Diclofenac-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DICLOFENAC-DARNITSA (DICLOFENAC-DARNITSA)

Composition:

Active substance: diclofenac;

1 tablet contains sodium diclofenac 25 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, maize starch, colloidal anhydrous silicon dioxide, talc, magnesium stearate; methacrylic acid copolymer dispersion, propylene glycol, talc, titanium dioxide (E 171), carmoisine (E 122).

Pharmaceutical form. Enteric-coated tablets.

Main physico-chemical properties: enteric-coated tablets of pink color, with a biconvex surface. Two layers are visible in cross-section.

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

Pharmacological Properties

Pharmacodynamics

Diclofenac-Darnytsia contains sodium diclofenac—a non-steroidal compound with pronounced anti-rheumatic, anti-inflammatory, analgesic, and antipyretic effects. The primary mechanism of action of diclofenac is considered to be the inhibition of prostaglandin biosynthesis. Prostaglandins play an important role in the pathogenesis of inflammation, pain, and fever.

In rheumatic diseases, the anti-inflammatory and analgesic properties of the medicinal product 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, and improvement in joint function.

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

In post-traumatic and postoperative inflammatory conditions, diclofenac rapidly relieves pain (both at rest and that occurring during movement), reduces inflammatory edema, and postoperative wound swelling.

Clinical studies have demonstrated a significant analgesic effect of the medicinal product in moderate to severe non-rheumatic pain. Clinical studies have also shown that diclofenac can relieve pain sensations and reduce the severity of bleeding in primary dysmenorrhea.

Diclofenac additionally exhibits a therapeutic effect during migraine attacks.

Pharmacokinetics

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

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

Transit of the tablet through the stomach is delayed when the medicinal product is taken with or after food (compared to administration before food), but the 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 approximately half that observed after parenteral administration of an equivalent dose. No drug accumulation has been observed when the recommended dosing interval is maintained.

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

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

Biological Transformation. Diclofenac undergoes biotransformation partly 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 converted into glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a lesser extent than diclofenac.

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

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

Pharmacokinetics in Various Patient Groups. 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 unlikely based on the kinetics of single-dose administration, provided the standard dosing regimen is followed. In cases of creatinine clearance < 10 mL/min, calculated steady-state plasma concentrations of hydroxymetabolites are approximately four times higher than in healthy individuals. Thus, metabolites are ultimately eliminated via bile.

In patients with chronic hepatitis or compensated 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.
• Non-articular rheumatism.
• Acute attacks of gout.
• 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 conditions of the ear, nose, and throat (ENT) organs accompanied by pain, e.g. pharyngotonsillitis, otitis. According to general therapeutic principles, the underlying condition should be treated with appropriate baseline therapy. Fever alone is not an indication for use of the medicinal product.

Contraindications.

• Hypersensitivity to the active substance or to any of the other components of the medicinal product.
• Diklofenak-Darnytsia, like other nonsteroidal anti-inflammatory drugs (NSAIDs), is contraindicated in patients who experience attacks of bronchial asthma, urticaria, acute rhinitis, nasal polyps, or other allergic symptoms in response to acetylsalicylic acid or other NSAIDs.
• Last trimester of pregnancy.
• Active peptic ulceration of the stomach or intestine; gastrointestinal hemorrhage or perforation.
• Inflammatory bowel diseases (Crohn's disease or ulcerative colitis).
• Severe hepatic insufficiency (Child-Pugh class C, cirrhosis or ascites).
• Severe renal insufficiency (creatinine clearance <30 mL/min).
• Congestive heart failure (NYHA II–IV).
• 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.
• Treatment of postoperative pain following coronary artery bypass grafting (or use of cardiopulmonary bypass).
• 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).

Interaction with other medicinal products and other forms of interaction.

The following interactions have been observed during administration of diclofenac-containing medicinal products in injectable solution and/or other dosage forms.

Lithium. 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. As with other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive agents (e.g. β-blockers, angiotensin-converting enzyme [ACE] inhibitors) may reduce their antihypertensive effect. Therefore, such combinations should be used with caution, and patients, especially elderly individuals, should be closely monitored for blood pressure.

Patients should receive adequate hydration. Renal function should also be monitored after initiation of concomitant therapy and regularly thereafter, particularly when diuretics or ACE inhibitors are used, due to increased risk of nephrotoxicity.

Medicinal products known to cause hyperkalemia. Concomitant use with potassium-containing medicinal products may lead to increased serum potassium levels, requiring continuous monitoring of patients.

Other NSAIDs and corticosteroids. Concomitant administration of diclofenac with other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal adverse reactions.

Anticoagulants and antithrombotic agents. Precautions are recommended, as concomitant use may increase the risk of bleeding. 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.

Like other nonsteroidal anti-inflammatory drugs, diclofenac at high doses may temporarily inhibit platelet aggregation.

Selective serotonin reuptake inhibitors (SSRIs). Concurrent use of systemic NSAIDs and SSRIs may increase the risk of gastrointestinal bleeding.

Antidiabetic medicinal products. Diclofenac may be used concomitantly with oral antidiabetic agents without affecting their clinical efficacy. However, isolated cases of both hypoglycemic and hyperglycemic effects have been reported, requiring dosage adjustment of antidiabetic agents during diclofenac treatment. Such conditions require monitoring of blood glucose levels as a precaution during concomitant therapy.

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

Medicinal products that induce drug-metabolizing enzymes. Medicinal products that induce enzymes, e.g. rifampicin, carbamazepine, phenytoin, St. John’s wort (Hypericum perforatum), may theoretically reduce plasma concentrations of diclofenac.

Metotrexate. Caution is recommended when administering NSAIDs less than 24 hours before or after metotrexate treatment, as this may increase blood concentrations of metotrexate and enhance its toxicity.

Cyclosporine and tacrolimus. Diclofenac, like other NSAIDs, may increase nephrotoxicity of cyclosporine by affecting renal prostaglandins. A similar risk exists during treatment with tacrolimus. Therefore, lower doses should be used compared to patients not receiving cyclosporine.

Quinolone antibiotics. Isolated reports have described seizures possibly associated with concomitant use of quinolones and NSAIDs.

Potent CYP2C9 inhibitors. Diclofenac should be used with caution concomitantly with CYP2C9 inhibitors (such as sulfinpyrazone and voriconazole), which may lead to a significant increase in plasma peak concentration and effect of diclofenac due to inhibition of diclofenac metabolism.

Phenytoin. When phenytoin is used concomitantly with diclofenac, monitoring of plasma phenytoin concentrations is recommended due to possible increased phenytoin effects.

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

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

Special precautions for use.

General warnings regarding systemic nonsteroidal anti-inflammatory drugs (NSAIDs).

To reduce the risk of gastrointestinal ulceration, bleeding, or perforation—which may occur at any time during NSAID therapy regardless of the drug's selectivity for COX-2 and even in the absence of warning symptoms or predisposing risk factors—the lowest effective dose should be used for the shortest possible duration.

This medicinal product should be administered to patients with gastrointestinal disorders, impaired liver function, or a history of gastric or intestinal ulcer only when absolutely indicated and under close medical supervision.

An increased risk of thrombotic cardiovascular and cerebrovascular complications has been reported with the use of certain selective COX-2 inhibitors. It is currently not definitively known whether this risk is directly correlated with the COX-1/COX-2 selectivity of individual NSAIDs.

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking) only after careful clinical evaluation. Since the cardiovascular risks associated with diclofenac may increase with higher doses and longer treatment duration, it should be used for the shortest possible time and at the lowest effective dose. The patient’s need for diclofenac therapy and response to treatment should be periodically reviewed. Use with caution in patients aged 65 years and older.

The effect of NSAIDs on the kidneys may lead to fluid retention and edema and/or arterial hypertension; therefore, diclofenac should be used with caution in patients with cardiac disorders or other conditions associated with a predisposition to fluid retention. Exercise caution when administering the medicinal product to patients who are concurrently using diuretics or angiotensin-converting enzyme (ACE) inhibitors or who have an increased risk of hypovolemia.

Gastrointestinal bleeding, ulcers, or perforation have been reported during treatment with NSAIDs, including diclofenac, and may be life-threatening. These events may occur at any time during therapy, with or without warning symptoms or a history of severe gastrointestinal disorders. In elderly patients, such complications usually have more serious consequences. If gastrointestinal bleeding or ulceration occurs in patients receiving Diclofenac-Darnytsia, the medicinal product should be discontinued immediately.

Very rarely, severe skin reactions (in some cases fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with NSAID use. The risk of such reactions is highest at the beginning of treatment, and these reactions typically occur within the first month of therapy. Diclofenac-Darnytsia 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 disorders.

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

As with all analgesics, prolonged use of the medicinal product for headache treatment may lead to improvement or worsening of symptoms (medication-overuse headache). If headache develops due to excessive analgesic use, the dose of analgesics should not be increased; in such cases, treatment should be discontinued. Medication-overuse headache should be suspected in patients with frequent or daily headache episodes occurring despite (or because of) regular analgesic use.

As with other NSAIDs, allergic reactions (including anaphylactic/anaphylactoid reactions) may rarely occur, even without prior exposure to diclofenac. Like other NSAIDs, Diclofenac-Darnytsia, due to its pharmacodynamic properties, may mask signs and symptoms of infection.

Warnings.

General.

Concomitant use of Diclofenac-Darnytsia and other systemically acting NSAIDs, including selective COX-2 inhibitors, should not be undertaken, as there is no evidence of synergistic benefit and the risk of additional adverse effects increases.

The medicinal product should be used with caution in elderly patients. In particular, the lowest effective doses are recommended for physically frail elderly patients or those with body weight below normal.

History of bronchial asthma.

In patients with bronchial asthma, seasonal allergic rhinitis, mucosal swelling of the nasal passages (e.g., nasal polyps), chronic obstructive pulmonary disease (COPD), or chronic respiratory tract infections (especially with symptoms resembling allergic rhinitis), adverse effects such as bronchial asthma exacerbation (so-called analgesic intolerance or analgesic-induced asthma), Quincke’s edema, or urticaria occur more frequently during NSAID use than in other patients. Therefore, special precautionary measures (readiness for emergency intervention) are required for these patients. The above also applies to patients with allergic manifestations (e.g., rash, pruritus, urticaria) upon use of other medicinal products.

Gastrointestinal (GI) tract effects.

As with other NSAIDs, careful medical supervision and special caution are required when prescribing the medicinal product to patients with symptoms indicating gastrointestinal disorders or a history of peptic ulcer, gastrointestinal bleeding, or perforation of the stomach or intestine. The risk of gastrointestinal bleeding increases with higher NSAID doses and in patients with a history of peptic ulcer, especially if complicated (bleeding or perforation), and in elderly patients. To reduce the risk of GI toxicity in such patients, treatment should be initiated and maintained at the lowest effective doses. For these patients, as well as for those requiring concomitant use of medicinal products containing acetylsalicylic acid or other agents increasing the risk of 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 GI toxicity, particularly elderly patients, should inform their physician about any unusual abdominal symptoms (especially gastrointestinal bleeding). Use with caution in patients receiving concomitant medications that may increase the risk of ulceration or bleeding (systemic corticosteroids, anticoagulants, antiplatelet agents, or selective serotonin reuptake inhibitors).

Hepatic effects.

Patients with hepatic impairment should be under continuous medical supervision, as their condition may worsen.

As with other NSAIDs, levels of one or more liver enzymes may increase. This has been observed very frequently with diclofenac use but rarely accompanied by clinical symptoms. In most cases, enzyme levels rose to borderline values. Elevations in liver enzyme levels were associated with clinical signs of liver injury. Increases in enzyme levels were usually reversible upon discontinuation of the medicinal product.

It should be noted that Diclofenac-Darnytsia is recommended only for short-term treatment (no more than 2 weeks). In cases of prolonged diclofenac use, regular monitoring of liver function is advised as a precaution. The use of this medicinal product should be discontinued if liver function impairment or deterioration occurs, if clinical signs or symptoms suggest liver disease development, or if other symptoms such as eosinophilia or rash appear. Hepatitis may occur without prodromal symptoms.

In addition to elevated liver enzyme levels, rare but serious hepatic reactions have been reported, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of which have been fatal.

Use diclofenac with caution in patients with hepatic porphyria due to the potential risk of provoking an attack.

Renal effects.

Prolonged use of high doses of NSAIDs often leads to edema and arterial hypertension.

Particular caution is required in patients with cardiac or renal impairment, a history of arterial hypertension, elderly patients, patients concurrently using diuretics or medicinal products significantly affecting renal function, and patients with marked reduction in extracellular fluid volume (e.g., pre-/post-surgery). Renal function should be monitored when prescribing Diclofenac-Darnytsia in such cases. Patient status usually normalizes after therapy discontinuation.

Hematological effects.

Diclofenac-Darnytsia is recommended only for short-term treatment. If this medicinal product is prescribed for a longer duration, regular monitoring of the hemogram is recommended, as with other NSAIDs.

Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation; therefore, patients with coagulation disorders should be carefully monitored.

Diclofenac-Darnytsia contains lactose and therefore should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Alcohol should not be consumed during treatment.

Use during pregnancy or breastfeeding.

The use of diclofenac in pregnant women has not been studied. Animal studies have not shown any direct or indirect toxic effects on pregnancy, embryonal development, fetal development, parturition, or postnatal development.

During the first and second trimesters of pregnancy, Diclofenac-Darnytsia enteric-coated tablets should be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus and only at the lowest effective dose. As with other NSAIDs, the medicinal product is contraindicated in the third trimester of pregnancy (due to possible inhibition of uterine contractility and premature closure of the fetal ductus arteriosus).

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonal/fetal development. Epidemiological data indicate an increased risk of miscarriage and/or congenital heart defects and gastroschisis following prostaglandin synthesis inhibitor use 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. Animal studies have shown that prostaglandin synthesis inhibitors increase pre- and post-implantation loss and embryonal/fetal mortality.

Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed. Starting from the 20th week of pregnancy, diclofenac use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after treatment initiation and is usually reversible upon discontinuation of therapy. If the medicinal product is used by a woman planning pregnancy or during the first trimester, the dose should be as low as possible and the treatment duration as short as possible. Oligohydramnios monitoring should be considered after diclofenac exposure for several days starting from the 20th week of pregnancy. Diclofenac use should be discontinued if oligohydramnios is detected.

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

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

On the mother and newborn, especially near 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, Diclofenac-Darnytsia enteric-coated tablets are contraindicated during the third trimester of pregnancy.

As with other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, Diclofenac-Darnytsia enteric-coated tablets should not be used by breastfeeding women. If treatment is absolutely necessary, breastfeeding should be discontinued.

As with other NSAIDs, Diclofenac-Darnytsia enteric-coated tablets may negatively affect female fertility; therefore, the medicinal product is not recommended for women planning pregnancy. In women experiencing conception difficulties or undergoing infertility investigations, discontinuation of the medicinal product should be considered.

Ability to influence reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness, vertigo, somnolence, or other central nervous system disorders during treatment with the medicinal product should refrain from driving or operating machinery.

Method of Administration and Dosage.

The dosage regimen should be individually determined based on indications and severity of the condition.

Diclofenac-Darnytsia is taken orally; tablets should be swallowed whole, without chewing, after meals, with sufficient amount of water.

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

Adults.

The initial dose is usually 100–150 mg per day. For mild symptoms, as well as for long-term therapy, a daily dose of 75–100 mg is sufficient. The daily dose should be divided into 2–3 administrations. To prevent nocturnal pain or morning stiffness, treatment with the drug may be supplemented by administration of rectal suppositories containing diclofenac before bedtime. The daily dose of the drug must not exceed 150 mg.

For 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 up to the maximum dose of 200 mg per day. Treatment should begin after the onset of the first pain symptoms and continued for several days depending on the symptom regression dynamics.

Children.

Tablets of 25 mg may be administered to children aged 8 years (with body weight not less than 25 kg) up to 18 years of age, as prescribed by a physician, 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 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.

In the treatment of juvenile rheumatoid arthritis, the daily dose may be increased up to 3 mg/kg—the maximum daily dose.

The maximum daily dose of 150 mg must not be exceeded.

Elderly patients.

Although the pharmacokinetics of the drug are not significantly altered in elderly patients to a clinically relevant extent, nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with particular caution in this population, who are generally more susceptible to adverse reactions. Particularly for frail elderly patients or those with low body weight, the lowest effective doses are recommended. Patients should also be monitored for gastrointestinal bleeding during NSAID therapy.

Children.

Diclofenac-Darnytsia, enteric-coated tablets, 25 mg, can be used in children aged 8 years and older (with body weight not less than 25 kg).

Overdose.

Symptoms. There is no typical clinical picture associated with diclofenac overdose. Overdose may cause symptoms such as headache, vomiting, epigastric pain and gastrointestinal bleeding, diarrhea, dizziness, disorientation, excitement, coma, drowsiness, tinnitus, or seizures. In cases of severe poisoning, acute renal failure and hepatic injury may occur.

Treatment. Management of acute poisoning primarily consists of supportive measures and symptomatic treatment. Supportive care and symptomatic therapy are required to manage complications such as hypotension, renal failure, seizures, gastrointestinal disturbances, and respiratory depression.

Specific interventions such as forced diuresis, dialysis, or hemoperfusion cannot reliably eliminate NSAIDs due to their high plasma protein binding and extensive metabolism. After ingestion of potentially toxic doses, activated charcoal may be administered; after ingestion of potentially life-threatening doses, gastric decontamination (e.g., induced emesis, gastric lavage) should be performed.

Adverse reactions.

The frequency category of adverse reactions, starting from the most frequent, is defined as follows: very common (>1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

The adverse effects listed below include events reported during short-term or long-term use of the medicinal product.

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

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

Psychiatric disorders: very rare – confusion, depression, insomnia, irritability, nightmares, psychiatric disturbances.

Nervous system disorders: common – headache, dizziness; rare – somnolence, fatigue; very rare – paresthesia, memory impairment, convulsions, restlessness, tremor, aseptic meningitis, taste disturbances, stroke; frequency not known – confusion, hallucinations, sensory disturbances, malaise.

Eye disorders: very rare – visual disturbances, blurred vision, diplopia; frequency not known – optic neuritis.

Ear and labyrinth disorders: common – vertigo; very rare – tinnitus, hearing disturbances.

Cardiac disorders: very rare – palpitations, chest pain, heart failure, myocardial infarction, arterial hypertension, arterial hypotension, vasculitis.

Respiratory, thoracic and mediastinal disorders: rare – asthma (including dyspnea); very rare – bronchospasm, pneumonitis.

Gastrointestinal disorders: common – nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia; rare – gastritis, gastrointestinal bleeding (hematemesis, melena, bloody diarrhea), gastrointestinal ulcers which may be complicated by bleeding or perforation (sometimes fatal, especially in elderly patients); very rare – colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, esophageal disorders, diaphragm-like intestinal stricture, pancreatitis.

Hepatobiliary disorders: common – increased transaminase levels; rare – hepatitis, jaundice, hepatic disorders; very rare – fulminant hepatitis, hepatic necrosis, liver failure.

Skin and subcutaneous tissue disorders: common – rash; rare – urticaria; very rare – bullous rash, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), exfoliative dermatitis, alopecia, photosensitivity reactions, purpura (including allergic purpura), pruritus.

Renal and urinary disorders: very rare – acute renal failure, hematuria, proteinuria, interstitial nephritis, nephrotic syndrome, renal papillary necrosis.

General disorders: rare – edema.

Reproductive system and breast disorders: very rare – impotence.

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

Shelf life.

3 years.

Storage conditions.

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

Packaging.

10 tablets in a blister pack; 3 blister packs in a carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13 Boryspylska Street, Kyiv, 02093, Ukraine.