Diclofenac sodium

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DICLOFENAC SODIUM (Diclofenac natrii)

Composition:

Active substance: diclofenac;

1 capsule contains sodium diclofenac equivalent to 100% substance – 25 mg;

Excipients: lactose monohydrate; magnesium stearate;

Hard gelatin capsule No. 4 contains:

gelatin, titanium dioxide (E 171), indigotine (E 132), erythrosine (E 127), iron oxide (E 172).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules with a white or dark red body and a cap of green, blue, black or yellow color; capsule contents – yellowish-white powder.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and anti-rheumatic drugs. Acetic acid derivatives and related compounds. ATC code M01AB05.

Pharmacological Properties.

Pharmacodynamics.

Diclofenac sodium is a non-steroidal compound that exerts pronounced anti-inflammatory, analgesic, and antipyretic effects. The primary mechanism of action of diclofenac is the inhibition of prostaglandin biosynthesis. Prostaglandins play a key role in the pathogenesis of inflammation, pain, and fever.

In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac provide a clinical effect characterized by a significant reduction in the severity of symptoms and complaints such as pain at rest and during movement, morning stiffness, joint swelling, as well as improvement in joint function.

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

In post-traumatic and postoperative inflammatory conditions, the drug rapidly relieves pain (both spontaneous and movement-related), reduces inflammatory edema, and decreases swelling of postoperative wounds.

The medicinal product demonstrates a significant analgesic effect in moderate to severe non-rheumatic pain syndromes and is capable of alleviating pain sensations and reducing the severity of blood loss in primary dysmenorrhea.

Pharmacokinetics.

Absorption. After oral administration, diclofenac is rapidly and completely absorbed. Food reduces the rate of absorption, but does not alter the total amount of active substance absorbed.

After a single oral dose of 50 mg diclofenac, maximum plasma concentration is reached approximately within 2 hours and amounts to 1.5 μg/mL (5 μmol/L). The amount of absorbed active substance is linearly proportional to the dose.

Gastric passage of the capsule is delayed when the drug is taken with or after food compared to administration before food, but the total amount of absorbed diclofenac remains unchanged. Since approximately half of the diclofenac dose undergoes metabolism during the first pass through the liver (first-pass effect), the area under the plasma concentration–time curve (AUC) after oral or rectal administration is about half of that observed after parenteral administration of an equivalent dose. No drug accumulation has been observed when the recommended dosing interval is maintained.

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

Distribution. Approximately 99.7% of diclofenac is bound to plasma proteins, primarily to albumin (99.4%). The apparent volume of distribution is calculated to be between 0.12 and 0.17 L/kg. Diclofenac penetrates into synovial fluid, where maximum concentrations are reached within 3–6 hours. Two hours after peak plasma concentration, levels of the active substance in synovial fluid exceed those in plasma and remain higher for up to 12 hours.

Biological Transformation. Diclofenac undergoes partial biotransformation via glucuronidation of the parent molecule, but primarily through single and multiple hydroxylations and methoxylations, leading to the formation of several phenolic metabolites (3'-hydroxy-, 4'-hydroxy-, 5-hydroxy-, 4',5-dihydroxy-, and 3'-hydroxy-4'-methoxy-diclofenac), most of which are subsequently converted into glucuronide conjugates. Two of these phenolic metabolites are biologically active, but significantly less so than diclofenac.

Elimination. Total systemic plasma clearance of diclofenac is 263 ± 56 mL/min (mean value ± standard deviation). The terminal elimination half-life from plasma ranges from 1 to 2 hours. Four metabolites, including two active ones, also have short elimination half-lives. The plasma elimination half-life of one metabolite, 3'-hydroxy-4'-methoxy-diclofenac, is considerably longer, but this metabolite is practically inactive.

Approximately 60% of the administered dose is excreted in urine as glucuronide conjugates of the parent compound and its metabolites, most of which are further converted into glucuronide conjugates. Less than 1% is excreted unchanged. The remainder of the dose is excreted in bile as metabolites.

Pharmacokinetics in Specific Patient Populations.

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

In patients with renal insufficiency, accumulation of unchanged active substance is not expected based on single-dose kinetics, provided the standard dosing regimen is followed. When creatinine clearance is < 10 mL/min, calculated steady-state plasma concentrations of hydroxymetabolites are approximately four times higher than in healthy individuals. However, these metabolites are excreted via bile.

In patients with chronic hepatitis or decompensated cirrhosis, the kinetics and metabolism of diclofenac 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 periarticular soft tissues;
• Acute gout attacks;
• Post-traumatic and postoperative pain syndromes associated with inflammation and edema, e.g., after dental or orthopedic procedures;
• Gynecological conditions associated with pain and inflammation, e.g., primary dysmenorrhea or adnexitis;
• Severe inflammatory conditions of ENT organs accompanied by pain, e.g., pharyngotonsillitis, otitis – as an adjunctive agent. According to general therapeutic principles, the underlying condition should be treated with basic therapy. Fever alone is not an indication for the use of this medicinal product.

Contraindications.

• Hypersensitivity to the active substance or to any other component of the drug.
• Active gastric or intestinal ulcer; gastrointestinal hemorrhage or perforation.
• History of gastrointestinal bleeding or perforation related to previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).
• Active peptic ulcer/hemorrhage or recurrent peptic ulcer/hemorrhage in 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 insufficiency (creatinine clearance < 15 ml/min/1.73 m²).
• Renal insufficiency.
• Congestive heart failure (NYHA II–IV).
• Ischemic heart disease in patients with angina or history of myocardial infarction.
• Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks.
• Peripheral arterial disease.
• Management of perioperative pain in coronary artery bypass graft (CABG) surgery (or use of cardiopulmonary bypass).
• Diclofenac sodium, like other NSAIDs, is contraindicated in patients who have experienced asthma attacks, angioedema, urticaria, or acute rhinitis 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 sodium diclofenac in capsule form and/or other doses and formulations of diclofenac.

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

Digoxin. Concomitant use of diclofenac may increase plasma digoxin concentrations. Monitoring of serum digoxin levels is recommended.

Diuretics and antihypertensive agents. Concomitant administration of diclofenac with diuretics or antihypertensive agents (e.g., beta-blockers, angiotensin-converting enzyme (ACE) inhibitors) may reduce antihypertensive effects by inhibiting the synthesis of vasodilatory prostaglandins. This combination should be used with caution, and blood pressure should be monitored periodically in elderly patients. Patients should receive adequate fluid intake, and renal function should be monitored after initiation of combined therapy and regularly thereafter, especially when diuretics and ACE inhibitors are used, due to increased risk of nephrotoxicity.

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

Anticoagulants and antiplatelet agents. Should be used with caution, as concomitant use with diclofenac increases the risk of bleeding. Although clinical studies have not shown that diclofenac affects the action of anticoagulants, there have been isolated reports of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously. Therefore, to ensure no dosage adjustments are needed, continuous monitoring of such patients is recommended. Like other NSAIDs, diclofenac at high doses may transiently inhibit platelet aggregation.

Other NSAIDs, including selective COX-2 inhibitors, and corticosteroids. Concomitant use of diclofenac with other systemic NSAIDs or corticosteroids increases 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 systemic NSAIDs, including diclofenac, and SSRIs increases the risk of gastrointestinal bleeding.

Antidiabetic agents. Clinical studies have shown that diclofenac can be used concomitantly with oral antidiabetic agents without affecting their clinical efficacy. However, isolated reports of hyperglycemia and hypoglycemia requiring dose adjustment of antidiabetic agents have been reported. Monitoring of blood glucose levels during combination therapy is recommended. Cases of metabolic acidosis have also been reported with concomitant use of diclofenac, particularly in patients with pre-existing renal impairment.

Methotrexate. Diclofenac may inhibit renal tubular clearance of methotrexate, leading to elevated methotrexate levels. Serious toxicity cases have been reported when methotrexate and NSAIDs, including diclofenac, were administered within 24 hours of each other. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine. Diclofenac, like other NSAIDs, may increase cyclosporine nephrotoxicity due to effects on renal prostaglandins. Therefore, diclofenac should be administered at lower doses than in patients not receiving cyclosporine.

Tacrolimus. Concomitant use of NSAIDs with tacrolimus increases the risk of nephrotoxicity, possibly mediated through renal anti-prostaglandin effects of NSAIDs and calcineurin inhibition.

Quinolone antibiotics. Seizures may occur in patients receiving quinolone derivatives and NSAIDs simultaneously, regardless of 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 potential for increased phenytoin effects.

Cholestyramine and colestipol. These agents may delay or reduce absorption of diclofenac. Therefore, diclofenac should be administered at least 1 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, and increase plasma glycoside levels.

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

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

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

Special precautions for use.

Careful medical monitoring is required for patients presenting symptoms indicating gastrointestinal disorders, patients with a history of gastric or intestinal ulceration, patients with ulcerative colitis or Crohn's disease, as well as patients with impaired liver function.

During prolonged use of diclofenac, as with other NSAIDs, systematic monitoring of the peripheral blood picture is recommended.

Diclofenac, like other NSAIDs, may temporarily inhibit platelet aggregation. Therefore, careful monitoring of relevant laboratory parameters is necessary for patients with coagulation disorders.

The use of NSAIDs, including diclofenac, may be associated with an increased risk of "anastomotic failure." Careful monitoring and caution are recommended in patients following surgical procedures on the gastrointestinal tract.

In accordance with general medical principles, caution is required when administering diclofenac to elderly patients, especially those who are frail or have low body weight. The lowest effective dose should be prescribed for such patients.

Alcoholic beverages should be avoided during diclofenac intake. If diclofenac is used prior to surgery, including dental procedures, the physician should be informed.

Premature discontinuation of the drug may lead to recurrence of painful symptoms.

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

Concomitant use of sodium diclofenac 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. Caution is required for elderly patients. In particular, the lowest effective dose should be used in frail elderly patients and 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.

Sodium diclofenac, like other NSAIDs, may mask signs of infection.

Sodium diclofenac capsules contain lactose. This medicinal product should not be used by patients with rare hereditary galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

If you have known intolerance to certain sugars, consult your doctor before taking this medicinal product.

Effect on the gastrointestinal tract

When using all NSAIDs, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation, which may be fatal, have been reported. These events may occur at any time during treatment, regardless of the presence or absence of warning symptoms or prior serious gastrointestinal 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.

Patients receiving diclofenac who experience symptoms indicating gastrointestinal disorders (GI) require medical supervision and special caution. The risk of GI bleeding, ulceration, or perforation increases with higher doses of diclofenac.

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 toxic effects on the GI tract, treatment should be initiated and maintained at the lowest effective doses. For such patients, as well as those requiring concomitant use of medications containing low-dose acetylsalicylic acid (ASA/aspirin) or other drugs that increase the risk of GI adverse effects, the use of combination therapy with protective agents (e.g., proton pump inhibitors or misoprostol) should be considered. Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly GI bleeding). Caution is also required for patients receiving concomitant medications that 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.

Effect on the liver

Close medical monitoring is required when sodium diclofenac is prescribed to patients with impaired liver function, as their condition may worsen. During NSAID use, including diclofenac, levels of one or more liver enzymes may increase.

During long-term treatment with sodium diclofenac, liver function and levels of liver enzymes should be monitored regularly. If liver function abnormalities persist or worsen, or if clinical symptoms indicate progressive liver disease or other manifestations (e.g., eosinophilia, rash), sodium diclofenac should be discontinued. Diseases such as hepatitis may progress without prodromal symptoms. Caution is required when sodium diclofenac is used in patients with hepatic porphyria, due to the potential for provoking an attack.

Effect on the kidneys

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, a history of hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs that significantly affect renal function, and patients with significant extracellular fluid volume depletion due to any cause, such as before or after major surgery. In such cases, monitoring of renal function is recommended. Discontinuation of therapy usually results in return to the pre-treatment state.

Effect on the skin

Serious skin reactions (some of which have been fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and generalized bullous fixed drug eruption, have very rarely been reported with diclofenac use. The highest risk for these reactions occurs early in the course of treatment, with most cases appearing within the first month of therapy. Sodium diclofenac should be discontinued at the first appearance 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 developing aseptic meningitis.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and recommendations are required for patients with a history of 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 suggest that diclofenac use, particularly at high doses (150 mg/day) and during prolonged treatment, slightly increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke).

Diclofenac is not recommended for patients with uncontrolled hypertension, mild to moderate congestive heart failure, stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Use may be considered only after careful risk-benefit assessment and at a dose not exceeding 100 mg per day.

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

Effect on hematological parameters

Complete blood count is recommended during prolonged use of this drug, as with other NSAIDs. Sodium diclofenac may temporarily inhibit platelet aggregation. Close monitoring is required for patients with coagulation 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 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 (emergency readiness) are recommended when treating such patients. This also applies to patients with allergic reactions to other substances (e.g., rash, pruritus, or urticaria).

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

Fertility in women

The use of sodium diclofenac may impair fertility in women and is not recommended for women wishing to become pregnant. For women experiencing difficulties with conception or undergoing infertility investigations, discontinuation of sodium diclofenac should be considered.

Use during pregnancy or breastfeeding.

Pregnancy.

From the 20th week of pregnancy, diclofenac use may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after starting treatment and is usually reversible upon discontinuation. During the first and second trimesters of pregnancy, sodium diclofenac may be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus, and only at the lowest effective dose, with treatment duration kept as short as possible. The drug is contraindicated during the last three months of pregnancy (due to possible inhibition of uterine contractility and premature closure of the fetal ductus arteriosus). Prenatal monitoring for oligohydramnios may be appropriate if diclofenac exposure occurred over several days starting from the 20th week of pregnancy. If oligohydramnios is detected, diclofenac use should be discontinued.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and of cardiac defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%.

The risk may increase with dose and duration of treatment. In animal studies, administration of prostaglandin synthesis inhibitors resulted in 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 defects, was observed. If sodium diclofenac is used by a woman trying to conceive or during the first trimester of pregnancy, the dose should be as low as possible and treatment duration as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may have the following effects:

on the fetus:

• cardiopulmonary toxicity (with 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 at the end of pregnancy and the newborn:

• 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, sodium diclofenac is contraindicated during the third trimester of pregnancy.

Breastfeeding.

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

Fertility in women.

Like other NSAIDs, diclofenac may negatively affect female fertility and is therefore not recommended for women planning pregnancy. For women experiencing fertility problems or undergoing infertility evaluation, discontinuation of sodium diclofenac should be considered.

Ability to affect reaction speed when driving or operating machinery.

Generally, when the drug is taken at the recommended dose and for a short-term course, no effect on reaction speed is observed. However, patients who experience visual disturbances, dizziness, vertigo, somnolence, or other central nervous system (CNS) disorders, lethargy, or fatigue during treatment with sodium diclofenac should not drive or operate machinery.

Method of Administration and Dosage

To minimize adverse effects, the drug should be used at the lowest effective dose for the shortest duration necessary, taking into account the individual treatment needs of each patient.

Capsules should be swallowed whole, without opening, with water, preferably before meals.

The recommended dose for adults is 100–150 mg per day. In cases of mild symptoms, a daily dose of 75–100 mg is usually sufficient. The daily dose should be divided into 2–3 doses.

For primary dysmenorrhea, the daily dose of sodium diclofenac should be individually adjusted, usually ranging from 50–150 mg. The initial dose may be 50–100 mg per day. If necessary, the dose may be increased during the following menstrual cycles up to the maximum dose of 200 mg per day. Treatment with sodium diclofenac capsules should be initiated at the onset of the first symptoms and continued for several days depending on the response and symptom severity.

Children (aged 6–14 years).

Capsules may be administered to children aged 6 to 14 years 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.

For children aged 14 years and older, the dose is 75–150 mg per day in 2–3 divided doses.

The daily dose of the drug should not exceed 150 mg.

Elderly patients.

Although clinically significant changes in the pharmacokinetics of the drug have not been observed in elderly patients, nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with particular caution in this population, as they are generally more susceptible to adverse reactions. In particular, 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.

Children.

Sodium diclofenac capsules may be used in children aged 6 years and older.

Overdose.

Symptoms. There is no typical clinical picture of diclofenac overdose. Symptoms that may occur include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, excitement, coma, drowsiness, tinnitus, or convulsions. In severe poisoning, acute renal failure and hepatic injury may develop.

Treatment. Management of acute poisoning with nonsteroidal anti-inflammatory drugs (NSAIDs), including diclofenac, generally involves supportive measures and symptomatic treatment of complications such as arterial hypotension, renal failure, seizures, gastrointestinal disturbances, and respiratory depression.

Specific interventions such as forced diuresis, dialysis, or hemoperfusion do not promote rapid 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. In cases of potentially life-threatening overdose, evacuation of gastric contents (induced emesis, gastric lavage) should be performed.

Adverse Reactions.

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

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

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

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

Eye disorders: optic neuritis. Visual disturbances such as blurred vision, worsening of vision, and diplopia are class effects of NSAIDs and are usually reversible upon discontinuation of the drug. The most likely mechanism of visual disturbances is inhibition of prostaglandin and related compounds synthesis, which may disrupt regulation of retinal blood flow and contribute to development of visual disturbances. If such symptoms occur during treatment with diclofenac, an ophthalmologic examination should be performed to rule out other possible causes.

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

Cardiovascular system disorders: palpitations, chest pain, heart failure, myocardial infarction, arterial hypertension, hypotension, vasculitis, Kounis syndrome.

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

Gastrointestinal disorders: nausea, vomiting, diarrhea, dyspepsia, heartburn, abdominal distension, abdominal pain, flatulence, loss of appetite, taste disturbances, anorexia, gastritis, gastrointestinal bleeding (hematemesis, hemorrhagic diarrhea, melena), gastric or intestinal ulcer (possibly with bleeding, gastrointestinal syndrome 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 dysfunction, diaphragm-like intestinal stricture, pancreatitis, gastric erosion, gastroenteropathy with malabsorption syndrome, maldigestion, polyserositis.

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; eczema, erythema, erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, alopecia, photosensitization, purpura, allergic purpura, pruritus.

Renal and urinary system disorders: acute kidney injury (acute renal failure), hematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.

Reproductive system and breast disorders: impotence.

General disorders: edema.

Diclofenac, particularly at high doses (150 mg per day) and with prolonged use, slightly increases the risk of arterial thromboembolic complications (e.g., myocardial infarction or stroke).

Shelf life.

3 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

10 capsules in a blister; 3 blisters in a carton.

Prescription status.

Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's address and location of business activity.

41 Kulikovska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.