maximum concentration (Cmax) is reached approximately within 20 minutes (10–45 minutes). It has been demonstrated that after single intramuscular or intravenous administration of 25–50 mg, 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 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. The elimination half-life (T1/2) ranges from 1 to 2.7 hours.

Metabolism and elimination.

Metabolism of dexketoprofen occurs mainly via conjugation with glucuronic acid followed by renal excretion. After administration, only the S-(+) optical isomer is detected in urine, indicating the absence of transformation of the drug into the R-(-) optical isomer in humans.

Elderly patients.

After administration of single and repeated doses, the extent of exposure to dexketoprofen 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 or time to reach it were observed. The mean T1/2 increased (by up to 48%), and total clearance decreased.

Preclinical safety data.

Standard preclinical studies—pharmacological safety, genotoxicity, and immunopharmacology studies—did not reveal any special hazard for humans. Chronic toxicity studies in animals identified the no-observed-adverse-effect level (NOAEL) of dexketoprofen, which was 2 times higher than the recommended human dose. When higher doses were administered to monkeys, the main adverse reactions included fecal blood, reduced body weight gain, and, at the highest dose, gastrointestinal tract pathologies such as erosions. These reactions occurred at doses where dexketoprofen exposure was 14–18 times higher than at the maximum recommended human dose. Carcinogenicity studies in animals were not 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 maternal organism.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to dexketoprofen, to any other nonsteroidal anti-inflammatory drug (NSAID), or to excipients of the medicinal product.
Asthmatic attacks, bronchospasm, acute rhinitis, nasal polyps, urticaria, or angioedema associated with previous use of drugs of similar action, such as 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 prior use of NSAIDs.
Active peptic ulcer/gastrointestinal bleeding, or history of gastrointestinal bleeding, ulcers, or perforations.
Chronic dyspepsia.
Crohn’s disease or ulcerative colitis (non-specific).
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, such as warfarin (due to high plasma protein binding of dexketoprofen, as well as inhibition of platelet function and damage to gastric and duodenal mucosa). If concomitant use is necessary, careful physician monitoring and laboratory parameter surveillance 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 parameter surveillance are required.
Corticosteroids: concomitant use of dexketoprofen with corticosteroids 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 (due to reduced renal excretion of lithium). At the start of dexketoprofen treatment, during dose adjustment, or upon discontinuation, plasma lithium levels should be monitored.
High-dose methotrexate (≥ 15 mg per 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 performed with caution.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists: concomitant use with dexketoprofen may reduce the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., due to dehydration or in elderly patients), concomitant use of cyclooxygenase inhibitors (including dexketoprofen) with ACE inhibitors, angiotensin II receptor antagonists, or aminoglycoside antibiotics may worsen renal function, which is usually reversible. When using these agents together, ensure the patient is not dehydrated, and monitor renal function at the beginning of treatment.
Low-dose methotrexate (< 15 mg per week): concomitant use with dexketoprofen reduces renal clearance of methotrexate and generally enhances its adverse effects on the blood system. During the first weeks of concomitant use, weekly blood tests should be performed. Patients with even mild renal impairment or elderly patients require careful monitoring.
Pentoxifylline: concomitant use of dexketoprofen with pentoxifylline increases the risk of bleeding. Enhanced monitoring and more frequent assessment of bleeding time are recommended.
Zidovudine: concomitant use of dexketoprofen with zidovudine may increase 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 during 1–2 weeks of concomitant use.
Sulfonylurea agents: concomitant use with dexketoprofen enhances the hypoglycemic effect of sulfonylureas due to displacement of sulfonylurea agents 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 glucuronide conjugation. 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 mifepristone efficacy due to prostaglandin synthetase inhibitors. Limited data suggest that concomitant use of NSAIDs on the same day as prostaglandin does not adversely affect mifepristone or prostaglandin efficacy regarding cervical ripening or contractility, nor does it reduce the clinical efficacy of medical abortion regimens.
Quinolone antibiotics: animal studies 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.
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. Extreme caution is required, 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 safety.

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

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

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher doses of NSAIDs, in patients with a history of peptic ulcer, especially if 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 of such patients should begin with the lowest possible dose of the medicinal product.

Prior to initiating dexketoprofen (as with all NSAIDs), patients with a history of esophagitis, gastritis, and/or peptic ulcer disease should be ensured to be in remission.

During treatment with the medicinal product, patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored for possible gastrointestinal disturbances, 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 lead to relapses of non-specific ulcerative colitis or Crohn's disease in patients who are in remission. For such patients and those taking low-dose acetylsalicylic acid or other agents increasing the risk of gastrointestinal adverse reactions, concomitant therapy with protective agents such as misoprostol or proton pump inhibitors should be considered.

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

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

Renal safety.

The medicinal product should be used with caution in patients with impaired renal function, as NSAID use may lead to worsening renal function, fluid retention, and edema. Due to the increased risk of nephrotoxicity, the medicinal product should be used with caution in patients concurrently taking diuretics and in those who may develop 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 blood urea nitrogen and 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 are most common in elderly patients.

Hepatic safety.

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

Hepatic function disturbances are most common in elderly patients.

Cardiovascular and cerebrovascular safety.

Patients with arterial 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 (the risk of developing heart failure increases during treatment), as fluid retention and edema may occur with NSAID therapy. Clinical studies and epidemiological data suggest that some NSAIDs (especially at high doses and with prolonged use) may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Data to exclude such risk with dexketoprofen use are insufficient.

The medicinal product may be used only after careful assessment of the patient's condition in cases of uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Similarly careful assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular disease (such as 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 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, such as warfarin, other coumarin derivatives, or heparins, should be under close medical supervision during treatment with the medicinal product. Cardiovascular adverse events are most common in elderly patients.

Skin reactions.

Rare but serious skin reactions (some fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported during NSAID therapy. The highest risk appears to be during the initial stages of treatment, with most cases occurring within the first month. If skin rashes, signs of mucosal involvement, or other hypersensitivity symptoms occur, the medicinal product should be discontinued.

Masking symptoms of underlying infections.

Dexketoprofen may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thereby complicating the disease course. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When the medicinal product is used for fever or pain relief during infection, monitoring for infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Other information.

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 should be monitored regularly.

Severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed very rarely during dexketoprofen use. If 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 in combination with chronic rhinitis, chronic sinusitis, and/or nasal polyps are at higher risk of allergy to acetylsalicylic acid and/or NSAIDs compared to other patients. The use of the medicinal product may trigger asthma attacks or bronchospasm, especially in patients allergic to acetylsalicylic acid or NSAIDs.

Serious skin and soft tissue infections may occur during varicella. Data to exclude a role of NSAIDs in exacerbating this infectious process are currently lacking. Therefore, the use of the medicinal product is not recommended during varicella.

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

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 a negative effect on individuals suffering from alcoholism. The ethanol content should be considered when using the medicinal product during the first and second trimesters of pregnancy, in breastfeeding women, children, and high-risk patients, e.g., those 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. Epidemiological studies indicate that use of prostaglandin synthesis inhibitors during early pregnancy increases the risk of miscarriage and congenital heart defects and abdominal wall defects in the fetus. The absolute risk of cardiovascular abnormalities increases from <1% to approximately 1.5%. The risk is considered to increase with higher doses of dexketoprofen and longer duration of therapy. Animal studies with prostaglandin synthesis inhibitors have shown increased pre- and post-implantation losses and increased embryofetal mortality. In addition, administration during organogenesis in animals increased the incidence of fetal malformations, including cardiovascular abnormalities. However, animal studies with dexketoprofen trometamol did not reveal toxicity to reproductive organs.

Starting 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.

Use of the medicinal product during the first and second trimesters of pregnancy is possible only if absolutely necessary.

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

Fetal oligohydramnios monitoring should be considered after several days of dexketoprofen exposure 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:

cardiopulmonary toxic syndrome (with closure of the ductus arteriosus and pulmonary hypertension);
impaired renal function, potentially progressing to renal failure and oliguria (see above);

Risks for the mother and child near term:

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

Period of breastfeeding.

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 attempting to conceive. Women experiencing infertility or undergoing fertility investigations should consider discontinuing the medicinal product.

Ability to affect reaction speed when driving or operating machinery.

Dizziness, visual disturbances, or somnolence may occur during dexketoprofen use. In such cases, the ability to drive 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, the 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; therefore, it should be used only during the period of acute pain (no longer than 2 days).

Patients should be switched to oral analgesics as soon as possible, 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 these patients. However, due to physiological reduction in renal function, a lower dose of dexketoprofen is recommended—specifically, the maximum daily dose should be reduced to 50 mg in patients with 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 one ampoule (2 mL of injection solution) should be administered slowly and deeply into the muscle.

Intravenous infusion.

The contents of one 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 should be prepared under aseptic conditions, avoiding exposure to natural daylight. The prepared solution must be clear.

The infusion should be administered intravenously slowly over 10–30 minutes.

Exposure of the prepared solution to natural daylight must be avoided.

The diluted medicinal product 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 and pentazocine.

Intravenous injection (bolus administration).

The contents of one 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 solutions of dopamine, promethazine, pentazocine, pethidine, and hydroxyzine, as a white precipitate may form.

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 the 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; therefore, 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 containing particulate matter must not be used.

Children.

The medicinal product should not be used in children and adolescents (under 18 years of age) due to lack of data on efficacy and safety.

Overdose.

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

In case of accidental overdose, immediate symptomatic treatment appropriate to the patient’s condition should be initiated. Dexketoprofen is eliminated from the body by dialysis.

Adverse reactions.

The adverse reactions listed below are classified by organ systems and frequency of occurrence. These reactions are considered at least possibly related to dexketoprofen based on available clinical data, as well as adverse reactions reported during the post-marketing period. Frequency categories are defined as follows: 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 – anemia; 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, restlessness.

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, superficial thrombophlebitis.

Respiratory, thoracic and mediastinal disorders:

Rare – bradypnea; very rare – bronchospasm, dyspnea.

Gastrointestinal disorders:

Common – nausea, vomiting; uncommon – abdominal pain, dyspepsia, diarrhea, constipation, vomiting of 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 edema, photosensitivity.

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 gland dysfunction.

General disorders and administration site conditions:

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

Investigations:

Rare – abnormalities in liver function tests.

Gastrointestinal disorders were the most frequently observed.

Peptic ulcer, perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients.

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

Edema, arterial hypertension, and heart failure have also been reported and may be associated with the use of NSAIDs.

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

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

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after a medicinal product has been authorized is important. It allows for continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

4 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, protected from light and kept out of 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.

Diluted infusion solutions, as prepared according to the section "Intravenous infusions", must not be mixed with promethazine or pentazocine.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

K.O. Rompharm Company S.R.L., Romania / S.C. Rompharm Company S.R.L. Romania.

Manufacturer's address and place of business.

Otopeni city, Eroilor str. № 1A, 075100, jud. Ilfov, Romania.

Marketing authorization holder.

LLC "WORLD MEDICINE", Ukraine / WORLD MEDICINE, LLC, Ukraine.

Rotalfen