Involics

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INVOLYX

Composition:

Active ingredient: dexketoprofen trometamol;

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

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

Pharmaceutical form. Solution for injection/infusion.

Main physicochemical properties: clear, colorless solution.

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 belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

The mechanism of action of NSAIDs is based on reducing the synthesis of prostaglandins by inhibiting cyclooxygenase activity. Specifically, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2α, PGD2, as well as prostacyclin PGI2 and thromboxanes TxА2 and TxВ2 are formed. In addition, inhibition of prostaglandin synthesis may affect other mediators of inflammation such as kinins, which may also indirectly influence the primary action of the drug.

Pharmacodynamic effects

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

Clinical efficacy and safety

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

Pharmacokinetics

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.

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 half-life of distribution of dexketoprofen is approximately 0.35 hours, and the elimination half-life is 1–2.7 hours.

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

Biotransformation and elimination

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

Elderly patients

After administration of single and multiple doses, the extent of drug exposure in elderly healthy volunteers (aged 65 years and older) participating in the study was significantly higher (up to 55%) compared to younger volunteers; however, no statistically significant differences in maximum concentration or time to reach it were observed. The mean elimination half-life increased (by up to 48%), and total clearance decreased.

Preclinical safety data

Standard preclinical studies—pharmacological safety, genotoxicity, and immunopharmacology studies—revealed no special hazard for humans. Chronic toxicity studies in animals identified the no-observed-adverse-effect level (NOAEL), which was twice the dose recommended for humans. When higher doses were administered to monkeys, the main adverse reactions included fecal blood, reduced body weight gain, and at the highest dose, gastrointestinal lesions such as erosions. These reactions occurred at doses resulting in 14–18 times higher drug exposure 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 due to a direct effect on development or indirectly via maternal gastrointestinal toxicity.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to dexketoprofen, to any other nonsteroidal anti-inflammatory drug (NSAID), or to excipients of the medicinal product;
• patients in whom administration of substances with similar action (e.g., acetylsalicylic acid or other NSAIDs) induces attacks of bronchial asthma, bronchospasm, acute rhinitis, nasal polyps, urticaria, or angioedema;
• occurrence of photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates;
• gastrointestinal bleeding or perforation in history associated with NSAID therapy;
• active peptic ulcer/gastrointestinal bleeding or history of gastrointestinal bleeding, ulcers, or perforations;
• chronic dyspepsia;
• active bleeding or increased bleeding tendency;
• Crohn’s disease or ulcerative colitis;
• severe heart failure;
• moderate to severe renal impairment (creatinine clearance ≤ 59 mL/min);
• severe hepatic impairment (10–15 points on the Child–Pugh scale);
• hemorrhagic diathesis and other coagulation disorders;
• severe dehydration (due to vomiting, diarrhea, or insufficient fluid intake);
• third trimester of pregnancy and breastfeeding.

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

Interaction with other medicinal products and other forms of interaction.

Medicinal products whose concomitant use with NSAIDs is not recommended

Other NSAIDs (including selective COX-2 inhibitors) and high-dose salicylates (≥ 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 may enhance the effect of anticoagulants such as warfarin due to high plasma protein binding of dexketoprofen, inhibition of platelet function, and damage to the gastric and duodenal mucosa. If avoidance of such combination use is not possible, careful clinical monitoring and laboratory parameter surveillance should be performed.

Heparins: increased risk of bleeding (due to inhibition of platelet function and damage to the gastric and duodenal mucosa). If avoidance of such combination use is not possible, careful clinical monitoring and laboratory parameter surveillance should be performed.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding.

Lithium (reports with several NSAIDs): NSAIDs increase lithium blood levels, which may reach toxic concentrations (reduced renal excretion of lithium). Therefore, lithium blood levels should be monitored at the start of dexketoprofen treatment, during dose adjustment, or upon discontinuation of the medicinal product.

High-dose methotrexate (15 mg/week or more): increased hematological toxicity of methotrexate due to reduced renal clearance caused by anti-inflammatory agents in general.

Hydantoins and sulfonamides: toxic effects of these substances may be enhanced.

Medicinal products whose concomitant use with NSAIDs requires caution

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists: dexketoprofen may reduce the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of cyclooxygenase-inhibiting agents and ACE inhibitors, angiotensin II receptor antagonists, or aminoglycoside antibiotics may lead to further deterioration of renal function, which is usually reversible. When combining dexketoprofen with a diuretic, adequate hydration of the patient must be ensured and renal function monitored at the beginning of treatment.

Low-dose methotrexate (less than 15 mg/week): due to reduced renal clearance of methotrexate during NSAID use, its negative effects on the blood system in general are enhanced. Weekly blood monitoring is required during the first weeks of combination therapy, and intensified monitoring is necessary in cases of even mild renal impairment, as well as in elderly patients.

Pentoxifylline: 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 1–2 weeks after starting NSAID treatment.

Sulfonylurea derivatives: NSAIDs may enhance the hypoglycemic effect of sulfonylurea derivatives by displacing them from plasma protein binding sites.

Potential interactions to consider when using the following medicinal products:

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

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

Thrombolytics: increased risk of bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.

Probenecid: plasma concentration of dexketoprofen may increase; this interaction may be due to inhibition of renal tubular secretion and glucuronic acid conjugation of the drug and may require dose adjustment of dexketoprofen.

Cardiac glycosides: NSAIDs may increase glycoside plasma concentrations.

Mifepristone: there is a theoretical risk that prostaglandin synthesis inhibitors may alter the efficacy of mifepristone. Limited data suggest that concomitant use of NSAIDs on the day of prostaglandin administration does not negatively affect the action of mifepristone or prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical abortion regimens.

Quinolone antibiotics: animal studies indicate that high doses of quinolones in combination with NSAIDs may increase the risk of seizures.

Tenofovir: concomitant use with NSAIDs may increase blood urea nitrogen and creatinine concentrations; therefore, renal function should be monitored to assess the potential impact of concomitant 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 the elimination of pemetrexed; therefore, caution is advised when prescribing higher NSAID doses. Patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min) should avoid NSAID use for 2 days before and 2 days after pemetrexed administration.

Special precautions for use.

Use with caution in patients with a history of allergic diseases.

Concomitant use of dexketoprofen with other NSAIDs, including selective COX-2 inhibitors, should be avoided. Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Gastrointestinal safety

Gastrointestinal bleeding, ulceration, or perforation, which may be fatal, have been reported with the use of all NSAIDs at any time during therapy, regardless of the presence or absence of warning symptoms or a history of serious gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs in patients receiving dexketoprofen, treatment 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: 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. As with all NSAIDs, patients with a history of esophagitis, gastritis, and/or peptic ulcer should be ensured to have these conditions in remission. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored for possible gastrointestinal disturbances during treatment, particularly gastrointestinal bleeding. NSAIDs should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as there is a risk of exacerbation. For such patients and those taking low-dose acetylsalicylic acid or other agents increasing the risk of gastrointestinal adverse reactions, combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

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

The drug should be used 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 function impairment

The drug should be used with caution in patients with impaired renal function, as NSAIDs may cause deterioration of renal function, 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 developing hypovolemia. Adequate fluid intake should be maintained during treatment to avoid dehydration, which may exacerbate renal toxicity. Like other NSAIDs, the drug may increase plasma urea nitrogen and creatinine concentrations. Similar to other inhibitors of prostaglandin synthesis, its use may be associated with renal adverse reactions, including glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Renal function disturbances occur most frequently in elderly patients.

Hepatic function impairment

The drug should be used with caution in patients with hepatic function impairment. Similar to other NSAIDs, the drug may cause transient and minor elevations in some liver function parameters, as well as marked increases in AST and ALT activity. Therapy should be discontinued if significant elevations in these parameters occur.

Hepatic function disturbances occur most frequently in elderly patients.

Cardiovascular and cerebrovascular disorders

Patients with arterial hypertension and/or mild to moderate heart failure require monitoring and medical advice. Particular caution is required when treating patients with a history of heart disease, especially previous episodes of heart failure (the risk of developing heart failure increases during treatment with the drug), as fluid retention and edema may occur during NSAID therapy.

Clinical studies and epidemiological data suggest that the use of some NSAIDs (particularly at high doses and for prolonged periods) 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. Therefore, dexketoprofen should be prescribed 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. A 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, or smoking).

Non-selective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. The concomitant use of dexketoprofen trometamol and low-molecular-weight heparin at prophylactic doses in the postoperative period has been studied in clinical trials, and no effect on coagulation parameters was observed. However, patients receiving dexketoprofen trometamol concurrently with drugs affecting hemostasis, such as warfarin, other coumarins, or heparins, require close medical supervision. Cardiovascular function disturbances occur most frequently in elderly patients.

Skin reactions

There have been reports of very rare cases of serious skin reactions (some fatal) associated with NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The risk of such reactions is likely highest at the beginning of treatment, with most cases occurring within the first month of therapy. If skin rashes, signs of mucosal involvement, or other symptoms of hypersensitivity occur, the drug should be discontinued.

Masking symptoms of underlying infections

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

Other information

Particular caution should be exercised when prescribing the drug to patients:

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

If prolonged use of dexketoprofen is deemed necessary by the physician, liver and kidney function should be monitored regularly.

Very rarely, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. Treatment should be discontinued at the first signs of severe hypersensitivity reactions after dexketoprofen administration. 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 have a higher risk of allergy to acetylsalicylic acid and/or NSAIDs than other patients. Administration of this drug may trigger asthma attacks or bronchospasm, particularly in patients allergic to acetylsalicylic acid or NSAIDs.

Severe infectious complications of the skin and soft tissues may occur during chickenpox. Data to exclude the role of NSAIDs in exacerbating this infectious process are lacking. Therefore, dexketoprofen is not recommended in chickenpox.

Dexketoprofen should be administered with caution in patients with coagulation disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

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

This medicinal product contains up to 200 mg of alcohol (ethanol) in each 2 ml vial (3 mg/kg/dose (10% w/v)), equivalent to 5 ml of beer or 2 ml of wine. The small amount of alcohol contained in this medicinal product will not have a noticeable effect.

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

Use during pregnancy or breastfeeding.

The use of dexketoprofen is contraindicated during the third trimester of pregnancy and during breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. According to epidemiological studies, the use of drugs that inhibit prostaglandin synthesis during early pregnancy increases the risk of miscarriage, congenital heart defects, and abdominal wall defects in the fetus. The absolute risk of cardiovascular malformations increased from <1% to approximately 1.5%. It is believed that the risk of such events increases with higher drug doses and longer treatment duration. Administration of prostaglandin synthesis inhibitors in animals resulted in increased pre- and post-implantation losses and increased embryofetal mortality. Furthermore, 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 reproductive toxicity. The use of dexketoprofen from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after the start of treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal ductus arteriosus constriction have been reported after maternal use of the drug in the second trimester, most of which resolved after discontinuation of treatment. Therefore, dexketoprofen trometamol may be prescribed during the first and second trimesters of pregnancy only if absolutely necessary. When prescribing dexketoprofen trometamol to women planning pregnancy or during the first and second trimesters of pregnancy, the lowest effective dose should be used for the shortest possible duration. Prenatal monitoring for oligohydramnios and fetal ductus arteriosus constriction should be considered if exposure to dexketoprofen occurs over several days starting from the 20th gestational week. Pregnant women should discontinue dexketoprofen if oligohydramnios or fetal ductus arteriosus constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks for the fetus:

• cardiopulmonary toxic syndrome (constriction/occlusion of the ductus arteriosus and pulmonary hypertension);
• renal function impairment (see above);

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

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

Breastfeeding

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

Fertility

Like all other NSAIDs, dexketoprofen trometamol may reduce female fertility and therefore is not recommended for women planning pregnancy. Women 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 dexketoprofen use. In such cases, the ability to react quickly, orient in traffic situations, and drive or operate machinery may be impaired.

Method of Administration and Dosage

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

Adults. The recommended dose is 50 mg administered at 8–12 hour intervals. If necessary, the dose may be repeated after 6 hours. The maximum daily dose should not exceed 150 mg. The medicinal product is intended for short-term use only 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, if feasible. 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. However, due to the physiological decline in renal function, a lower dose is recommended—specifically, the maximum daily dose should be limited to 50 mg in patients with mild renal impairment.

Hepatic impairment. For 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 medicinal product is contraindicated in patients with severe hepatic impairment (10–15 points on the Child-Pugh scale).

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

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

Method of Administration

Intramuscular injection

The contents of one vial (2 mL) should be administered slowly as a deep intramuscular injection.

Intravenous infusion

For intravenous infusion, the contents of a 2 mL vial should be diluted in 30–100 mL of 0.9% sodium chloride solution, glucose solution, or Ringer's lactate solution. The infusion solution should be prepared under aseptic conditions, avoiding exposure to natural daylight. The prepared solution should be clear and colorless. The infusion should be administered slowly intravenously over 10–30 minutes.

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

Intravenous bolus injection

If necessary, the contents of one vial (2 mL of injection solution) may 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, or hydroxyzine, as precipitation may occur.

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 drawing the solution from the vial, the medicinal product should be administered immediately when administered intramuscularly or as an intravenous bolus.

No changes in active ingredient 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 ethylene-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 trometamol is eliminated from the body by dialysis.

Adverse reactions.

The table below lists adverse reactions by system organ class and frequency, which have been considered at least possibly related to the use of dexketoprofen trometamol based on clinical trial data, as well as adverse reactions reported during the post-marketing period.

Gastrointestinal disorders were observed most frequently.

There is a possibility of developing peptic ulcer, perforation, or gastrointestinal bleeding, sometimes with fatal outcomes, particularly in elderly patients. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, vomiting with blood, ulcerative stomatitis, exacerbation of colitis, and Crohn's disease may occur during treatment with this medicinal product. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure, which may be caused by NSAID use, have also been reported. As with other NSAIDs, the following adverse reactions are possible: aseptic meningitis, which generally occurs in patients with systemic lupus erythematosus or mixed connective tissue disorders, and blood-related reactions (purpura, aplastic and hemolytic anemia, rarely agranulocytosis and bone marrow hypoplasia). Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), may also occur.

Based on clinical trials and epidemiological data, the use of certain NSAIDs, especially at high doses and over 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 medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibility.

Involix must not be mixed in small volumes (e.g., in a syringe) with dopamine, promethazine, pentazocine, meperidine, or hydrocortisone solutions, as a white precipitate forms.

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

This medicinal product must not be mixed with other medicinal products except those specified in the section "Administration and dosage."

Packaging.

2 mL in a vial; 5 vials in a blister pack; 1 or 2 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer.

Limited liability company "Novopharm-Biosyntez".

Manufacturer's address and location of business activity.

38 Zhytomyrska Street, Zhytomyr Oblast, Zvyahel, Ukraine, 11700.

Date of last review.