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

Composition:

Active substance: dexketoprofen;

1 ml of solution contains 36.9 mg of dexketoprofen trometamol, equivalent to 25 mg of dexketoprofen (1 ampoule of 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 liquid.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. 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 the activity of cyclooxygenase. In particular, 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.

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

Clinical efficacy and safety

Clinical studies in various types of pain have demonstrated that dexketoprofen trometamol has pronounced analgesic activity. The analgesic effect of dexketoprofen trometamol following intramuscular and intravenous administration to 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 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 typically lasts 8 hours. Clinical studies have demonstrated that using Prodex allows a significant reduction in opioid dosage when used concomitantly to manage postoperative pain. In postoperative pain studies where patients received morphine via a patient-controlled analgesia device, those receiving dexketoprofen trometamol required significantly less morphine (by 35–45%) compared to patients receiving placebo.

Pharmacokinetics.

Absorption

After intramuscular administration of dexketoprofen trometamol in humans, maximum concentration is reached approximately within 20 minutes (10–45 minutes). It has been demonstrated that after single intramuscular or intravenous administration of 25–50 mg of the drug, the area under the concentration-time curve (AUC) is proportional to the dose. Pharmacokinetic studies with repeated administration of the drug demonstrated that AUC and Cmax (mean maximum value) after the last intramuscular or intravenous administration did 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 − 1–2.7 hours.

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 drug conversion into the R-(-) optical isomer in humans.

Elderly patients

In healthy elderly individuals (aged 65 years and older), exposure was significantly higher compared to younger volunteers after single and repeated oral dosing (up to 55%), whereas no statistically significant differences were observed in peak concentrations or time to reach peak concentration. The mean elimination half-life increased (by up to 48%), and the total systemic clearance decreased.

Pharmacological safety, genotoxicity, and immunopharmacology studies revealed no particular hazard for humans. Chronic toxicity studies in animals allowed identification of the no-observed-adverse-effect level (NOAEL), which was twice the dose recommended for humans. When higher doses of the drug were administered to monkeys, the main adverse reactions were fecal blood, reduced body weight gain, and at the highest dose, gastrointestinal tract pathologies such as erosions. These reactions occurred at doses where drug exposure was 14–18 times higher than at the maximum recommended human dose. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen may lead to embryonic or fetal death in animals, either directly by affecting development, or indirectly via harmful 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.

Contraindications.

Hypersensitivity to dexketoprofen, to any other NSAID, or to excipients of the drug;
Use in patients in whom substances with a similar mechanism of action, such as acetylsalicylic acid and other NSAIDs, induce attacks of bronchial asthma, bronchospasm, acute rhinitis, or lead to the development of nasal polyps, urticaria, or angioedema;
If photoallergic or phototoxic reactions occurred during treatment with ketoprofen or fibrates;
Gastrointestinal bleeding or perforation in medical history associated with previous NSAID therapy;
Active peptic ulcer/gastrointestinal bleeding or history of gastrointestinal bleeding, ulcers, or perforations;
In chronic dyspepsia;
In gastrointestinal bleeding, other active bleeding, or increased bleeding tendency;
In Crohn’s disease or ulcerative colitis;
In severe heart failure;
In moderate or severe renal impairment (creatinine clearance ≤ 59 mL/min);
In severe hepatic impairment (10–15 points on the Child–Pugh scale);
In hemorrhagic diathesis and other coagulation disorders;
In pronounced dehydration (due to vomiting, diarrhea, or insufficient fluid intake);
In the third trimester of pregnancy and during breastfeeding.

Due to the ethanol content in the medicinal product, Prodeks is contraindicated for neuraxial (intrathecal or epidural) administration.

Interaction with other medicinal products and other types of interactions.

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). Concomitant use of multiple NSAIDs increases the risk of gastrointestinal ulceration and gastrointestinal bleeding due to their mutually enhancing effects;
Anticoagulants: NSAIDs enhance the effects of anticoagulants, such as warfarin, due to the high degree of 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 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 strict medical supervision and appropriate laboratory monitoring;
Corticosteroids: increased risk of gastrointestinal ulceration and gastrointestinal bleeding;
Lithium preparations (reports exist for 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 adjustment, or upon discontinuation;
High-dose methotrexate (≥ 15 mg per week): due to reduced renal clearance of methotrexate during NSAID therapy, its adverse effects on the blood system are 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 impaired renal function (e.g., dehydration or elderly patients), the use of cyclooxygenase inhibitors concomitantly with ACE inhibitors, angiotensin II receptor antagonists, or aminoglycoside antibiotics may lead to further deterioration of renal function, which is usually reversible. When using dexketoprofen concomitantly with any diuretic, adequate hydration of the patient must be ensured, and renal function should be monitored during treatment;
Methotrexate administered in low doses (less than 15 mg per week): due to reduced renal clearance of methotrexate during NSAID therapy, its toxic effects on the blood system are enhanced. During the first weeks of concomitant use, weekly blood tests are required. Even with mild renal impairment and in elderly patients, treatment should be conducted under strict medical supervision;
Pentoxifylline: increased risk of bleeding. Monitoring should be intensified, and bleeding time should be checked more frequently;
Zidovudine: risk of increased toxic effects on erythrocytes due to effects on reticulocytes, leading to severe anemia after the first week of NSAID use. A blood test and reticulocyte count should be performed within 1–2 weeks after initiating NSAID therapy;
Sulfonylurea preparations: 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:

Beta-blockers: NSAIDs may reduce their antihypertensive effect due to inhibition of 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, possibly 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 concurrent administration of NSAIDs on the same day as prostaglandins does not adversely affect the efficacy of mifepristone or prostaglandins regarding cervical ripening or contractility, nor does it reduce the clinical efficacy of drugs for medical termination of pregnancy;
Quinolone antibiotics: animal studies have shown that high-dose quinolone derivatives used in combination with NSAIDs increase the risk of seizures;
Tenofovir: when used concomitantly with NSAIDs, plasma concentrations of blood urea nitrogen and creatinine may increase; therefore, monitoring of renal function is required to assess the potential impact of combined use of these medicinal products;
Deferasirox: concomitant use with NSAIDs may increase the risk of gastrointestinal toxicity. Careful patient monitoring is required when using this medicinal product together with deferasirox;
Pemetrexed: concomitant use with NSAIDs may reduce pemetrexed elimination; therefore, particular caution is required when using NSAIDs at high doses. Patients with mild to moderate renal impairment (creatinine clearance of 45–79 mL/min) should avoid concomitant use of pemetrexed with NSAIDs for 2 days before and 2 days after pemetrexed administration.

Special precautions for use.

Use with caution in patients with a history of allergic disorders. Avoid using Prodex in combination with other NSAIDs, including selective cyclooxygenase-2 inhibitors. 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 any stage of treatment, regardless of the presence of warning symptoms or a history of gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued.

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

Elderly patients: Elderly patients have an increased risk of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, sometimes fatal. Treatment in these patients should be initiated at the lowest possible dose.

Before starting 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 should be monitored during treatment for possible complications, particularly gastrointestinal bleeding. NSAIDs should be used cautiously 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 ulcerative colitis or Crohn’s disease in patients in remission. For such patients and those taking low-dose acetylsalicylic acid or other agents increasing gastrointestinal risk, consider concomitant therapy with gastroprotective agents such as misoprostol or proton pump inhibitors.

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.

Use with caution in patients concurrently taking 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 safety.

Use 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, Prodex may increase plasma urea and creatinine levels. Similar to other prostaglandin synthesis inhibitors, its use may negatively affect the renal system, potentially leading to glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Renal dysfunction occurs more frequently in elderly patients.

Hepatic safety.

Use with caution in patients with impaired liver function. As with other NSAIDs, the drug may cause transient and mild elevations in liver function tests, as well as marked increases in AST and ALT levels. If significant elevations occur, treatment should be discontinued.

Liver function disturbances occur most frequently in elderly patients.

Cardiovascular and cerebrovascular safety.

Patients with arterial hypertension and/or mild to moderate heart failure require monitoring and medical advice. Particular caution is required in patients with a history of cardiac disease, especially prior episodes of heart failure (the drug increases the risk of heart failure), as NSAIDs may cause fluid retention and edema. Clinical studies and epidemiological data suggest that some NSAIDs (especially at high doses and long-term use) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Data to exclude such risk for dexketoprofen trometamol are insufficient. Therefore, dexketoprofen trometamol should be used only after careful patient assessment in cases of 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, or smoking.

Non-selective NSAIDs can inhibit 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 evaluated in clinical trials, with no effect on coagulation parameters observed. However, patients receiving dexketoprofen trometamol concomitantly with agents affecting hemostasis (e.g., warfarin, other coumarins, or heparins) require close medical supervision. Cardiovascular adverse events occur most frequently in elderly patients.

Skin reactions.

Rare cases of serious skin reactions (some fatal) have been reported with NSAIDs, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk occurs early in treatment, mostly within the first month. If skin rash, mucosal lesions, or any signs of hypersensitivity appear, Prodex should be discontinued immediately.

Masking symptoms of underlying infections.

Dexketoprofen may mask symptoms of infection, potentially delaying diagnosis and treatment and worsening infection outcomes. Such cases have been observed in bacterial pneumonia and bacterial complications of varicella. If Prodex is used to relieve pain associated with an infection, monitoring of the infection is recommended. Outpatients should consult a physician if symptoms persist or worsen.

In rare cases, varicella may lead to serious skin and soft tissue infections. At present, a potential role of NSAIDs in exacerbating these infections cannot be excluded. Therefore, it is advisable to avoid using Prodex in cases of varicella.

Other information.

Particular caution is required when prescribing the drug to patients:

with inherited porphyrin metabolism disorders (e.g., acute intermittent porphyria);
with dehydration;
immediately after major surgical procedures.

If long-term dexketoprofen therapy is deemed necessary by the physician, regular monitoring of liver and kidney function and blood counts is recommended.

Severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been reported rarely. Treatment must be discontinued at the first signs of severe hypersensitivity following Prodex administration. Depending on symptoms, appropriate treatment should be administered under medical supervision.

Patients with bronchial asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyps are more prone to allergic reactions when using acetylsalicylic acid and/or NSAIDs than other patients. This drug may trigger asthma attacks or bronchospasm, particularly in patients allergic to acetylsalicylic acid or NSAIDs.

Prodex should be used with caution in patients with blood coagulation disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

Isolated cases of soft tissue infection exacerbation have been reported with NSAID use. Therefore, patients should seek immediate medical attention if symptoms of bacterial infection appear or worsen during treatment.

Each Prodex ampoule contains 12.35 vol.% ethanol, i.e., 200 mg ethanol, equivalent to 5 mL of beer or 2.08 mL of wine per dose. The drug may adversely affect individuals with alcoholism. The ethanol content should be considered when using the drug in pregnant women, breastfeeding women, children, and patients at risk (e.g., liver disease, epilepsy).

The medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Prodex is contraindicated during the third trimester of pregnancy and during breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. According to epidemiological studies, the use of prostaglandin synthesis inhibitors in early pregnancy increases the risk of miscarriage, congenital heart defects, and gastroschisis (failure of abdominal wall closure). The absolute risk of cardiovascular malformations increases from <1% to approximately 1.5%. This risk is believed to increase with higher drug doses and longer treatment duration. Animal studies with prostaglandin synthesis inhibitors have shown increased pre- and post-implantation losses and embryofetal mortality. In animals treated during organogenesis, the frequency of various fetal malformations, including cardiovascular anomalies, was increased. However, animal studies with dexketoprofen trometamol did not reveal reproductive toxicity.

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.

Additionally, cases of fetal arterial duct constriction have been reported with dexketoprofen use during the second trimester, most of which resolved after treatment cessation.

Therefore, dexketoprofen trometamol may be prescribed during the first and second trimesters only if absolutely necessary. When prescribing dexketoprofen trometamol to women planning pregnancy or during the first and second trimesters, the lowest effective dose for the shortest possible duration should be used. Monitoring for oligohydramnios and arterial duct constriction should begin after a few days of Prodex exposure, starting from the 20th week of pregnancy. If oligohydramnios is detected, the drug should be discontinued.

During the third trimester, all prostaglandin synthesis inhibitors may cause:

Risks to the fetus:

cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
impaired renal function, which may progress to renal failure and oligohydramnios.

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

prolonged bleeding time, inhibition of platelet aggregation (possible even with very low doses);
inhibition of uterine contractility, leading to delayed or prolonged labor.

Breastfeeding.

There are no data on the passage of dexketoprofen into breast milk. Prodex is contraindicated during breastfeeding.

Fertility.

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Adults. The recommended dose is 50 mg every 8–12 hours. If necessary, the dose may be repeated after 6 hours. The total daily dose should not exceed 150 mg. Prodex is intended for short-term use and should be administered only during episodes of acute pain (no longer than 2 days). Patients should be switched to oral analgesics as soon as possible. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. In 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 limited to 50 mg in patients with mild renal impairment.

Hepatic impairment. In patients with mild or moderate liver disease (5–9 points on the Child-Pugh scale), the total 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. In patients with mild renal impairment (creatinine clearance 60–89 mL/min), the total daily dose should be reduced to 50 mg. The drug Prodex is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 59 mL/min).

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

Method of Administration

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

Intravenous infusion. For intravenous infusion, the contents of a 2 mL ampoule should be diluted in 30–100 mL of 0.9% sodium chloride solution, 5% 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 over 10–30 minutes.

Prodex, when diluted in 100 mL of 0.9% sodium chloride solution or 5% glucose solution, may be mixed with dopamine, heparin, hydroxyzine, lidocaine, morphine, pethidine, and theophylline.

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

Intravenous bolus injection.

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

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

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

Prodex may only be mixed with medicinal products listed above.

After drawing the solution from the ampoule, the drug should be administered immediately when given by intramuscular or intravenous injection. The solution for intravenous infusion should be used immediately after preparation.

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

Prodex 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. Solutions containing visible particles must not be used.

Children.

The drug 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 trometamol is eliminated from the body by dialysis.

Side effects

Adverse reactions are categorized by frequency as follows:
common – ≥ 1/100 to < 1/10;
uncommon – ≥ 1/1000 to < 1/100;
rare – ≥ 1/10,000 to < 1/1000;
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, hot flushes;
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 with blood, dry mouth;
rare – peptic ulcer, 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, 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 and administration site conditions:
common – injection site pain, injection site reactions including inflammation, hematoma, bleeding;
uncommon – fever, fatigue, pain, chills, asthenia, malaise;
rare – tremor, peripheral edema.

Investigations:
rare – abnormalities in liver function tests.

Gastrointestinal disorders are the most commonly observed.

Peptic ulcer, perforation, or gastrointestinal bleeding (sometimes fatal), especially in elderly patients, may occur. Nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, hematochezia, ulcerative stomatitis, and exacerbation of colitis or Crohn’s disease have been reported. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure have also been reported in association with NSAID therapy. As with other NSAIDs, aseptic meningitis (predominantly in patients with systemic lupus erythematosus or mixed connective tissue diseases), hematological reactions (purpura, aplastic and hemolytic anemia, 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 trials and epidemiological data, the use of certain NSAIDs (particularly at high doses and for prolonged periods) may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction and stroke.

Reporting of suspected adverse reactions.

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

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

The reconstituted solution should be stored for no more than 30 minutes. Avoid exposure of the prepared solution to natural daylight.

Incompatibilities.

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

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

The medicinal product should not be mixed with other medicinal products except those specified in the section "Instructions for use and dosage."

Packaging.

Date of last revision.