Ortofen-zdorovya

INSTRUCTIONS FOR MEDICAL USE of the medicinal product ORTOFEN-ZDOROV'YA

Composition:

Active ingredient: 1 tablet contains 25 mg of sodium diclofenac;

Excipients: microcrystalline cellulose; lactose monohydrate; sodium croscarmellose; crosspovidone; magnesium stearate; colloidal anhydrous silicon dioxide; dry mixture "Acryl-eze white" containing talc, titanium dioxide (E 171), methacrylate copolymer (type C), sodium lauryl sulfate, sodium bicarbonate, silicon dioxide; macrogol 6000; Ponceau 4R (E 124); Yellow FCF (E 110).

Pharmaceutical form. Enteric-coated tablets.

Main physico-chemical properties: enteric-coated tablets of orange-pink to pink-orange color. Two layers are visible in cross-section.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents.

ATC code M01AB05.

Pharmacological properties.

Pharmacodynamics. The drug contains diclofenac sodium, a non-steroidal compound with pronounced analgesic and anti-inflammatory effects.

It is an inhibitor of prostaglandin synthetase (cyclooxygenase).

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

Pharmacokinetics. Although absorption is complete, onset of action may be delayed due to passage through the stomach, which can be influenced by food intake slowing gastric emptying. Mean peak plasma concentrations of 1.48 ± 0.65 µg/mL (1.5 µg/mL = 5 µmol/L) are reached on average 2 hours after administration of a 50 mg tablet.

Approximately half of the administered diclofenac undergoes metabolism during the first pass through the liver (first-pass effect); the area under the concentration-time curve (AUC) after oral administration is approximately half that obtained with an equivalent parenteral dose.

The pharmacokinetic characteristics of the drug do not change upon repeated administration. Accumulation does not occur when the recommended dosage regimen is followed.

Plasma concentrations in children receiving equivalent doses (mg/kg body weight) are similar to those observed in adults.

Binding of diclofenac to plasma proteins is 99.7%, with albumin binding at 99.4%.

Diclofenac penetrates into synovial fluid, where its Cmax is reached 2–4 hours later than in plasma. The half-life (T½) from synovial fluid is 3–6 hours. Two hours after Cmax is reached in plasma, diclofenac concentration in synovial fluid remains higher; this phenomenon persists for up to 12 hours.

Diclofenac was detected at low concentrations (100 ng/mL) in breast milk in one lactating woman. The estimated amount of drug transferred to the infant via breast milk corresponds to a dose of 0.03 mg/kg/day.

Diclofenac is partially metabolized by glucuronidation of the unchanged molecule, but primarily by mono- and poly-hydroxylation and methoxylation, leading to the formation of several phenolic metabolites, most of which form conjugates with glucuronic acid. Two of these phenolic metabolites are biologically active, but significantly less so than diclofenac.

Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean value ± SD). The terminal T½ from plasma is 1–2 hours. The T½ of plasma for four metabolites, including two pharmacologically active ones, is also short, ranging from 1–3 hours. Approximately 60% of the administered dose is excreted in urine as glucuronide conjugates of the intact molecule and as metabolites, most of which are also converted into glucuronide conjugates. Less than 1% of diclofenac is excreted unchanged. The remainder of the administered dose is excreted in feces as metabolites.

No significant effect of patient age on absorption, metabolism, or elimination of the drug has been observed, except that in five elderly patients, a 15-minute intravenous infusion resulted in plasma concentrations 50% higher than those expected in young healthy subjects.

In patients with impaired renal function receiving therapeutic doses, accumulation of the unchanged active substance is not expected based on the drug's kinetics after single administration. In patients with creatinine clearance less than 10 mL/min, calculated steady-state plasma concentrations of hydroxylated metabolites were approximately four times higher than in healthy individuals. However, ultimately, all metabolites were excreted via bile.

In patients with chronic hepatitis or compensated cirrhosis of the liver, pharmacokinetic parameters and diclofenac metabolism are similar to those in patients without liver disease.

Clinical characteristics.

Indications.

• Inflammatory and degenerative forms of rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritides);
• Spinal pain syndromes;
• Rheumatic diseases of soft periarticular 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 associated with pronounced 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.
• Acute gastric or intestinal ulcer; gastrointestinal bleeding or perforation.
• History of gastrointestinal bleeding or perforation associated with previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).
• Active peptic ulcer disease of the stomach or duodenum/bleeding, or recurrent peptic ulcer/bleeding in history (two or more separate episodes of diagnosed ulcer or bleeding).
• Third trimester of pregnancy.
• Inflammatory bowel diseases (e.g. Crohn's disease or ulcerative colitis).
• Hepatic failure.
• Renal failure (glomerular filtration rate < 15 mL/min/1.73 m²).
• Congestive heart failure (NYHA II–IV).
• Treatment of perioperative pain in coronary artery bypass grafting (or use of cardiopulmonary bypass apparatus).
• Ischemic heart disease in patients with angina pectoris or history of myocardial infarction.
• Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks.
• Peripheral arterial disease.
• The drug, like other NSAIDs, is contraindicated in patients who experience attacks of bronchial asthma, angioneurotic edema, urticaria, or acute rhinitis, nasal polyps, or other allergic symptoms in response to ibuprofen, acetylsalicylic acid, or other NSAIDs.

Interaction with other medicinal products and other types of interactions.

The interactions listed below have been observed with diclofenac in tablet form and/or other dosage forms.

Litium. Concomitant use of diclofenac may increase plasma lithium concentration. Monitoring of serum lithium levels is recommended.

Digoxin. Concomitant use of diclofenac may increase plasma digoxin concentration. 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 should be ensured, and monitoring of renal function is recommended both at the start and regularly during concomitant therapy, particularly with diuretics and ACE inhibitors due to increased risk of nephrotoxicity.

Agents causing hyperkalemia. Concomitant therapy with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may be associated with increased serum potassium levels; therefore, more frequent monitoring of patients is required.

Anticoagulants and antithrombotic agents. Concomitant use may increase the risk of bleeding, so precautionary measures are recommended. Although existing clinical data do not indicate an effect of diclofenac on anticoagulant activity, there are individual reports of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously. Therefore, to ensure no dosage adjustments are needed, careful monitoring of such patients is recommended. Like other NSAIDs, diclofenac at high doses may temporarily inhibit platelet aggregation.

Other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, and corticosteroids. Concurrent use of diclofenac with other NSAIDs or systemic 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. Diclofenac may be used with oral antidiabetic agents without altering their therapeutic effect. However, there are some reports of both hypoglycemia and hyperglycemia, necessitating dosage adjustments of antidiabetic agents during diclofenac use. Therefore, as a precaution, blood glucose levels should be monitored during combination therapy.

There are also isolated reports of metabolic acidosis with concomitant use of diclofenac, particularly in patients with pre-existing renal impairment.

Methotrexate. Diclofenac may inhibit methotrexate clearance in renal tubules, leading to elevated methotrexate levels. Caution should be exercised when prescribing NSAIDs, including diclofenac, less than 24 hours before or after methotrexate administration, as this may increase methotrexate blood concentration and enhance its toxic effects. Serious toxicity cases 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 and tacrolimus. The effect of diclofenac, like other NSAIDs, on prostaglandin synthesis in the kidneys may potentiate the nephrotoxicity of cyclosporine and tacrolimus. Therefore, diclofenac should be used at lower doses than in patients not receiving cyclosporine or tacrolimus.

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 quinolone use in patients already receiving NSAIDs.

Phenytoin. When phenytoin is used concomitantly with diclofenac, monitoring of plasma phenytoin concentrations is recommended due to the expected increased effect of phenytoin.

Cholestyramine and colestipol. These agents may delay or reduce diclofenac absorption. Therefore, diclofenac should be administered at least 1 hour before or 4–6 hours after cholestyramine/colestipol administration.

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

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

CYP2C9 inhibitors. Caution is recommended when co-administering diclofenac with CYP2C9 inhibitors (e.g. voriconazole), which may lead to a significant increase in plasma Cmax and exposure to diclofenac.

CYP2C9 inducers. Caution is required when co-administering diclofenac with CYP2C9 inducers (e.g. rifampicin), which may lead to a significant decrease in plasma concentration and exposure to diclofenac.

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 the drug with systemic NSAIDs, such as selective COX-2 inhibitors, should be avoided due to lack of evidence for synergistic effect and potential additive adverse effects.

Placebo-controlled trials have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications with certain selective COX-2 inhibitors. As there are no comparative clinical data on long-term use of diclofenac at maximum doses, a similar risk cannot be excluded. A direct correlation between this risk and the COX-1/COX-2 selectivity of individual NSAIDs has not been established. In the absence of such data, a careful risk-benefit assessment should be performed before prescribing diclofenac to patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial occlusive diseases, or significant risk factors (e.g. arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Due to this risk, the lowest effective dose should be used for the shortest possible duration.

The effect of NSAIDs on the kidneys includes fluid retention with edema and/or arterial hypertension. Diclofenac should be used with caution in patients with cardiac dysfunction or other conditions predisposing to fluid retention. This is also recommended for patients receiving concomitant diuretics or ACE inhibitors, or those prone to hypovolemia.

Consequences are generally more serious in elderly patients. Caution should be exercised when prescribing the drug to elderly individuals. Special caution is required for 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, even without prior exposure to diclofenac. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may cause myocardial infarction. Symptoms of such reactions may include chest pain occurring in combination with an allergic reaction to diclofenac.

Due to its pharmacodynamic properties, the drug, like other NSAIDs, may mask signs and symptoms of infection.

If a patient has intolerance to certain sugars, consultation with a physician is necessary before taking this drug.

The dyes tartrazine (FD&C Yellow No. 5) and Ponceau 4R included in the formulation may cause allergic reactions.

Gastrointestinal (GI) tract effects. Cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported with all NSAIDs, including COX-2 selective and non-selective agents such as diclofenac. These events may be fatal and may occur at any time during treatment, with or without warning symptoms or prior history of serious GI events. These events generally have more serious consequences in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.

As with other NSAIDs, medical supervision and special caution are mandatory for patients with symptoms indicating GI disturbances when diclofenac is prescribed. The risk of GI bleeding, ulceration, or perforation increases with higher NSAID doses, particularly diclofenac.

Elderly patients have a higher frequency of adverse reactions to NSAIDs, especially 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 doses. For such patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid (ASA/aspirin) or other agents that may increase GI adverse effects, consideration should be given to combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol). Patients with a history of gastrointestinal toxicity, especially elderly ones, should report any unusual abdominal symptoms (particularly GI bleeding). Caution is also required for patients receiving concomitant agents 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 (SSRIs).

The use of NSAIDs, including diclofenac, may be associated with an increased risk of gastrointestinal anastomotic insufficiency. Careful medical monitoring is recommended when using diclofenac after gastrointestinal surgery.

Hepatic effects. Close medical supervision is required when the drug is prescribed to patients with hepatic impairment, as their condition may worsen.
As with other NSAIDs, one or more liver enzymes may increase during diclofenac use. Such increases were usually reversible upon discontinuation of the drug.

Elevated liver enzymes were very commonly observed in clinical trials with diclofenac (approximately 15% of patients), but rarely associated with clinical symptoms. Most cases involved borderline elevations. Moderate increases (≥3 to <8 times the upper limit of normal) were frequently observed (in 2.5% of cases), while marked increases (≥8 times the upper limit of normal) occurred in approximately 1% of cases. Elevated liver enzymes were associated with clinically evident liver injury in 0.5% of cases in the aforementioned clinical trials.

Regular monitoring of liver function and liver enzyme levels is recommended as a precaution during long-term treatment. The drug should be discontinued if hepatic impairment persists or worsens, if clinical signs or symptoms suggest progressive liver disease, or if other manifestations occur (e.g. eosinophilia, rash).

In addition to elevated liver enzymes, rare reports of severe hepatic reactions have been documented, including jaundice, fulminant hepatitis, hepatic necrosis, and hepatic failure, some of which were fatal.

Diseases such as hepatitis may progress without prodromal symptoms. Caution is necessary when prescribing the drug to patients with porphyria, due to the potential for provoking an attack.

Renal effects. NSAIDs, including diclofenac, reduce prostaglandin levels, which are important for maintaining renal blood flow.

Since fluid retention, edema, and hypertension have been frequently (1–10%) reported during treatment with NSAIDs, including diclofenac, special attention should be paid to patients with cardiac or renal dysfunction, history of arterial hypertension, elderly patients, patients receiving concomitant diuretics or agents significantly affecting renal function, and patients with significant extracellular fluid volume depletion due to any cause (e.g. before or after major surgery). As a precaution, monitoring of renal function is recommended in such cases. Discontinuation of therapy usually results in return to the pre-treatment state.

Skin effects. Serious skin reactions (some of which were fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), generalized fixed bullous drug eruption, and drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS), have been very rarely reported with diclofenac use. The highest risk for these reactions occurs early in the treatment course, with most cases appearing within the first month of therapy. The drug should be discontinued at the first sign of skin rash, mucosal lesions, or any other signs of hypersensitivity.

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

Cardiovascular and cerebrovascular effects. Treatment with the drug is generally not recommended for patients with diagnosed cardiovascular diseases (heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled arterial hypertension.

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (e.g. arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation and, if treatment exceeds 4 weeks, at doses not exceeding 100 mg daily. Since cardiovascular risks associated with diclofenac may increase with dose and duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The need for diclofenac and response to therapy should be periodically reviewed, especially if treatment exceeds 4 weeks.

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and advice, as fluid retention and edema have been reported with NSAIDs, including diclofenac.

The drug should be used with caution in patients receiving concomitant diuretics or ACE inhibitors or those at increased risk of hypovolemia.

Existing data indicate that diclofenac, particularly at high doses (150 mg/day) and with prolonged use, may slightly increase the 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, at a dose not exceeding 100 mg daily for no more than 4 weeks.

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

Hematological effects. With prolonged use of this drug, as with other NSAIDs, monitoring of blood counts including leukocyte formula is recommended.

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

History of asthma. Patients with asthma, seasonal allergic rhinitis, nasal mucosal edema (i.e. nasal polyps), chronic obstructive lung diseases, or chronic respiratory tract infections (especially those associated with allergic, rhinitis-like symptoms) are more likely to experience NSAID-related reactions 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 agents inhibiting prostaglandin synthetase activity, sodium diclofenac and other NSAIDs may provoke bronchospasm in patients with bronchial asthma or a history thereof.

Use during pregnancy or breastfeeding.

Pregnancy. From the 20th week of pregnancy, use of diclofenac may lead to impaired renal function in the fetus, causing oligohydramnios and, in some cases, renal failure in the newborn. These adverse effects are observed on average after several days or weeks of treatment, although oligohydramnios has developed as early as 48 hours after starting NSAID use in rare cases. Oligohydramnios often, but not always, resolves after discontinuation of NSAID therapy. Complications of prolonged oligohydramnios may include, for example, limb contractures and pulmonary hypoplasia. In some post-marketing clinical observations, neonatal renal failure required invasive procedures such as exchange transfusion or dialysis.

Additionally, constriction of the ductus arteriosus has been reported after second-trimester treatment, which resolves in most cases after discontinuation of therapy.

If treatment with the drug lasts more than 48 hours, consideration should be given to ultrasound monitoring of amniotic fluid and fetal heart. If oligohydramnios or ductus arteriosus constriction occurs, the drug should be discontinued and appropriate treatment initiated according to clinical practice.

Inhibition of prostaglandin synthesis may adversely affect pregnancy course and/or embryonic/fetal development. Epidemiological data suggest 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%. This risk is believed to be proportional to the dose and duration of treatment.

Animal studies have shown that administration of prostaglandin synthesis inhibitors leads to increased pre- and post-implantation loss and embryonic/fetal mortality. In animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

In the first and second trimesters of pregnancy, the drug may be prescribed only if the expected benefit to the woman outweighs the potential risk to the fetus. If the drug is used by a woman planning pregnancy or during the first or second trimester, the dose should be as low as possible and the duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus as follows:

• Cardio-pulmonary toxicity (premature closure of the ductus arteriosus and pulmonary hypertension);
• Impaired renal function, which may progress to renal failure with oligohydramnios (see above).

On the mother and newborn, especially at the end of pregnancy:

• Possible prolonged bleeding time, anti-aggregatory effect, which may occur even at very low doses;
• Inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, the drug is contraindicated during the third trimester of pregnancy.

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

If treatment is necessary, breastfeeding should be discontinued.

Female fertility. Like other NSAIDs, the drug may negatively affect female fertility and is therefore not recommended for women planning pregnancy. For women experiencing infertility or undergoing fertility investigations, discontinuation of the drug should be considered.

Based on relevant animal studies, impairment of male reproductive function cannot be excluded. The relevance of these data to humans has not been established.

Ability to affect reaction speed when driving vehicles or operating machinery. Patients who experience visual disturbances, dizziness, vertigo, somnolence, central nervous system disorders, lethargy, or increased fatigue during treatment should not drive vehicles or operate complex machinery.

Method of administration and dosage. To minimize adverse effects, the drug should be used at the lowest effective doses for the shortest duration necessary to control symptoms, considering the treatment goal for each individual patient. Tablets should preferably be taken before meals, with liquid, and should not be divided or chewed.

The initial dose is usually 100–150 mg daily. For mild symptoms and long-term therapy, a dose of 75–100 mg daily is sufficient. The daily dose should be divided into 2–3 doses. To prevent nocturnal pain or morning joint stiffness, treatment may be supplemented with rectal suppositories before bedtime. The daily dose should not exceed 150 mg.

For primary dysmenorrhea, the daily dose should be individually adjusted, usually 50–150 mg. The initial dose may be 50–100 mg daily, but may be increased over several menstrual cycles to the maximum of 150 mg daily if necessary. Treatment should begin after the onset of the first pain symptoms and continue for several days, depending on symptom regression.

The recommended maximum daily dose is 150 mg.

Children (1–14 years of age). The drug may be used in children from 1 year of age under medical supervision at a daily dose of 0.5–2 mg/kg body weight, depending on symptom severity; this dose should be divided into 2–3 administrations. In the treatment of juvenile rheumatoid arthritis, the daily dose may be increased to 3 mg/kg in divided doses.

For example, for a child weighing 30 kg, the daily dose may range from 15 to 60 mg. Based on this range, the child may be prescribed 2 tablets of 25 mg twice daily.

If the prescribed dose cannot be achieved, other dosage forms of diclofenac with appropriate strengths should be used.

Children aged 14 to 18 years should receive 75 to 150 mg daily in 2 or 3 divided doses.

The daily dose should not exceed 150 mg.

Elderly patients (aged 65 years and older): Although the pharmacokinetics of the drug is not significantly impaired in elderly patients to a clinically relevant extent, NSAIDs should be used with particular caution in elderly patients, who are generally more susceptible to adverse reactions. Specifically, the lowest effective doses are recommended for frail elderly patients or those with low body weight; patients should also be monitored for gastrointestinal bleeding during NSAID therapy.

Existing cardiovascular diseases or significant risk factors: Diclofenac may be prescribed to patients with significant cardiovascular risk factors (e.g. arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation and, if used for more than 4 weeks, at a maximum daily dose of 100 mg (see "Special precautions for use"). Since cardiovascular risks of diclofenac may increase with dose and duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The need for diclofenac and response to therapy should be periodically reviewed.

Patients with renal impairment: The drug is contraindicated in patients with renal failure (glomerular filtration rate < 15 mL/min/1.73 m²).

No specific studies have been conducted in patients with renal impairment, and no dosage recommendations are available. The drug should be prescribed with caution in patients with renal impairment.

Patients with hepatic impairment: The drug is contraindicated in patients with hepatic failure.

No specific studies have been conducted in patients with hepatic impairment, and no dosage recommendations are available. The drug should be prescribed with caution in patients with moderate to severe hepatic impairment.

Children. The drug may be used in children from 1 year of age with juvenile chronic arthritis, provided the prescribed weight-based doses can be achieved.

Overdose. There is no typical clinical picture characteristic of diclofenac overdose. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, agitation, coma, somnolence, tinnitus, or seizures. Acute renal failure and hepatic injury are possible in severe intoxication.

Treatment. Management of acute NSAID poisoning, including diclofenac, involves supportive and symptomatic therapy. This includes treatment of arterial hypotension, renal failure, seizures, gastrointestinal disturbances, and respiratory depression. Specific interventions such as forced diuresis, dialysis, or hemoperfusion are unlikely to be effective in eliminating NSAIDs, including diclofenac, due to extensive protein binding and intensive metabolism of the active substances. Activated charcoal may be administered after ingestion of potentially toxic doses, and gastric decontamination (e.g. induced emesis, gastric lavage) may be performed after ingestion of potentially life-threatening doses.

Side effects.

The undesirable effects listed below are those reported during short-term or long-term use of diclofenac.

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

Immune system disorders: hypersensitivity; anaphylactic and anaphylactoid reactions (including arterial hypotension and shock); angioneurotic edema (including facial swelling).

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

Nervous system disorders: headache; dizziness; somnolence; fatigue; paresthesia; memory impairment; convulsions; anxiety; tremor; aseptic meningitis; taste disturbances; stroke; confusion; hallucinations; sensory disturbances; malaise.

Eye disorders: visual disturbances; blurred vision; diplopia; optic neuritis.

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

Cardiac and vascular disorders: palpitations; chest pain; heart failure; myocardial infarction; arterial hypertension; arterial hypotension; vasculitis; Kounis syndrome.

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

Gastrointestinal disorders: nausea; vomiting; diarrhea; dyspepsia; abdominal pain; flatulence; anorexia; gastritis; gastrointestinal bleeding, hematemesis, melena, hemorrhagic diarrhea; gastric and intestinal ulcers, with or without bleeding, gastrointestinal stenosis or perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis; colitis (including hemorrhagic colitis, ischemic colitis, and exacerbation of ulcerative colitis or Crohn’s disease); constipation; stomatitis (including ulcerative stomatitis); glossitis; esophageal disorders; diaphragm-like intestinal stricture; pancreatitis.

The medicinal product may cause chronic inflammatory conditions with pseudomembranes and strictures in the distal intestine (small and large intestine).

Hepatobiliary disorders: increased transaminase levels; hepatitis; jaundice; liver disorders; fulminant hepatitis; liver necrosis; liver failure.

Skin and subcutaneous tissue disorders: rash (including with "unknown" frequency: fixed drug eruption, generalized bullous fixed drug eruption); urticaria; blistering rash; eczema; erythema; erythema multiforme; Stevens-Johnson syndrome; Lyell’s syndrome (toxic epidermal necrolysis); exfoliative dermatitis; alopecia; photosensitivity reactions; purpura, including allergic purpura; pruritus; drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

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

General disorders: rarely – edema.

Reproductive system and breast disorders: impotence.

Available 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 with prolonged use.

Visual disturbances.

Visual disturbances such as impaired vision, worsening of vision, and diplopia are class effects of NSAIDs and are generally reversible upon discontinuation of the drug. The most likely mechanism of visual disturbances is inhibition of prostaglandin and related compounds synthesis, which, due to disruption of retinal blood flow regulation, may alter regulation of intraocular arterial pressure and lead to changes in visual acuity. If such symptoms occur during treatment with diclofenac, an ophthalmological examination should be performed to rule out other possible causes.

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. Tablets|tablets|, coated, enteric-coated, 25 mg, № 30 (10×3), № 30 (30×1) in blister packs in a carton.

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

(packaging № 30 (10×3), № 30 (30×1) in blister packs in a carton)

Limited Liability Company "FARMEKS GROUP".

(packaging № 30 (30×1) in blister packs in a carton)

Manufacturer's address and place of business. Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, 100.

(Limited Liability Company "FARMEKS GROUP")