Raptin retard

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RAPTEN RETARD (RAPTEN RETARD)

Composition:

Active substance: diclofenac;

1 tablet contains: sodium diclofenac 100 mg;

Excipients: sucrose, cetyl alcohol, magnesium stearate, talc, povidone K-25, colloidal anhydrous silicon dioxide;

Coating: hypromellose, talc, titanium dioxide (E 171), macrogol 6000, polysorbate 80, sunset yellow (E 110), cochineal red (E 124), brown dye (sunset yellow (E 110), azorubine (E 122), patent blue V (E 151)).

Pharmaceutical form. Prolonged-release film-coated tablets.

Main physicochemical properties: pink-colored, round, biconvex, film-coated tablets.

Pharmacotherapeutic group. Drugs affecting the musculoskeletal system. Nonsteroidal anti-inflammatory drugs. Acetic acid derivatives and related compounds. ATC code M01AB05.

Pharmacological Properties

Pharmacodynamics

Diclofenac sodium is a non-steroidal agent with anti-rheumatic, anti-inflammatory, analgesic, and antipyretic effects. The main mechanism of action of diclofenac involves inhibition of prostaglandin biosynthesis through inhibitory effects on cyclooxygenase isoenzymes: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Prostaglandins play a key role in the development of inflammation, pain, and fever. In vitro, diclofenac sodium does not inhibit proteoglycan biosynthesis in cartilage tissue at concentrations equivalent to those achieved in humans.

The anti-inflammatory and analgesic effects of diclofenac in rheumatic diseases are manifested by significant reduction of pain at rest and during movement, morning stiffness, general swelling, and improvement in mobility. Diclofenac rapidly relieves spontaneous pain and pain during movement, reduces inflammatory swelling and post-traumatic or postoperative edema. Diclofenac also provides analgesic effects in moderate to severe non-rheumatic pain, in primary dysmenorrhea, and shortens the duration of bleeding.

Rapten Retard has been specifically designed for patients whose clinical condition requires a daily dose of diclofenac of 100 mg. A single daily dose is adequate for long-term treatment, as it improves patient compliance and reduces the risk of dosing errors during dose titration.

Pharmacokinetics

When diclofenac is administered as prolonged-release tablets, the amount of active substance released and absorbed is the same as when diclofenac is administered as film-coated tablets. Maximum plasma concentrations are reached approximately 4 hours after administration and amount to 0.508 ± 0.185 µg/mL. Due to the slow release of the substance, plasma concentrations 24 hours after administration reach values of 13 ng/mL. Food does not affect the absorption of the drug.

The systemic bioavailability of diclofenac in the form of tablets with prolonged release of the active substance is approximately 82% of the bioavailability observed with film-coated diclofenac tablets. Due to the slow release of the active substance, maximum plasma concentrations are lower than those achieved after administration of an equivalent dose in film-coated tablets. Pharmacokinetic parameters do not change after repeated administration. No accumulation of the drug occurs when recommended doses and dosing intervals are followed. The average plasma concentration of diclofenac in prolonged-release tablets is approximately 22 ng/mL.

Diclofenac is reversibly and extensively bound to plasma proteins (99.7%), primarily to albumin (99.4%). It penetrates into synovial fluid, reaching maximum concentrations 2–4 hours after maximum plasma concentrations are achieved. The half-life in synovial fluid is 3–6 hours. Two hours after maximum plasma concentrations are reached, concentrations of the active substance in synovial fluid become higher than in plasma and remain elevated for up to 12 hours.

Biotransformation of the drug occurs partially via glucuronidation of the parent molecule and mainly via hydroxylation and methoxylation, resulting in phenolic metabolites, most of which are converted into glucuronic acid conjugates. Two phenolic metabolites are active, although to a considerably lesser extent than diclofenac.

Total systemic clearance of diclofenac in plasma is 263 ± 56 mL/min. The terminal elimination half-life in plasma is 1–2 hours. Four metabolites, including both active ones, also exhibit a short terminal elimination half-life in plasma of 1–3 hours. Approximately 60% of the administered dose is excreted in urine as glucuronide conjugates of the parent molecule and its metabolites, which are also predominantly converted into glucuronide conjugates. Less than 1% is excreted unchanged. The remainder of the administered dose is excreted via the liver and biliary tract as metabolites in feces.

Pharmacokinetics in specific patient populations. The influence of patient age on absorption, metabolism, and elimination of the drug has not been established.

In patients with impaired renal function receiving therapeutic doses, no accumulation of unchanged active substance was observed. In patients with creatinine clearance below 10 mL/min, calculated steady-state plasma concentrations of hydroxylated metabolites were approximately four times higher than in healthy subjects. However, ultimately, all metabolites were excreted via bile.

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

Clinical characteristics.

Indications

Relief of pain and reduction of inflammation of varying degrees in various conditions, including:

Joint disorders: rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, acute gout attacks;

• Acute musculoskeletal disorders such as periartitis (e.g., periarthritis of the shoulder and scapula), tendinitis, tenosynovitis, bursitis;
• Other pathological conditions caused by trauma, including fractures, low back pain, sprains, dislocations, orthopedic, dental, and other minor surgical procedures.

Contraindications

• Hypersensitivity to the active substance or to any other component of the medicinal product.
• Diclofenac, like other nonsteroidal anti-inflammatory drugs (NSAIDs), is contraindicated in patients who have experienced attacks of bronchial asthma, angioneurotic edema, urticaria, or acute rhinitis, nasal polyps, or other allergic symptoms in response to the use of ibuprofen, acetylsalicylic acid, or other NSAIDs.
• Active peptic ulcer of the stomach or intestine; gastrointestinal bleeding or perforation; history of gastrointestinal bleeding or perforation associated with previous NSAID therapy; active or recurrent peptic ulcer of the stomach or intestine in the patient's history.
• Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis).
• Hepatic failure.
• Renal failure.
• Congestive heart failure (functional class II–IV according to NYHA — New York Heart Association criteria).
• Ischemic heart disease in patients with angina pectoris or history of myocardial infarction.
• Cerebrovascular diseases in patients with a history of stroke or transient ischemic attacks.
• Peripheral arterial disease.
• Should not be used for the treatment of perioperative pain associated with coronary artery bypass grafting (or when using a cardiopulmonary bypass machine).
• Third trimester of pregnancy.
• Use of Rapten Retard in children and adolescents (under 18 years of age) is contraindicated due to the high content of the active substance.

Interaction with other medicinal products and other forms of interaction

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

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

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

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of Rapten Retard may reduce the antihypertensive effect of diuretics or antihypertensive agents (e.g., beta-blockers, angiotensin-converting enzyme [ACE] inhibitors) by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, such combinations should be used with caution, and blood pressure should be monitored regularly, especially in elderly patients. Adequate hydration should be ensured, and renal function should be assessed at the start of combination therapy and monitored regularly thereafter, particularly due to the increased risk of nephrotoxicity associated with concomitant use of diuretics and ACE inhibitors.

Anticoagulants and antithrombotic agents. Should be prescribed with caution, as concomitant use increases the risk of bleeding.

Although clinical studies have not demonstrated that diclofenac affects the efficacy of anticoagulants, there are reports of an increased risk of bleeding in patients receiving diclofenac and anticoagulants concomitantly. Therefore, careful monitoring of such patients is recommended, and dosage adjustment of anticoagulants may be necessary. Like other NSAIDs, high-dose diclofenac may reversibly inhibit platelet aggregation.

Other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors and corticosteroids. Concomitant use of diclofenac and other systemic NSAIDs or corticosteroids increases the risk of gastrointestinal bleeding or ulceration. Concomitant use of two or more NSAIDs should be avoided. Concomitant use of diclofenac and corticosteroids may increase the frequency of adverse reactions.

Antidiabetic agents. Clinical studies have shown that diclofenac can be co-administered with oral antidiabetic agents without affecting their clinical efficacy. However, isolated reports of both hypoglycemic and hyperglycemic reactions following diclofenac use have been reported, requiring dose adjustment of antidiabetic agents. Therefore, monitoring of blood glucose levels is recommended as a precaution during combination therapy.

Methotrexate. Diclofenac may inhibit tubular renal clearance of methotrexate, leading to elevated methotrexate levels. NSAIDs, including diclofenac, should be used with caution when administered less than 24 hours before methotrexate therapy, as methotrexate blood levels may increase and its toxicity may be enhanced. Cases of severe toxicity have been reported when methotrexate and NSAIDs, including diclofenac, were administered within less than 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 enhance the nephrotoxicity of cyclosporine by affecting renal prostaglandins. Therefore, the drug should be administered at lower doses in patients receiving cyclosporine compared to those not receiving cyclosporine.

Tacrolimus. Concomitant use of NSAIDs with tacrolimus increases the risk of nephrotoxicity, which may be mediated through inhibition of renal prostaglandins by both the NSAID and the calcineurin inhibitor.

Quinolone antibiotics. The interaction between quinolone antibiotics and NSAIDs may lead to seizures. This may occur both in patients with epilepsy or a history of seizures and in those without such history. Therefore, quinolone antibiotics should be used with caution in patients already receiving NSAIDs.

Phenytoin. When phenytoin is used concomitantly with diclofenac, monitoring of plasma phenytoin concentrations is recommended due to the expected increase in phenytoin exposure.

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

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

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

Strong CYP2C9 inhibitors. Diclofenac should be prescribed with caution concomitantly with strong CYP2C9 inhibitors (e.g., sulfaphenazole, voriconazole), which may lead to a significant increase in maximum plasma concentration and exposure to diclofenac due to inhibition of its metabolism.

Selective serotonin reuptake inhibitors (SSRIs).

Concomitant use of NSAIDs and SSRIs increases the risk of gastrointestinal bleeding.

Medicinal products that may cause hyperkalemia.

Concomitant use of potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels, which should be monitored.

Special precautions for use.

Placebo-controlled studies have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications associated with the use of certain selective COX-1/COX-2 inhibitors. Currently, there are no available data on long-term treatment with the maximum dose of diclofenac; therefore, a similar increased risk cannot be excluded. Until such data become available, careful assessment of the risk-benefit ratio is required when 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). Therefore, the lowest effective dose should be used for the shortest duration possible.

Concomitant use of the medicinal product Rapten Retard and systemic nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, should be avoided due to the lack of evidence for synergistic effects and the potential for additive adverse effects.

Treatment should be prescribed with caution in elderly patients according to the recommendations for this patient group. In particular, the use of the minimum effective dose is recommended for frail elderly patients and those with low body weight.

Rarely, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur during the use of NSAIDs, including diclofenac, even in the absence of prior exposure to the drug. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction. Symptoms of such reactions may include chest pain associated with an allergic reaction to diclofenac.

Like other NSAIDs, diclofenac, due to its pharmacodynamic properties, may mask signs and symptoms of infection.

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

Rapten Retard tablets contain sucrose. Therefore, they are not recommended for patients with hereditary fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.

Due to the presence of sucrose, the medicinal product should be used with caution in patients with diabetes mellitus.

Gastrointestinal (GI) effects.

NSAIDs, including diclofenac, are associated with an increased risk of gastrointestinal anastomotic failure. Close medical monitoring and caution are recommended when using diclofenac after gastrointestinal surgery.

Gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation, which may be fatal, have been reported during treatment with NSAIDs, including diclofenac, at any time during therapy, regardless of the presence or absence of warning symptoms or a history of serious gastrointestinal events. In elderly patients, such complications usually have more serious consequences. If gastrointestinal bleeding or ulceration occurs, diclofenac should be discontinued.

When prescribing diclofenac to patients with symptoms indicating gastrointestinal disorders or with suspected ulcer, gastrointestinal bleeding, or perforation in their history, careful medical monitoring and special caution are required. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher doses of NSAIDs, including diclofenac, and in patients with a history of peptic ulcer, particularly complicated by bleeding or perforation.

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 gastrointestinal toxicity in patients with a history of peptic ulcer, particularly complicated by bleeding or perforation, and in elderly patients, the lowest effective dose should be prescribed.

For such patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid (ASA)/aspirin or other drugs that increase gastrointestinal risk, consideration should be given to combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors).

Patients with a history of gastrointestinal toxicity, especially elderly patients, require monitoring for unusual abdominal symptoms (particularly gastrointestinal bleeding).

Caution is required in patients receiving concomitant therapy with drugs that increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents such as ASA.

Hepatic effects. Close medical monitoring is required if Rapten Retard is prescribed to patients with impaired liver function, as their condition may worsen.

During the use of all NSAIDs, including diclofenac, the levels of one or more liver enzymes may increase. Regular monitoring of liver function is recommended as a precaution during long-term diclofenac therapy.

If liver function tests do not improve or worsen, clinical symptoms of liver disease appear, or other manifestations occur (e.g., eosinophilia, rash), diclofenac should be discontinued.

Hepatitis may develop during diclofenac use without prodromal symptoms.

Caution is required when using diclofenac in patients with hepatic porphyria, as it may trigger an acute attack.

Renal effects. Since fluid retention and edema have been observed during the use of NSAIDs, including diclofenac, special caution is required when treating patients with impaired cardiac or renal function, a history of arterial hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs that may significantly affect renal function, and patients with significant reduction in extracellular fluid volume due to any cause, such as before or after major surgery. In such cases, monitoring of renal function is recommended during diclofenac use. After discontinuation of therapy, the condition of patients usually returns to the pre-treatment state.

Skin effects. Serious skin reactions, some of which are fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely during NSAID use. The highest risk of these reactions occurs at the beginning of therapy, usually within the first month of treatment. The use of Rapten Retard should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity.

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

Cardiovascular and cerebrovascular effects. Patients with hypertension and/or mild to moderate congestive heart failure in their history require appropriate medical monitoring and consultation, as fluid retention and edema have been observed during NSAID use, including diclofenac.

Results of clinical studies and epidemiological data indicate that the use of diclofenac, particularly at high doses (150 mg per day) and during long-term treatment, slightly increases the risk of arterial thrombosis (myocardial infarction or stroke).

Diclofenac should be prescribed to patients with uncontrolled hypertension, congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful consideration. This also applies to long-term treatment of patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).

Hematological effects. During long-term diclofenac therapy, as with other NSAIDs, periodic blood tests to determine the count of formed elements are recommended.

Rapten Retard may reversibly inhibit platelet aggregation. Patients with coagulation disorders, hemorrhagic diathesis, or hematological abnormalities require careful monitoring.

Use in patients with asthma. In patients with asthma, seasonal allergic rhinitis, nasal mucosal edema (i.e., nasal polyps), chronic obstructive lung diseases, or chronic respiratory tract infections (especially if associated with symptoms resembling allergic rhinitis), reactions to NSAIDs resembling asthma exacerbations (so-called aspirin-induced asthma with analgesic intolerance), Quincke's edema, and urticaria occur more frequently than in other patients. In such cases, special precautions (readiness for emergency intervention) are recommended. This also applies to patients who have allergic reactions (e.g., rash, pruritus, or urticaria) to other substances.

Like other agents that inhibit prostaglandin synthetase activity, diclofenac sodium may cause bronchospasm when administered to patients with current or past history of asthma.

Female fertility. Rapten Retard may affect female fertility and therefore is not recommended for women planning pregnancy. Consideration should be given to discontinuing diclofenac in women who are unable to conceive and in women undergoing infertility evaluation.

Use during pregnancy or breastfeeding.

From the 20th week of pregnancy, the use of Rapten Retard may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after the start of treatment and is usually reversible upon discontinuation of therapy. During the first and second trimesters of pregnancy, Rapten Retard may be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus, at the minimum effective dose, and for the shortest possible duration. Prenatal monitoring for oligohydramnios may be appropriate after taking the medicinal product Rapten Retard for several days starting from the 20th week of pregnancy. If oligohydramnios is detected, the medicinal product should be discontinued. Like other NSAIDs, Rapten Retard is contraindicated in the third trimester of pregnancy (possible inhibition of uterine contractility and premature closure of the ductus arteriosus in the fetus).

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

An increased risk with higher doses and longer duration of therapy cannot be excluded. Animal studies have shown that administration of prostaglandin synthesis inhibitors leads to increased pre- and post-implantation loss and embryonic/fetal mortality.

Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the frequency of various developmental abnormalities, including cardiovascular defects, increased. If diclofenac is used in women wishing to become pregnant or during the first trimester of pregnancy, 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:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction (see above);
• impaired kidney function, which may progress to renal failure with oligohydramnios;

the mother and 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, diclofenac is contraindicated during the third trimester of pregnancy.

Lactation period. Like other NSAIDs, diclofenac passes into breast milk in small amounts. Thus, to avoid undesirable effects on the infant, diclofenac should not be used during breastfeeding.

Fertility. Like other NSAIDs, diclofenac may affect female fertility. The medicinal product is not recommended for women planning pregnancy. Women experiencing difficulties with conception or those who have undergone infertility evaluation should discontinue the use of the drug.

Ability to influence reaction speed when driving vehicles or operating machinery.

If dizziness, somnolence, or other central nervous system disturbances, including visual disturbances, occur during treatment with Rapten Retard, driving vehicles or operating machinery is not recommended.

Dosage and Administration.

For adults, the recommended dose is 1 tablet (100 mg) once daily. Tablets should be taken before meals, without chewing, with a glass of water. If symptoms intensify at night or in the morning, Raptan Retard 100 mg tablets are recommended to be taken in the evening.

In general, the dose should be individually adjusted. The drug should be used at the lowest effective dose for the shortest duration necessary, taking into account the individual treatment goals for each patient.

Maximum daily dose – 200 mg.

Dosing in elderly patients.

Although the pharmacokinetic characteristics of diclofenac do not differ significantly in elderly patients, all nonsteroidal anti-inflammatory drugs (NSAIDs) should be prescribed with particular caution in this patient group due to their increased susceptibility to adverse reactions. The lowest effective dose of diclofenac is recommended for elderly and debilitated patients, as well as for those with low body weight. Prolonged use of NSAIDs is not recommended in the elderly. Regular monitoring of the patient's condition during therapy is advised. If no clinical improvement is observed or if adverse reactions occur, the drug should be discontinued.

Children.

Not recommended for use in pediatric practice.

Overdose.

Symptoms. There is no typical clinical picture specific to diclofenac overdose. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, excitement, coma, drowsiness, tinnitus, and convulsions. Acute renal failure and liver damage are possible in cases of severe intoxication.

Treatment. Management of acute poisoning with NSAIDs, including diclofenac, consists of supportive and symptomatic therapy. This includes treatment of arterial hypotension, renal failure, convulsions, 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 the high degree of protein binding and extensive metabolism of these drugs. Activated charcoal may be administered after potentially toxic doses, and gastric decontamination (e.g., induction of emesis, gastric lavage) may be performed after potentially life-threatening doses.

Adverse Reactions

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

Immune system disorders. Hypersensitivity reactions, including asthma, systemic anaphylactic and anaphylactoid reactions (including hypotension and shock); angioneurotic edema (including facial swelling).

Psychiatric disorders. Disorientation, depression, insomnia, nightmares, irritability, psychotic disorders; confusion, hallucinations.

Nervous system disorders. Headache, dizziness; somnolence; paresthesia, memory impairment, convulsions, restlessness, anxiety and fear, hand tremor, aseptic meningitis, sensory disturbances, taste disturbances, cerebrovascular disorders; optic neuritis.

Eye disorders. Vision disturbances (diplopia, blurred vision).

Ear and labyrinth disorders. Dizziness; tinnitus, hearing disturbances.

Cardiac and vascular disorders. Palpitations, chest pain, heart failure, myocardial infarction; Kounis syndrome; arterial hypertension, vasculitis; arterial hypotension; impotence.

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

Gastrointestinal disorders. Nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence and anorexia; gastritis, gastrointestinal bleeding, hematemesis, melena (tarry stools), gastric and intestinal ulcers with or without bleeding or perforation (sometimes fatal, especially in elderly patients); colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis, glossitis, esophageal disorders, diaphragm-like intestinal strictures, pancreatitis; stomatitis (including ulcerative stomatitis).

Hepatobiliary disorders. Increased transaminase levels; hepatitis, jaundice, liver disorders; fulminant (rapidly progressive) hepatitis; liver necrosis, hepatic failure.

Skin and subcutaneous tissue disorders. Rash, urticaria; bullous eruptions, eczema, erythema (redness), polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, alopecia, photosensitivity reactions, purpura, allergic purpura, pruritus.

Renal and urinary disorders. Acute renal failure, hematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.

General disorders. Edema; fatigue; malaise.

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

Shelf life.

5 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging to protect from light and moisture.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

«HEMOFARM» AD.

Manufacturer’s address and place of business.

Beogradski put bb, 26300, Vrsac, Republic of Serbia.