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

Composition:

Active substance: sodium diclofenac;

1 tablet contains 25 mg of sodium diclofenac;

Excipients: lactose monohydrate, potato starch, povidone 25, magnesium stearate, methacrylic acid copolymer dispersion, propylene glycol, talc, titanium dioxide (E 171), yellow azo dye FCF (E 110).

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: coated tablets, yellow to orange in color, with a biconvex surface. When broken and examined under a magnifying glass, a core surrounded by a single continuous layer is visible.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related substances. ATC code M01AB05.

Pharmacological properties.

Pharmacodynamics.

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) with pronounced analgesic, anti-inflammatory, and antipyretic effects. Its main mechanism of action is inhibition of prostaglandin biosynthesis, which play a key role in the development of inflammation, pain, and fever.

In vitro, at concentrations equivalent to those achieved in humans, diclofenac does not inhibit proteoglycan biosynthesis in cartilage tissue.

Orthofen tablets, due to their rapid absorption, are suitable for the treatment of acute conditions associated with pain and inflammation, where a rapid onset of action (within 30 minutes) is desired. In post-traumatic pain and inflammation, diclofenac rapidly relieves both spontaneous pain and pain on movement, as well as reduces swelling at the site of injury and inflammatory edema.

Furthermore, diclofenac may alleviate pain and reduce bleeding in primary dysmenorrhea. Diclofenac also provides analgesic effects in other conditions associated with moderate to severe pain.

Pharmacokinetics.

Absorption.

Diclofenac is rapidly and completely absorbed. Absorption begins immediately after administration, and the amount of absorbed substance corresponds to that absorbed following administration of an equivalent dose of sodium diclofenac in the form of gastro-resistant tablets. Administration with food does not affect the total amount of diclofenac absorbed, although the onset and rate of absorption may be slightly delayed.

Distribution.

Diclofenac is 99.7% bound to plasma proteins, primarily to albumin (99.4%). The volume of distribution is 0.12–0.17 L/kg.

Diclofenac penetrates into synovial fluid, where maximum concentrations are reached 2–4 hours after peak plasma levels. The apparent half-life in synovial fluid is 3–6 hours. Two hours after peak plasma concentrations, the concentration of the active substance in synovial fluid exceeds that in plasma and remains higher for up to 12 hours.

Metabolism.

Diclofenac metabolism occurs partially via glucuronidation of the intact molecule, but mainly through single and multiple hydroxylations and methoxylation.

Elimination.

Total systemic clearance of diclofenac from plasma is 263±56 mL/min (mean ± standard deviation). The terminal elimination half-life is 1–2 hours. The elimination half-life of four metabolites, including two active ones, is 1–3 hours. An essentially inactive metabolite has a much longer elimination half-life.

Approximately 60% of the dose is excreted in urine as metabolites, with less than 1% excreted unchanged. The remainder is excreted in bile and feces as metabolites.

Pharmacokinetics in specific patient groups.

No significant differences in absorption, metabolism, or elimination of the drug have been observed based on patient age.

In patients with impaired renal function, the pharmacokinetics of a single dose do not indicate accumulation of unchanged active substance under normal dosing regimens.

In patients with creatinine clearance less than 10 mL/min, theoretical steady-state plasma concentrations of metabolites are approximately four times higher than in healthy volunteers. However, ultimately, these metabolites are excreted in bile.

Clinical characteristics.

Indications.

Inflammatory and degenerative forms of rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritides);
Spinal pain syndromes;
Rheumatic diseases of periarticular soft tissues;
Acute gout attacks;
Post-traumatic and postoperative pain syndromes associated with inflammation and edema, e.g., following dental or orthopedic procedures;
Gynecological conditions associated with pain and inflammation, e.g., primary dysmenorrhea or adnexitis;
As an adjunctive agent in severe inflammatory ENT disorders accompanied by pain, e.g., pharyngotonsillitis, otitis.

According to general therapeutic principles, the underlying disease should be treated with basic therapy agents. Fever alone is not an indication for the use of this drug.

Contraindications.

Hypersensitivity to the active substance or to any other component of the drug.
Gastrointestinal bleeding or perforation in medical history related to previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).
Active peptic ulcer/hemorrhage or recurrent peptic ulcer/hemorrhage in medical history (two or more separate episodes of confirmed ulcer or bleeding).
Third trimester of pregnancy.
Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis).
Hepatic failure.
Renal failure.
Congestive heart failure (NYHA II–IV);
Management of perioperative pain in coronary artery bypass grafting (CABG) (or use of cardiopulmonary bypass);
Ischemic heart disease in patients with angina pectoris or history of myocardial infarction;
Cerebrovascular disorders in patients with history of stroke or transient ischemic attacks;
Peripheral arterial disease;
Orphen, like other nonsteroidal anti-inflammatory agents, is contraindicated in patients who develop attacks of bronchial asthma, angioedema, urticaria, or acute rhinitis, nasal polyps, or other allergic symptoms in response to administration of ibuprofen, acetylsalicylic acid, or other NSAIDs.

Interaction with other medicinal products and other types of interactions.

The interactions listed below have been observed with the use of diclofenac in enteric-coated tablets and/or other dosage forms.

Lithium. Diclofenac may increase plasma lithium concentrations when used concomitantly. Monitoring of serum lithium levels is recommended.

Digoxin. Diclofenac may increase digoxin plasma concentrations when used concomitantly. Monitoring of serum digoxin levels is recommended.

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g., β-blockers, angiotensin-converting enzyme (ACE) inhibitors) may reduce their antihypertensive effect by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, such combinations should be used with caution, and patients, especially elderly ones, should be closely monitored for blood pressure. Adequate hydration is recommended, and renal function should be monitored after initiation and regularly during concomitant therapy, particularly with diuretics and ACE inhibitors, due to increased risk of nephrotoxicity.

Medicinal products known to cause hyperkalemia. Concomitant use with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, more frequent monitoring of patients is recommended.

Anticoagulants and antiplatelet agents. Concomitant use may increase the risk of bleeding; therefore, precautionary measures are recommended. Although clinical studies have not demonstrated an effect of diclofenac on anticoagulant activity, isolated reports indicate an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended to ensure no dosage adjustments of anticoagulants are needed. Like other nonsteroidal anti-inflammatory drugs, diclofenac at high doses may transiently inhibit platelet aggregation.

Other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, and corticosteroids.

Concomitant use of diclofenac with other NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Concomitant use of two or more NSAIDs should be avoided.

Selective serotonin reuptake inhibitors (SSRIs).

Concomitant use of NSAIDs and SSRIs may increase the risk of gastrointestinal bleeding.

Antidiabetic agents. Clinical studies have shown that diclofenac can be used together with oral antidiabetic agents without altering their therapeutic effect. However, there have been reports of both hypoglycemia and hyperglycemia requiring dosage adjustments of antidiabetic agents during diclofenac therapy. Therefore, as a precautionary measure, blood glucose levels should be monitored during combination therapy.

Methotrexate. Diclofenac may inhibit renal tubular clearance of methotrexate, leading to elevated methotrexate levels. Caution should be exercised when prescribing NSAIDs, including diclofenac, less than 24 hours before methotrexate administration, as this may increase methotrexate plasma concentrations and enhance its toxicity. Serious cases of toxicity have been reported when the interval between methotrexate and NSAID (including diclofenac) administration was within 24 hours. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine. The effect of diclofenac, as with other NSAIDs, on prostaglandin synthesis in the kidneys may potentiate the nephrotoxicity of cyclosporine. Therefore, diclofenac should be administered at lower doses in patients receiving cyclosporine compared to those not receiving cyclosporine.

Tacrolimus. Concomitant use of NSAIDs with tacrolimus may increase the risk of nephrotoxicity, possibly mediated by renal anti-prostaglandin effects of NSAIDs and calcineurin inhibitors.

Antibacterial quinolones. Seizures may occur in patients receiving quinolone derivatives and NSAIDs concomitantly. This may occur in patients both with and without a history of epilepsy or seizures. Therefore, caution should be exercised when considering the use of quinolones in patients already receiving NSAIDs.

Phenytoin. Monitoring of plasma phenytoin concentrations is recommended when phenytoin is administered concomitantly with diclofenac due to the expected increase in phenytoin effects.

Cholestyramine and colestipol. These agents may delay or reduce the absorption of diclofenac. Therefore, diclofenac should be administered at least one hour before or 4–6 hours after cholestyramine/colestipol.

Cardiac glycosides. Concomitant use of cardiac glycosides and NSAIDs may exacerbate heart failure, reduce glomerular filtration rate (GFR), and increase glycoside levels in plasma.

Mifepristone. NSAIDs should not be used within 8–12 days after mifepristone administration, as NSAIDs may reduce the efficacy of mifepristone.

Strong CYP2C9 inhibitors. Caution is recommended when co-prescribing diclofenac with strong CYP2C9 inhibitors (e.g., voriconazole), which may lead to a significant increase in maximum plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.

Special precautions for use.

General

To minimize adverse effects, treatment should be initiated with the lowest effective dose for the shortest duration necessary to control symptoms.

Concomitant use of Ortofen with systemic NSAIDs, such as selective cyclooxygenase-2 inhibitors, should be avoided due to lack of evidence for synergistic effect and potential for additive adverse effects.

Caution is required when administering the drug to patients over 65 years of age. In particular, the lowest effective dose is recommended for frail elderly patients or those with low body weight.

As with other NSAIDs, allergic reactions including anaphylactic/anaphylactoid reactions may occur rarely during treatment with diclofenac. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction. Symptoms of this reaction may include chest pain occurring in combination with an allergic reaction to diclofenac.

Diclofenac, as with other NSAIDs, may mask signs and symptoms of infection.

One tablet contains 50.6 mg of lactose monohydrate. Patients with rare hereditary forms of fructose intolerance, glucose-galactose malabsorption syndrome, or deficiency of sucrase-isomaltase enzymes must not take this medicinal product.

Gastrointestinal effects

When using all NSAIDs, including diclofenac, cases of gastrointestinal bleeding (e.g., vomiting blood, melena), ulceration, or perforation have been reported. These events may be fatal and may occur at any time during treatment, with or without warning symptoms or prior history of serious gastrointestinal events. These events are usually more severe in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued immediately.

As with other NSAIDs, including diclofenac, medical supervision and special caution are mandatory in patients with symptoms indicating gastrointestinal (GI) tract disorders. The risk of GI bleeding, ulceration, or perforation increases with higher doses of NSAIDs, including diclofenac.

Use of NSAIDs, including diclofenac, may increase the risk of gastrointestinal anastomotic dehiscence. Close monitoring and caution are recommended when using diclofenac after gastrointestinal surgery.

Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal.

To reduce the risk of such GI toxicity, treatment should be initiated and maintained at the lowest effective dose. For such patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid (ASA/aspirin) or other drugs likely to increase the risk of GI adverse effects, consideration should be given to combined therapy with protective agents (e.g., proton pump inhibitors or misoprostol). Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly GI bleeding). Caution is also required in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., ASA), or selective serotonin reuptake inhibitors.

Hepatic effects

Careful medical monitoring is required when the drug is prescribed to patients with impaired liver function, as their condition may worsen.

As with other NSAIDs, including diclofenac, elevation of one or more liver enzymes may occur.

During long-term treatment, regular monitoring of liver function and liver enzyme levels is recommended as a precautionary measure. If liver dysfunction persists or worsens, or if clinical signs or symptoms suggest progressive liver disease or other manifestations (e.g., eosinophilia, rash), the drug should be discontinued. Diseases such as hepatitis may progress without prodromal symptoms. Caution is required when Ortofen is used in patients with hepatic porphyria due to the potential to provoke an attack.

Renal effects

Since fluid retention and edema have been reported during treatment with NSAIDs, including diclofenac, particular attention should be paid to patients with impaired cardiac or renal function, history of arterial hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs significantly affecting renal function, and patients with substantial extracellular fluid volume depletion due to any cause (e.g., before or after major surgery). In such cases, monitoring of renal function is recommended as a precaution. Discontinuation of therapy usually leads to reversal to the pre-treatment state.

Skin effects

Serious skin reactions (some of which were fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and generalized bullous fixed drug eruption, have been reported very rarely in association with diclofenac use (see section "Adverse reactions"). The highest risk of these reactions occurs early in the course of therapy, with most cases appearing within the first month of treatment. Ortofen should be discontinued immediately at the first sign of skin rash, mucosal lesions, or any other signs of hypersensitivity.

SLE and mixed connective tissue disorders

Patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders may have an increased risk of aseptic meningitis.

Cardiovascular and cerebrovascular effects

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation. Since cardiovascular risks of diclofenac may increase with higher doses and longer duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The patient's need for symptom relief and response to therapy should be reviewed periodically.

Appropriate monitoring and advice are necessary for patients with a history of arterial hypertension and/or mild to moderate congestive heart failure, as fluid retention and edema have been reported with NSAID use, including diclofenac.

Clinical trial data and epidemiological evidence indicate that diclofenac use, particularly at high doses (150 mg/day) and during prolonged treatment, may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Diclofenac is not recommended for patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. If use is necessary, it may be considered only after careful risk-benefit assessment and at a daily dose not exceeding 100 mg.

Patients should be informed about the possibility of serious thrombotic complications (chest pain, dyspnea, weakness, speech disturbances), which may occur at any time. In such cases, immediate medical attention is required.

Hematological effects

With long-term use of this drug, as with other NSAIDs, monitoring of complete blood count is recommended.

The drug may temporarily inhibit platelet aggregation. Careful monitoring is required in patients with hemostatic disorders, hemorrhagic diathesis, or hematological disorders.

History of asthma

Patients with asthma, seasonal allergic rhinitis, nasal mucosal edema (e.g., nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory infections (especially those associated with allergic, rhinitis-like symptoms) are more likely to experience reactions to NSAIDs, such as asthma exacerbation (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria. Therefore, special precautionary measures (readiness for emergency care) are recommended for such patients. This also applies to patients with allergic reactions to other substances, such as rash, pruritus, or urticaria.

Like other drugs that inhibit prostaglandin synthetase activity, sodium diclofenac and other NSAIDs may provoke bronchospasm when administered to patients with bronchial asthma or a history of bronchial asthma.

Use during pregnancy or breastfeeding.

Pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and/or congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. An increased risk with dose and duration of treatment cannot be excluded. Animal studies have shown that administration of prostaglandin synthesis inhibitors leads to increased pre- and post-implantation loss and embryonic/fetal mortality.

Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular malformations, has been observed.

First and second trimesters. From the 20th week of pregnancy, use of Ortofen may cause oligohydramnios due to fetal renal dysfunction. This effect may occur soon after initiation of treatment and is usually reversible upon discontinuation. There have also been reports of fetal ductus arteriosus constriction after second-trimester treatment, most of which resolved after stopping the drug. Therefore, Ortofen should not be prescribed during the first and second trimesters unless clearly necessary. If Ortofen is used by a woman attempting to become pregnant or during the first and second trimesters, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction may be appropriate if exposure to Ortofen occurred for several days starting from the 20th gestational week. Ortofen should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

Third trimester. During the third trimester, all prostaglandin synthesis inhibitors may pose risks:

Risks to the fetus:

Cardio-pulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
Renal dysfunction (see above).

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

Prolonged bleeding time, antiaggregatory effect, which may occur even at very low doses;
Inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, Ortofen is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding. Like other NSAIDs, diclofenac is excreted in small amounts in breast milk. Therefore, the drug should not be used during breastfeeding to avoid potential adverse effects on the infant.

Female fertility. As with other NSAIDs, Ortofen may negatively affect female fertility and therefore is not recommended for women attempting to conceive. For women experiencing infertility or undergoing fertility investigations, discontinuation of the drug should be considered.

Ability to influence reaction speed when driving or operating machinery.

Generally, when the drug is taken at the recommended dose and for short-term treatment, no effect on reaction speed is observed. However, patients who experience visual disturbances, dizziness, vertigo, somnolence, or other central nervous system (CNS) disorders during treatment should refrain from driving or operating machinery.

Method of Administration and Dosage.

The treatment should be initiated as early as possible after the onset of the first painful symptoms. The duration of treatment depends on the symptoms and usually lasts for several days.

The drug should be used at the lowest effective dose for the shortest possible duration, taking into account the individual therapeutic needs of each patient.

For adults, the recommended initial daily dose is 100–150 mg. In mild cases and during long-term therapy, a daily dose of 75–100 mg is usually sufficient.

The total daily dose for adults is generally divided into 2–3 doses. The daily dose should not exceed 150 mg.

In primary dysmenorrhea, the daily dose should be individually adjusted and usually ranges from 50 to 150 mg. The initial dose may be 50–100 mg, but if necessary, it can be increased over several menstrual cycles, though not exceeding 200 mg/day.

For children aged 8 years (with body weight not less than 25 kg) to 14 years, 25 mg tablets should be administered according to the physician's prescription at a daily dose of 1–2 mg/kg body weight, depending on symptom severity. This dose should be divided into 2–3 administrations.

For example, for a child weighing 30 kg, the daily dose may range from 30 to 60 mg. Based on this range, the child may be prescribed one 25 mg tablet twice daily.

In the treatment of juvenile rheumatoid arthritis, the daily dose may be increased up to 3 mg/kg, which is the maximum daily dose. The maximum daily dose of 150 mg should not be exceeded.

Children.

Children aged 8 to 14 years (with body weight not less than 25 kg) should only be prescribed 25 mg tablets. Children aged 14 years and older may be prescribed 50 mg tablets.

Overdose.

Symptoms. There is no typical clinical picture of diclofenac overdose. Symptoms of overdose may include vomiting, gastrointestinal bleeding, diarrhea, dizziness, tinnitus, or convulsions. In cases of severe poisoning, acute renal failure and hepatic damage may develop.

Treatment. Management of acute poisoning with nonsteroidal anti-inflammatory drugs (NSAIDs), including diclofenac, generally involves supportive care and symptomatic treatment of complications such as arterial hypotension, renal failure, convulsions, gastrointestinal disturbances, and respiratory depression. Specific interventions such as forced diuresis, dialysis, or hemoperfusion do not significantly enhance the elimination of NSAIDs from the body due to their high degree of protein binding and extensive metabolism.

In cases of potentially toxic overdose, activated charcoal should be administered, and gastric contents should be evacuated (induce vomiting, gastric lavage).

Adverse Reactions

The following adverse effects include reactions reported during short-term or long-term treatment with the medicinal product Ortofen and/or other dosage forms of diclofenac.

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, anemia (including hemolytic and aplastic anemia), agranulocytosis.

Immune system disorders: hypersensitivity, anaphylactic and anaphylactoid reactions (including arterial hypotension and shock), angioedema (including facial swelling).

Psychiatric disorders: disorientation, depression, insomnia, nightmares, irritability, psychotic disorders.

Central nervous system disorders: headache, dizziness, drowsiness, paraesthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disturbances, stroke.

Eye disorders: visual disturbances, blurred vision, diplopia.

Ear and labyrinth disorders: vertigo, tinnitus, hearing disturbances.

Cardiac disorders: palpitations, heart failure, myocardial infarction, arterial hypertension, vasculitis, chest pain which may indicate a potentially serious allergic reaction known as Kounis syndrome.

Respiratory, thoracic and mediastinal disorders: asthma (including dyspnea), pneumonitis.

Gastrointestinal disorders: nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, loss of appetite, gastritis, gastrointestinal bleeding, vomiting of blood, hemorrhagic diarrhea, melena, gastrointestinal ulceration (with or without bleeding or perforation), colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis, glossitis, esophageal disorders, diaphragm-like intestinal strictures, pancreatitis.

Hepatobiliary and biliary tract disorders: increased transaminase levels, hepatitis, jaundice, liver function abnormalities, fulminant hepatitis, hepatic necrosis, liver failure.

Skin and subcutaneous tissue disorders: rash, urticaria, bullous eruptions, eczema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, alopecia, photosensitization, allergic purpura, pruritus; frequency unknown – fixed drug eruption, generalized bullous fixed drug eruption.

Renal and urinary disorders: fluid retention, edema, acute renal failure, hematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.

General disorders: swelling, injection site abscess.

Reproductive system and breast disorders: impotence.

Clinical studies and epidemiological data indicate an increased risk of thrombotic complications (e.g., myocardial infarction or stroke) associated with the use of diclofenac, particularly at high therapeutic doses (150 mg per day) and during prolonged treatment.

Reporting of adverse reactions. Reporting of adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare 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 the following link: 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 of children.

Packaging.

10 tablets in a blister;

10 tablets in a blister; 3 blisters in a cardboard box;

10 tablets in a blister; 100 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

JSC "Tekhnolog".

Manufacturer's address and place of business.

8 Stara Prorizna Street, Uman, Cherkasy region, 20300, Ukraine.