DOLAREN

INSTRUCTION for medical use of medicinal product DOLAREN® (Dolaren®)

Composition:
Active substances: diclofenac sodium, paracetamol.
1 tablet contains: diclofenac sodium 50 mg, paracetamol 500 mg.
Excipients: maize starch, talc, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium croscarmellose, colouring agent Sunset Yellow FCF (E 110).

Dosage form. Tablets.

Main physicochemical properties:
Round, biconvex, two-layered, two-coloured tablets (white on one side, orange on the other). White and/or dark orange specks may be present on the tablet surface.

Pharmacotherapeutic group. Analgesics and antipyretics. Paracetamol, combinations without psychotropic agents.
ATC code: N02BE51.

Pharmacological properties.

Pharmacodynamics.
Dolaren® is a combined preparation exerting pronounced anti-inflammatory, analgesic, and antipyretic effects. The pharmacological activity of the drug is due to the properties of diclofenac and paracetamol contained in its composition. Diclofenac sodium exerts pronounced anti-inflammatory and analgesic effects, as well as moderate antipyretic action. Paracetamol demonstrates pronounced analgesic and mild antipyretic and anti-inflammatory effects. The mechanism of action is associated with inhibition of prostaglandin synthesis.

Pharmacokinetics.
After oral administration, the drug is rapidly and completely absorbed. Food does not affect the absorption of the drug. Plasma concentrations of active substances show a linear dependence on the dose; maximum levels are reached within 60–90 minutes after administration. Diclofenac binding to plasma proteins (mainly albumin) reaches 99.7%. The expected volume of distribution is 0.12–0.17 L/kg. Diclofenac penetrates into synovial fluid, where its maximum concentration is achieved 2–4 hours later than in plasma. The elimination half-life from synovial fluid is 3–6 hours. Diclofenac metabolism occurs via glucuronidation of the unchanged molecule and methoxylation, leading to the formation of several phenolic metabolites, whose biological activity is significantly lower than that of the parent substance. The total systemic plasma clearance of diclofenac is approximately 300 mL/min. The terminal elimination half-life is 1–2 hours. 60% of the administered dose is excreted in urine as glucuronide conjugates of unchanged diclofenac, the remainder – with bile and feces.

Paracetamol is metabolized in the liver and mainly excreted in urine. After repeated administration, the pharmacokinetic parameters of active substances do not change. When recommended intervals between tablet doses are observed, no drug accumulation occurs.

Clinical characteristics.

Indications.

• Acute pain (muscular, headache, toothache, spinal pain), non-articular rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, acute gout attacks, primary dysmenorrhea, adnexitis, pharyngotonsillitis, otitis.
• Post-traumatic and postoperative pain syndrome.

Contraindications.

• Hypersensitivity to diclofenac, paracetamol, or any other component of the drug.
• Active form of peptic ulcer/bleeding or recurrent peptic ulcer/bleeding in medical history (two or more separate episodes of confirmed ulcer or bleeding).
• Hepatic insufficiency.
• Renal insufficiency.
• Congestive heart failure (NYHA II-IV).
• Ischemic heart disease in patients with angina who have experienced myocardial infarction.
• Patients in whom administration of diclofenac, paracetamol, acetylsalicylic acid, or other non-steroidal anti-inflammatory drugs (NSAIDs) triggers attacks of bronchial asthma, angioneurotic edema, urticaria, or acute rhinitis.
• Blood disorders, severe anemia, leukopenia.
• Congenital hyperbilirubinemia.
• Glucose-6-phosphate dehydrogenase deficiency.
• Gastrointestinal bleeding or perforation in medical history associated with previous treatment with non-steroidal anti-inflammatory drugs (NSAIDs).
• Inflammatory bowel diseases (Crohn's disease or ulcerative colitis).
• Alcoholism.
• Treatment of perioperative pain in aortocoronary bypass surgery (or use of cardiopulmonary bypass apparatus).
• Peripheral arterial diseases.
• Cerebrovascular diseases in patients who have experienced stroke or transient ischemic attacks.
• High risk of postoperative bleeding, blood coagulation disorders, hemostasis disorders, hematopoietic disorders, or cerebrovascular bleeding.

Interaction with other medicinal products and other types of interactions.

Diclofenac.

Lithium. Concurrent use of diclofenac may increase lithium plasma concentrations. Monitoring of serum lithium levels is recommended.

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

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g., beta-blockers, angiotensin-converting enzyme (ACE) inhibitors) may lead to reduced antihypertensive effect due to inhibition of vasodilatory prostaglandin synthesis. Therefore, such combinations should be used with caution, and patients, especially elderly ones, should be closely monitored for arterial pressure. Patients should receive adequate hydration; monitoring of kidney function is also recommended after initiation of concomitant therapy and regularly thereafter, particularly with diuretics and ACE inhibitors due to increased risk of nephrotoxicity.

Agents known to cause hyperkalemia. Concomitant treatment with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may be associated with increased serum potassium levels; therefore, patient monitoring should be performed more frequently.

Anticoagulants and antithrombotic agents. Precautions are recommended, as concomitant administration may increase the risk of bleeding. Although clinical studies do not indicate an effect of diclofenac on anticoagulant activity, there are individual reports of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously. Therefore, to ensure no dosage adjustments of anticoagulants are needed, careful monitoring of such patients is recommended. As with other NSAIDs, diclofenac in high doses may temporarily inhibit platelet aggregation.

Other NSAIDs, including selective cyclooxygenase-2 inhibitors, and corticosteroids. Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Simultaneous use of two or more NSAIDs should be avoided.

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

Antidiabetic agents. Clinical studies have shown that diclofenac can be used together with oral antidiabetic agents without affecting their clinical efficacy. However, individual cases of both hypoglycemic and hyperglycemic effects requiring dosage adjustments of antidiabetic agents during diclofenac treatment have been reported. In such cases, blood glucose monitoring is necessary as a precaution during concomitant therapy.

Methotrexate. Diclofenac may inhibit methotrexate clearance in renal tubules, leading to increased methotrexate levels. Caution is recommended when administering NSAIDs, including diclofenac, less than 24 hours before methotrexate treatment, as methotrexate blood concentration may increase and its toxicity may rise. Serious toxicity cases have been reported when methotrexate and NSAIDs, including diclofenac, were administered within a 24-hour interval. 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 its effect on renal prostaglandins. Therefore, it should be used at lower doses than in patients not receiving cyclosporine.

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

Antibacterial quinolones. There are individual reports of seizures that may result from concomitant use of quinolones and NSAIDs. This may occur in patients both with and without a history of epilepsy or seizures. Therefore, caution should be exercised when considering quinolone use in patients already receiving NSAIDs.

Phenytoin. When phenytoin is administered concurrently with diclofenac, monitoring of phenytoin plasma concentration is recommended due to expected increased phenytoin exposure.

Colestyramine and cholestyramine. 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 colestyramine/cholestyramine.

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

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

Potent CYP2C9 inhibitors. Caution is recommended when co-administering diclofenac with potent CYP2C9 inhibitors (e.g., voriconazole), which may lead to significant increases in maximum plasma concentration and exposure of diclofenac due to inhibition of its metabolism.

Paracetamol.
The absorption rate of paracetamol may be increased by metoclopramide and domperidone and decreased by cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced with long-term regular daily use of paracetamol, increasing the risk of bleeding. Occasional use has no significant effect. Barbiturates reduce the antipyretic effect of paracetamol. Anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol due to increased conversion of the drug into hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic agents increases the toxic effect of drugs on the liver. Concomitant use of high-dose paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Paracetamol reduces the efficacy of diuretics. Paracetamol should be used cautiously concomitantly with flucloxacillin, as concomitant intake has been associated with high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions for use"). Do not use concomitantly with alcohol.

Special precautions for use.

General
Adverse effects can be minimized by using the lowest effective dose for the shortest possible duration required to control symptoms. Concomitant use of Dolaren® with systemic NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided due to lack of any synergistic benefit and potential for additional adverse effects. Caution is required when prescribing the drug to elderly patients. In particular, for frail elderly patients and those with low body weight, the lowest effective doses are recommended. As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur even without prior exposure to diclofenac. As with other NSAIDs, Dolaren® may mask signs and symptoms of infection due to its pharmacodynamic properties.

Gastrointestinal effects
When using all NSAIDs, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulcer formation, or perforation, which may be fatal, have been reported. These may occur at any time during treatment, with or without warning symptoms, and in patients with a history of serious gastrointestinal events. These events usually have more serious consequences in elderly patients. If gastrointestinal bleeding or ulcer formation occurs in patients receiving diclofenac, drug use must be discontinued. As with all NSAIDs, including diclofenac, careful medical monitoring is necessary; particular caution should be exercised when prescribing diclofenac to patients with symptoms indicating gastrointestinal disorders or with a history of gastric or intestinal ulcer, bleeding, or perforation. The risk of gastrointestinal bleeding, ulcer formation, or perforation is higher with increasing doses of NSAIDs, including diclofenac, and in patients with a history of ulcers, especially with complications such as bleeding or perforation. Elderly patients have an increased frequency of adverse reactions when using NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal. To reduce the risk of gastrointestinal toxicity in patients with a history of ulcers, especially with complications such as bleeding or perforation, and in elderly patients, treatment should be initiated and maintained at the lowest effective doses. For such patients, as well as those requiring concomitant use of drugs containing low-dose acetylsalicylic acid (ASA) or other drugs likely to increase the risk of gastrointestinal adverse effects, consideration should be given to combination therapy with protective drugs (e.g., proton pump inhibitors or misoprostol). Patients with a history of gastrointestinal toxicity, especially elderly ones, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding). Caution is also required for patients receiving concomitant drugs that may increase the risk of ulcer or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antithrombotic agents (e.g., acetylsalicylic acid), or selective serotonin reuptake inhibitors.

Hepatic effects
Careful medical monitoring is required if Dolaren® is prescribed to patients with impaired liver function, as their condition may worsen. As with other NSAIDs, including diclofenac, levels of one or more liver enzymes may increase. During long-term treatment with Dolaren®, regular monitoring of liver function should be performed as a precaution. If liver function abnormalities persist or worsen, if clinical signs or symptoms may be related to progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), use of Dolaren® should be discontinued. The course of diseases such as hepatitis may occur without prodromal symptoms. Caution is required if Dolaren® is used in patients with hepatic porphyria due to the potential risk of provoking an attack.

Renal effects
Since fluid retention and edema have been reported with NSAID treatment, including diclofenac, particular attention should be paid to patients with impaired heart or kidney function, a history of arterial hypertension, elderly patients, those receiving concomitant diuretic therapy or drugs significantly affecting renal function, and patients with significant reduction in extracellular fluid volume for any reason, e.g., before or after major surgery. In such cases, monitoring of renal function is recommended as a precaution. Discontinuation of therapy usually leads to return to the pre-treatment state.

Dermatological effects
Serious skin reactions (some of which were fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported with the use of NSAIDs, including Dolaren®. The highest risk of these reactions appears to occur at the beginning of treatment, in most cases within the first month of therapy. Dolaren® use must 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
Diclofenac may be prescribed to patients with significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes, smoking) only after careful clinical evaluation. Since cardiovascular risks of diclofenac may increase with dose and duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The need for diclofenac use for symptom relief and response to therapy should be periodically reviewed. Use with caution in patients aged 65 years and older. For patients with a history of arterial hypertension and/or mild to moderate congestive heart failure, appropriate monitoring and recommendations are necessary, as fluid retention and edema have been reported with NSAID use, including diclofenac. Clinical trial data and epidemiological evidence indicate that diclofenac use, particularly at high doses (150 mg/day) and for prolonged periods, may be associated with a slight increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Diclofenac is not recommended for patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial diseases, and/or cerebrovascular disease. If use is necessary, it may be considered only after careful risk-benefit assessment at a dosage not exceeding 100 mg per day. A similar assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g., arterial hypertension, hyperlipidemia, diabetes, and smoking). Patients should be informed about the possibility of serious complications (chest pain, dyspnea, weakness, speech disturbances) that may occur at any time. In such cases, immediate medical attention is required.

Hematological effects
With prolonged use of the drug, as with other NSAIDs, monitoring of blood tests is recommended. As with other NSAIDs, Dolaren® may temporarily inhibit platelet aggregation. Careful monitoring is required in patients with hemostasis disorders, hemorrhagic diathesis, or hematological disorders.

Asthma in medical history
Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory tract infections (especially associated with allergic, rhinitis-like symptoms) more frequently experience NSAID reactions resembling asthma exacerbation (so-called analgesic intolerance/analgesic asthma), Quincke's edema, or urticaria than others. Therefore, special precautionary measures (readiness for emergency care) are recommended for such patients. This also applies to patients with allergies to other substances manifesting as skin reactions, pruritus, or urticaria. As with other drugs inhibiting prostaglandin synthetase activity, diclofenac sodium and other NSAIDs may provoke bronchospasm in patients with bronchial asthma or with a history of bronchial asthma.

Before using the drug, consult a doctor if the patient is taking warfarin or similar drugs with anticoagulant effects.
Consider that in patients with alcoholic liver damage, the risk of hepatotoxic effect of paracetamol increases; the drug may affect laboratory test results for blood glucose and uric acid levels.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal insufficiency and sepsis, or in patients with malnutrition or other causes of glutathione deficiency (e.g., chronic alcoholism), who used paracetamol at therapeutic doses for prolonged periods or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and careful monitoring of the patient's condition are recommended. Determination of 5-oxoproline levels in urine may be useful to confirm pyroglutamic acidosis as the primary cause of HAGMA in patients with multiple risk factors.

Patients taking analgesics daily for mild arthritis should consult a doctor. Do not exceed the indicated doses. Do not take the drug with other products containing paracetamol. If symptoms do not resolve, consult a doctor. If headache becomes persistent, consult a doctor.

Use during pregnancy or breastfeeding.
From the 20th week of pregnancy, use of diclofenac sodium may cause oligohydramnios due to fetal kidney dysfunction and may lead to arterial duct constriction in the second trimester of pregnancy. The drug is contraindicated during pregnancy or breastfeeding.

Fertility.
As with other non-steroidal anti-inflammatory drugs, the drug may affect female fertility. The drug is not recommended for women planning pregnancy. Women experiencing fertility problems or undergoing infertility investigations should discontinue use of Dolaren®.

Ability to affect reaction speed when driving vehicles or operating machinery.
Patients who experience visual disturbances, dizziness, vertigo, drowsiness, or other central nervous system disorders during treatment should refrain from driving vehicles or operating machinery.

Method of administration and dosage.
The dose is determined by the doctor individually for each patient depending on age, nature and course of the disease, individual tolerance, and therapeutic efficacy of the drug. The drug should be used at the lowest effective doses for the shortest possible duration, considering the treatment goals for each individual patient. Adults and children aged 14 years and older: 1 tablet 2–3 times a day after meals. Treatment duration should not exceed 5–7 days and depends on the course of the disease. The maximum daily dose for adults and children aged 14 years and older is no more than 3 tablets.

Children.
The drug is contraindicated in children under 14 years of age.

Overdose.

Diclofenac.
Symptoms. A typical clinical picture of diclofenac overdose is absent. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, excitement, coma, drowsiness, tinnitus, loss of consciousness, or seizures. In severe poisoning, acute renal failure and liver damage may occur.

Treatment. Within 1 hour after ingestion of a potentially toxic amount of the drug orally, consider activated charcoal administration. Additionally, in adults, consider gastric lavage within 1 hour after ingestion of a potentially toxic amount of the drug. For frequent or prolonged seizures, diazepam should be administered intravenously. Other measures may be indicated depending on the patient's clinical condition. Treatment is symptomatic.

Paracetamol.
Liver damage may occur in adults who have ingested 10 g or more of paracetamol and in children who have ingested more than 150 mg/kg body weight. In patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; regular excessive ethanol consumption; glutathione cachexia (digestive disorders, cystic fibrosis, HIV infection, starvation, cachexia)), ingestion of 5 g or more of paracetamol may lead to liver damage.

Symptoms of overdose within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12–48 hours after overdose. Glucose metabolism disorders and metabolic acidosis may occur. In severe poisoning, liver failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and fatal outcome. Acute renal failure with acute tubular necrosis may manifest as severe lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmia and pancreatitis have also been reported.

With prolonged use of the drug in high doses, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia may develop from the hematopoietic system. With high-dose intake, from the CNS – dizziness, psychomotor agitation, and disorientation; from the urinary system – nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

In case of overdose, prompt medical assistance is required. The patient should be immediately taken to a hospital, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. Consider treatment with activated charcoal if excess paracetamol dose was taken within 1 hour. Paracetamol plasma concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours after ingestion. The effectiveness of the antidote decreases sharply after this time. If necessary, N-acetylcysteine should be administered intravenously according to the established dosage schedule. In the absence of vomiting, methionine may be used orally as an appropriate alternative in remote areas outside the hospital.

Adverse reactions.
The following adverse effects include those associated with Dolaren® administration during short-term and long-term use.

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, anemia (including hemolytic and aplastic anemia), agranulocytosis, sulfhemoglobinemia, and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruises or bleeding.

Immune system disorders: hypersensitivity, anaphylactic and anaphylactoid reactions (including arterial hypotension and shock), angioneurotic edema (including facial edema), skin pruritus, skin and mucosal rashes (usually generalized rashes, erythematous rashes, urticaria), multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Metabolism and nutrition disorders: metabolic acidosis with high anion gap (frequency unknown).

Psychiatric disorders: disorientation, depression, insomnia, nightmares, irritability, and other psychiatric disorders.

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

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

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

Cardiac disorders: palpitations, chest pain, heart failure, myocardial infarction.

Vascular disorders: arterial hypertension, arterial hypotension, vasculitis.

Respiratory, thoracic, and mediastinal disorders: bronchospasm in patients sensitive to aspirin and other NSAIDs, asthma (including dyspnea), pneumonitis.

Gastrointestinal disorders: nausea, vomiting, diarrhea, dyspepsia, abdominal pain, epigastric pain, flatulence, anorexia, gastritis, gastrointestinal bleeding, hematemesis, hemorrhagic diarrhea, melena, gastric or intestinal ulcer with or without bleeding or with perforation (sometimes fatal, especially in elderly patients), colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, esophageal disorders, intestinal membrane strictures, pancreatitis.

Hepatobiliary disorders: increased transaminase levels, hepatitis, jaundice, liver function impairment, increased liver enzyme activity, usually without jaundice development, fulminant hepatitis, hepatic necrosis, liver failure.

Skin and subcutaneous tissue disorders: rash, urticaria, bullous rash, eczema, erythema, multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), exfoliative dermatitis, hair loss, photosensitivity reaction, purpura, allergic purpura, pruritus.

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

General disorders and administration site conditions: injection site reaction, pain, induration, swelling, necrosis at injection site, abscess at injection site.

Reproductive system and breast disorders: impotence.

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

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

Metabolic acidosis with high anion gap
Cases of metabolic acidosis with high anion gap caused by pyroglutamic acidosis have been observed in patients with risk factors who used paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur due to low glutathione levels in such patients.

Reporting suspected adverse reactions
Reporting of adverse reactions after drug registration is of great importance. This allows monitoring of the benefit-risk ratio of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions. Store in original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.
No. 4 (4x1) – 4 tablets in a blister; 1 blister in a paper envelope;
No. 200 (4x50) – 4 tablets in a blister; 1 blister in a paper envelope; 50 paper envelopes in a cardboard box;
No. 10 – 10 tablets in blisters;
No. 10 (10x1) – 10 tablets in a blister; 1 blister in a cardboard box;
No. 100 ((10x1)x10) – 10 tablets in a blister; 1 blister in a cardboard box; 10 boxes in a box;
No. 100 (10x10) – 10 tablets in a blister; 10 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Nabros Pharma Pvt. Ltd.

Manufacturer's location and address of business activity.
Survey No. 110/A/2 Amit Farm, Jayanpuria Road, near Coca Cola factory, NH No. 8, Kajipura – 387411, Kheda, India.