Naproxen-zdorovya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NAPROXEN-ZDOROVYE (NAPROXEN-ZDOROVYE)

Composition:

Active substance: naproxen;

1 tablet contains 550 mg of naproxen sodium;

Excipients: microcrystalline cellulose; povidone; talc; magnesium stearate; indigo carmine (E 132); dry mixture "Opadry white" containing: titanium dioxide (E 171), hypromellose, triacetin (E 1518).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets ranging from light blue to dark blue in color, with a biconvex surface, oval-shaped, with a score line on one side. The tablet cross-section is white or almost white.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. Naproxen. ATC code M01AE02.

Pharmacological Properties.

Pharmacodynamics.

Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic effects. Sodium naproxen was developed as a rapidly absorbed form of naproxen for use as an analgesic. The mechanism of action of the naproxen anion, as with other NSAIDs, is not fully understood but may be related to inhibition of prostaglandin synthetase.

Naproxen is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen concentrations achieved during therapy produce effects in vivo. Prostaglandins sensitize afferent nerves and potentiate the pain-inducing action of bradykinin in animal models. Prostaglandins are mediators of inflammation. Since naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to reduced levels of prostaglandins in peripheral tissues.

Pharmacokinetics.

Sodium naproxen is rapidly and completely absorbed from the gastrointestinal tract, with an in vivo bioavailability of 95%. The elimination half-life (T½) of naproxen ranges from 12 to 17 hours. Steady-state levels of naproxen are reached within 4–5 days, and the extent of naproxen accumulation corresponds to its half-life.

Absorption. After oral administration, peak plasma concentration (Cmax) is achieved within 1–2 hours.

Distribution. The volume of distribution of naproxen is 0.16 L/kg. Therapeutic levels of naproxen are more than 99% bound to albumin. At naproxen doses exceeding 500 mg per day, increases in plasma concentrations are less than proportional due to increased clearance caused by saturation of plasma protein binding at higher doses (mean minimum Css values are 36.5, 49.2, and 56.4 mg/L at daily naproxen doses of 500, 1000, and 1500 mg, respectively). The naproxen anion has been detected in the milk of lactating women at concentrations equivalent to approximately 1% of the maximum naproxen plasma concentration.

Metabolism. Naproxen is actively metabolized in the liver to 6-O-desmethylnaproxen. Neither the parent compound nor its metabolites induce enzyme metabolism. Both naproxen and 6-O-desmethylnaproxen undergo further metabolism to their respective acylglucuronide conjugated metabolites.

Excretion. Naproxen clearance is 0.13 mL/min/kg. Approximately 95% of the dose is excreted in the urine, primarily as naproxen (<1%), 6-O-desmethylnaproxen (<1%), or their conjugates (66–92%). The half-life (T½) of the naproxen anion in human plasma is 12–17 hours. The corresponding half-lives of metabolites and conjugates are less than 12 hours, and their excretion rates closely parallel the rate of naproxen elimination from plasma. Small amounts, 3% or less of the administered dose, are excreted in feces. In patients with renal insufficiency, metabolites may accumulate.

Clinical Characteristics.

Indications.

Symptomatic relief of:

• rheumatoid arthritis;
• osteoarthritis;
• ankylosing spondylitis;
• tendinitis;
• bursitis;
• acute gout;
• pain management;
• primary dysmenorrhea.

Contraindications.

The drug is contraindicated in patients with known hypersensitivity to sodium naproxen.

The drug should not be administered to patients who have a history of asthma, urticaria, or allergic reactions induced by aspirin or other NSAIDs. In such patients, severe anaphylactoid reactions to NSAIDs, rarely fatal, have been observed.

The drug should not be used for the treatment of perioperative pain in coronary artery bypass graft (CABG) surgery.

Interaction with other medicinal products and other types of interactions.

Angiotensin-converting enzyme inhibitors (ACE inhibitors)/angiotensin II receptor blockers. NSAIDs may reduce the antihypertensive effect of ACE inhibitors, angiotensin II receptor blockers, or β-blockers (including propranolol).

Careful monitoring of blood pressure changes is recommended in patients receiving NSAIDs concomitantly with ACE inhibitors, angiotensin II receptor blockers, or β-blockers.

In elderly patients with extracellular fluid volume depletion (including those taking diuretics) and impaired renal function, concomitant use of NSAIDs with ACE inhibitors or angiotensin II receptor blockers may lead to deterioration of renal function, including acute renal failure. Therefore, close monitoring of such patients for signs of worsening renal function is recommended.

Antacids/sucralfate. Concomitant administration of certain antacids (magnesium oxide or aluminum hydroxide) and sucralfate may delay naproxen absorption.

Aspirin. When the drug is taken together with aspirin, naproxen protein binding is reduced, although the clearance of free naproxen remains unchanged. The clinical significance of this interaction is unknown; however, as with other NSAIDs, concomitant administration of sodium naproxen and aspirin is not recommended due to the potential for adverse effects.

It is known that concomitant use of NSAIDs and analgesic doses of aspirin does not provide greater therapeutic benefit than NSAID use alone. Concomitant use of NSAIDs and aspirin has been associated with a significantly increased frequency of adverse effects compared to use of NSAIDs alone.

Cholestyramine. As with other NSAIDs, concomitant administration of cholestyramine may delay naproxen absorption.

Diuretics. Data indicate that the drug may reduce the natriuretic effect of furosemide and thiazides in some patients. This reaction has been associated with inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, patients should monitor for signs of renal impairment and ensure adequate diuresis.

Lithium. NSAIDs increase lithium plasma levels and reduce renal lithium clearance. The average minimum lithium concentration increases by 15%, and renal clearance decreases by approximately 20%. These effects are associated with NSAID inhibition of renal prostaglandin synthesis. Therefore, special attention should be paid to signs of lithium toxicity when NSAIDs and lithium are administered concomitantly.

Methotrexate. NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Sodium naproxen and other NSAIDs also reduce tubular secretion of methotrexate in animals. This may suggest that they can increase methotrexate toxicity. Concomitant use of NSAIDs with methotrexate should be done with caution.

Warfarin. The effects of warfarin and NSAIDs on gastrointestinal bleeding are synergistic; thus, concomitant use of both drugs increases the risk of serious gastrointestinal bleeding compared to use of either drug alone. No significant interactions between naproxen and coumarin-type anticoagulants have been observed. However, caution is recommended due to reported interactions with other NSAIDs of this class. The free fraction of warfarin may be significantly increased in some individuals, and naproxen antagonizes platelet function.

Selective serotonin reuptake inhibitors (SSRIs). There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors are used in combination with NSAIDs. Concomitant use of NSAIDs with SSRIs should be done with caution.

Digoxin. Concomitant use of naproxen with digoxin has been reported to increase serum digoxin concentration and prolong its half-life (T½). Serum digoxin levels should be monitored when the drug is used concomitantly with digoxin.

NSAIDs and salicylates. Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of toxicity, with little or no increase in efficacy.

Pemetrexed. Concomitant use of naproxen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression and toxicity.

When naproxen and pemetrexed are used concomitantly in patients with impaired renal function (creatinine clearance of 45 to 79 mL/min), monitoring for myelosuppressive and renal toxicity is recommended.

Other information on drug interactions. Naproxen is highly bound to plasma albumin; thus, it has a theoretical potential for interaction with other drugs that bind to albumin, such as coumarin-type anticoagulants, sulfonylurea derivatives, hydantoins, other NSAIDs, and aspirin. Dose adjustments may be necessary in patients receiving naproxen concomitantly with hydantoin derivatives, sulfonamides, or sulfonylureas.

Concomitant administration with probenecid increases plasma levels of the naproxen anion and significantly prolongs its plasma half-life (T½).

Drug/laboratory test interactions. Naproxen may reduce platelet aggregation and increase the risk of bleeding. This should be considered when determining bleeding time.

Naproxen intake may lead to increased 17-ketosteroid levels due to interaction of the drug and/or its metabolites with m-dinitrobenzene used in the assay. Although 17-hydroxycorticosteroid levels (Porter-Silber test) are not artificially altered, it is recommended to temporarily discontinue naproxen 72 hours before performing adrenal function tests if the Porter-Silber test is to be conducted.

Naproxen may affect the results of urinary 5-hydroxyindoleacetic acid determination.

Special precautions for use.

General information. The drug is not a corticosteroid replacement and should not be used in the treatment of corticosteroid deficiency.

The pharmacological activity of the drug, which includes reduction of fever and inflammation, may diminish the significance of these diagnostic signs when identifying complications of disease states presumed to be non-infectious and non-inflammatory.

In case of any visual changes or disturbances, ophthalmological examinations are recommended.

Effect on the liver. Elevated levels in one or more liver function tests have been observed in up to 15% of patients taking NSAIDs, including naproxen. Liver function abnormalities are more likely due to hypersensitivity rather than direct toxic effects. Such laboratory abnormalities may progress, remain essentially unchanged, or be transient despite continued drug use. Alanine aminotransferase (ALT) testing is the most sensitive indicator of hepatic dysfunction.

Patients who develop symptoms or signs of liver dysfunction, or who have abnormal liver function tests during treatment, should be monitored for the development of more severe hepatic reactions.

If clinical signs and symptoms suggest the development of liver disease or in the presence of systemic manifestations (e.g., eosinophilia, rash), the drug should be discontinued.

Chronic liver cirrhosis and possibly other conditions associated with reduced or pathological plasma protein (albumin) levels decrease the total plasma concentration of naproxen, while the concentration of unbound naproxen in plasma increases. The drug should be used with caution when high doses are required, and dose adjustment may be necessary for such patients. The drug should be administered at the lowest effective dose.

Effect on hematological parameters. Anemia has been observed in some patients receiving NSAIDs, including naproxen. This may be due to fluid retention, occult or overt gastrointestinal blood loss, or an incompletely described effect on erythropoiesis. Patients undergoing long-term treatment with NSAIDs, including naproxen, should have regular monitoring of hemoglobin and hematocrit levels if any signs or symptoms of anemia occur.

NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. In contrast to aspirin, their effect on platelet function is quantitatively less, shorter in duration, and reversible. Close monitoring is required in patients taking naproxen who may be at risk for adverse reactions related to altered platelet function (patients with coagulation disorders or those receiving anticoagulants).

History of asthma. Patients with asthma may have aspirin-sensitive asthma. Administration of aspirin in patients with aspirin-induced asthma may cause severe bronchospasm, which can be fatal. Due to the possibility of cross-reactivity, including bronchospasm, between aspirin and other NSAIDs, the drug should not be prescribed to patients with known hypersensitivity to aspirin, and should be used with caution in patients with a history of asthma.

Laboratory tests. Since gastrointestinal ulcers and bleeding may occur without preceding symptoms, physicians should regularly monitor for signs or symptoms of gastrointestinal bleeding. During long-term NSAID therapy, patients should undergo periodic clinical and biochemical blood tests. If clinical signs and symptoms suggest hepatic or renal dysfunction, or if systemic manifestations (e.g., eosinophilia, rash) appear, or if abnormal liver function test results persist or worsen, naproxen should be discontinued.

Effect on the cardiovascular system.

Cardiovascular thrombotic events. The use of NSAIDs, both COX-2 selective and non-selective, increases the risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which may be fatal. Patients with known cardiovascular disease or risk factors for cardiovascular disease are at greater risk. To minimize the risk of cardiovascular adverse reactions in patients taking NSAIDs, the lowest effective dose should be used for the shortest duration necessary. Physicians and patients should be aware that such events can occur even in the absence of prior cardiovascular symptoms. Patients should be informed about the signs and/or symptoms of serious cardiovascular complications and the necessary actions to take if they occur.

There is no convincing evidence that concomitant use of aspirin reduces the increased risk of serious cardiovascular thrombotic events associated with NSAID use. Concurrent use of aspirin and NSAIDs increases the risk of serious gastrointestinal complications.

Arterial hypertension. NSAIDs, including naproxen, may cause new-onset hypertension or worsen pre-existing hypertension, potentially increasing the incidence of cardiovascular complications. In patients receiving thiazide or loop diuretics, the effectiveness of such therapy may be diminished during NSAID use. NSAIDs, including naproxen, should be used with caution in patients with arterial hypertension. Careful monitoring of blood pressure is recommended at the start of NSAID therapy and throughout the treatment course.

Heart failure and edema.

Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs. Naproxen should be used with caution in patients predisposed to edema, hypertension, or heart failure.

Effect on the gastrointestinal tract – risk of ulceration, bleeding, and perforation.

NSAIDs, including naproxen, can cause serious gastrointestinal adverse reactions, including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which may be fatal.

Such serious adverse reactions can occur at any time, with or without preceding symptoms, in patients taking NSAIDs. Only one in five patients experiencing serious upper gastrointestinal adverse reactions to NSAIDs has symptoms. Upper gastrointestinal ulcers, acute bleeding, or perforation occur in approximately 1% of patients treated for 3–6 months and in about 2–4% of patients treated for 1 year. This trend continues with longer treatment duration, increasing the likelihood of serious gastrointestinal complications during therapy. However, even short-term therapy does not eliminate the risk. The benefit of periodic laboratory monitoring has not been demonstrated and has not been adequately evaluated.

NSAIDs should be prescribed with particular caution to patients with a history of peptic ulcer or gastrointestinal bleeding. Patients with a history of peptic ulcer and/or gastrointestinal bleeding who use NSAIDs have more than a 10-fold increased risk of bleeding compared to patients without these risk factors. Other factors that increase the risk of bleeding in patients receiving NSAIDs include: concomitant use of oral corticosteroids or anticoagulants, long duration of NSAID use, smoking, alcohol consumption, advanced age, and poor general health. Most reports of fatal gastrointestinal complications have occurred in elderly or debilitated patients; therefore, special attention should be paid to this patient group during treatment. To minimize the risk of gastrointestinal adverse effects in patients taking NSAIDs, the lowest effective dose should be used for the shortest duration necessary. Patients and physicians should be informed about the signs and symptoms of gastrointestinal ulcers and bleeding during NSAID use, and prompt additional evaluation and treatment should be initiated if a serious gastrointestinal adverse reaction is suspected. NSAID use should be discontinued until a serious adverse reaction is ruled out. Alternative non-NSAID therapy should be considered for patients at high risk.

NSAIDs should be used with caution in patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease), as their condition may worsen.

Effect on the kidneys. Long-term use of NSAIDs can lead to renal papillary necrosis and other kidney damage. Renal toxicity may also occur in patients in whom renal prostaglandins play a compensatory role in maintaining renal perfusion. In such patients, NSAID administration may cause dose-dependent reduction in prostaglandin synthesis and decreased renal blood flow, potentially leading to significant renal decompensation. Patients at greatest risk include those with impaired renal function, hypovolemia, heart failure, hepatic dysfunction, salt depletion, those taking diuretics or ACE inhibitors or ARBs, and elderly patients. Discontinuation of NSAID therapy usually results in return to the pre-treatment state.

Progressive renal failure.

Treatment with naproxen is not recommended in patients with progressive renal failure. If naproxen therapy must be initiated, careful monitoring of renal function is recommended, and patients should maintain adequate fluid intake.

Anaphylactoid reactions.

As with other NSAIDs, anaphylactoid reactions may occur in patients who have not previously taken naproxen. Naproxen should not be prescribed to patients with aspirin triad. This syndrome complex typically occurs in patients with asthma who have rhinitis with or without nasal polyps, or who develop severe, potentially fatal bronchospasm after taking aspirin or another NSAID. In case of an anaphylactoid reaction, emergency medical assistance should be sought. Anaphylactoid reactions, like anaphylaxis, can be fatal.

Skin reactions.

NSAIDs, including naproxen, may cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug-induced eosinophilia with systemic symptoms (DRESS), which may be fatal. These serious complications may occur without warning symptoms. Patients should be informed about the signs and symptoms of serious skin reactions, and drug use should be discontinued at the first appearance of skin rash or any other signs of hypersensitivity. If a patient develops DRESS during drug use, treatment must not be resumed and should be permanently discontinued.

This medicinal product contains 2.1808 mmol (or 50.16 mg) of sodium per dose (1 tablet). Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

The drug may be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus.

Starting from the 20th week of pregnancy, NSAID use may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after starting treatment and is usually reversible upon discontinuation of therapy. Additionally, there have been reports of fetal ductus arteriosus constriction after NSAID treatment in the second trimester, which in most cases resolved after discontinuation of treatment. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction may be advisable if NSAID exposure occurred for several days starting from the 20th gestational week. NSAID use should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

Use of naproxen in late pregnancy to delay labor has been associated with persistent pulmonary hypertension, renal dysfunction (see above), and abnormal prostaglandin E levels in preterm infants. Due to the known effects of NSAIDs on the fetal cardiovascular system (premature constriction/closure of the ductus arteriosus), the drug should be avoided during pregnancy starting from the 30th week (third trimester).

The effect of the drug on labor is unknown. However, naproxen products are not recommended for use during labor because, due to their inhibitory effect on prostaglandin synthesis, they may adversely affect fetal circulation and suppress uterine contractions, thereby increasing the risk of uterine hemorrhage.

Naproxen anion has been detected in the milk of breastfeeding women at concentrations equivalent to approximately 1% of the naproxen Cmax in plasma. Due to the potential adverse effects of prostaglandin-inhibiting drugs on newborns, the drug should not be administered to breastfeeding mothers.

Ability to affect reaction speed when driving or operating machinery.

Patients whose activities require alertness should exercise caution if they experience somnolence, dizziness, or depression while taking naproxen.

Method of Administration and Dosage.

The potential benefits and risks of using the drug, as well as other treatment options, should be carefully considered before deciding to initiate therapy. The lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals.

Pain relief may occur within 30 minutes after administration of sodium naproxen.

Based on observations of the effect and/or adverse reactions following the initial dose, subsequent dosage adjustments are recommended. Lower doses are recommended for patients with renal or hepatic impairment or elderly patients.

Elderly patients. Although total plasma concentrations of naproxen in elderly patients are generally unchanged, unbound (free) naproxen plasma concentrations are increased. Elderly patients should be administered the drug cautiously at high doses, and dose adjustment may be required. As with other drugs used in elderly patients, the lowest effective dose should be used.

Patients with moderate to severe renal impairment. Naproxen is not recommended for use in patients with moderate to severe renal impairment (creatinine clearance < 30 mL/min).

In rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis, the recommended dose is 550 mg (500 mg naproxen and 50 mg sodium) twice daily.

During long-term treatment, the dose of naproxen may be increased or decreased depending on the clinical response in the individual patient. A lower daily dose may be sufficient for long-term use. There is no need to administer the drug more frequently than twice daily.

In patients who tolerate the drug well, the naproxen dose may be increased up to 1375 mg daily for a limited period of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating patients with naproxen at a dose of 1375 mg daily, the physician should observe a significant clinical benefit that outweighs the potential for increased risk.

In pain conditions, primary dysmenorrhea, acute tendinitis, and bursitis, the recommended initial dose is 550 mg of sodium naproxen, followed by 550 mg every 12 hours. The initial total daily dose of sodium naproxen should not exceed 1375 mg. Subsequently, the total daily dose of sodium naproxen should not exceed 1100 mg. Since the sodium salt of naproxen is rapidly absorbed, the drug is recommended for the treatment of acute conditions requiring rapid pain relief.

In acute gout, the recommended initial dose of sodium naproxen is 825 mg, followed by 275 mg every 8 hours until the attack subsides.

Children. The drug in this pharmaceutical form is not recommended for use in children.

Overdose.

Symptoms and signs. Significant overdose with naproxen may be characterized by apathy, dizziness, somnolence, epigastric pain, abdominal discomfort, heartburn, dyspepsia, nausea, transient changes in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation, or vomiting. Gastrointestinal bleeding may occur. Hypertension, acute renal failure, respiratory depression, and coma may occur rarely. Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs and are also possible in overdose. Because sodium naproxen is rapidly absorbed, high and early blood levels are expected. Seizures have been reported in several patients, although a causal relationship with the drug has not been established. There is no information on the dose that constitutes a life-threatening overdose. The oral LD50 in animals is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000 mg/kg in dogs.

Treatment. Patients should receive symptomatic and supportive therapy following NSAID overdose. There are no specific antidotes. Hemodialysis does not reduce naproxen plasma concentrations due to its high degree of plasma protein binding. In patients, vomiting should be induced, and activated charcoal (60–100 g for adults, 1–2 g/kg for children) and/or an osmotic laxative should be administered within 4 hours of overdose. Forced diuresis, urine alkalinization, or hemoperfusion are not useful due to the high protein binding of naproxen.

Adverse reactions.

Gastrointestinal tract: heartburn, abdominal pain, nausea, constipation, diarrhea, dyspepsia, stomatitis, flatulence, vomiting, bleeding (sometimes fatal, especially in elderly patients), perforation and obstruction of upper or lower gastrointestinal tract, gastric/duodenal ulcer, esophageal ulcer and perforation, inflammation, hemorrhage, ulceration, perforation, esophagitis, hematemesis, pancreatitis, colitis, exacerbation of inflammatory bowel disease (non-specific ulcerative colitis, Crohn’s disease), dry mouth, gastritis, glossitis, belching.

Hepatobiliary system: jaundice, abnormal liver function tests, hepatitis (in some cases fatal), hepatic failure.

Central nervous system: headache, dizziness, somnolence, inability to concentrate, vertigo, depression, sleep disturbances, insomnia, weakness, muscle pain, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions, anxiety, asthenia, confusion, nervousness, paresthesia, drowsiness, tremor, coma, hallucinations.

Skin and subcutaneous tissues: exfoliative dermatitis, pruritus, skin rashes, bruising, sweating, purpura, alopecia, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, erythema nodosum, fixed drug eruption, lichenoid eruption, pustular reaction, systemic lupus erythematosus, bullous reactions including Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases of chronic hematoporphyrism (pseudoporphyria) or bullous epidermolysis; frequency unknown – fixed drug eruption, drug-induced eosinophilia with systemic symptoms (DRESS). If skin fragility, blistering or other symptoms characteristic of pseudoporphyria occur, treatment with the drug should be discontinued and the patient should be closely monitored.

Sensory organs: tinnitus, visual disturbances, hearing impairment, worsening of hearing, corneal opacity, papillitis, retrobulbar optic neuritis, optic disc edema, blurred vision, conjunctivitis.

Cardiovascular system: edema, palpitations, congestive heart failure, vasculitis, arterial hypertension, pulmonary edema, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction.

General disorders: dyspnea, thirst, renal dysfunction, anemia, elevated liver enzymes, prolonged bleeding time, anaphylactoid reactions, angioneurotic edema, menstrual cycle disturbances, hyperthermia (chills and fever), infection, sepsis, anaphylactic reactions, appetite changes, fatal outcome.

Blood and lymphatic system: eosinophilia, leukopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia, rectal bleeding, lymphadenopathy, pancytopenia.

Metabolism and nutrition: hyperglycemia, hypoglycemia, weight changes.

Respiratory system: eosinophilic pneumonia, asthma, respiratory depression, pneumonia.

Urinary system: glomerulonephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal damage, renal failure, renal papillary necrosis, elevated serum creatinine.

Reproductive system (women): infertility.

Urinary tract: cystitis, dysuria, oliguria/polyuria, proteinuria.

Reporting of adverse reactions.

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

Shelf life. 3 years.

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

Keep out of reach and sight of children.

Packaging. Tablets No. 10 (10x1), No. 20 (10x2) in blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and location of business activity.

22 Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.