INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BOL-RAN® (BOL-RAN®)

Composition:

Active substances: paracetamol, sodium diclofenac;

1 tablet contains: paracetamol 500 mg, sodium diclofenac 50 mg;

Excipients: corn starch, microcrystalline cellulose, sodium starch glycolate (type A), sodium croscarmellose, povidone, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, round, flat tablets with a score line on one side.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01AB55.

Pharmacological Properties.

Pharmacodynamics.

Bol-Ran® is a combination drug that exerts a pronounced anti-inflammatory, analgesic, and antipyretic effect. The pharmacological activity of the medicinal product is due to the properties of diclofenac and paracetamol contained in the formulation.

Diclofenac sodium exerts a pronounced anti-inflammatory and analgesic effect, as well as a moderate antipyretic action. Paracetamol produces a pronounced analgesic effect, mild antipyretic activity, and a slight anti-inflammatory effect. 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 drug absorption.

Plasma concentrations of the active ingredients show a linear dependence on the administered dose; maximum levels are reached within 60–90 minutes after administration.

Diclofenac binding to plasma proteins (mainly to 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 half-life in synovial fluid is 3–6 hours.

Diclofenac metabolism occurs via glucuronidation of the unchanged molecule and via methoxylation, leading to the formation of several phenolic metabolites, whose biological activity is significantly lower than that of the parent compound.

Total systemic plasma clearance of diclofenac is approximately 300 mL/min. The terminal elimination half-life is 1–2 hours. About 60% of the administered dose is excreted in urine as glucuronide conjugates of unchanged diclofenac, the remainder is excreted with bile and feces.

Paracetamol is metabolized in the liver and is primarily excreted in urine.

After repeated administration, pharmacokinetic parameters of the active ingredients do not change. When recommended dosing intervals are observed, no drug accumulation occurs.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to diclofenac, paracetamol, or to any other component of the medicinal product. Active peptic ulcer of the stomach or intestine; gastrointestinal bleeding or perforation. Inflammatory bowel diseases (Crohn’s disease or ulcerative colitis). Gastrointestinal bleeding or perforation associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in medical history. Active phase of peptic ulcer/bleeding or recurrent peptic ulcer/bleeding in history (two or more separate episodes of confirmed ulcer or bleeding). Third trimester of pregnancy. Severe hepatic insufficiency (Child–Pugh class C, cirrhosis or ascites). Renal insufficiency (creatinine clearance < 30 mL/min). Severe heart failure (NYHA class III–IV), congestive heart failure (NYHA II–IV), decompensated heart failure, marked increase in arterial pressure, organic cardiovascular diseases including severe atherosclerosis, severe hypertensive disease, acute myocardial infarction, paroxysmal tachycardia, hyperthyroidism. Acute pancreatitis. Severe forms of diabetes mellitus. Glaucoma. Contraindicated in patients who experience attacks of bronchial asthma ("aspirin-induced asthma"), angioneurotic edema, urticaria, or acute rhinitis, nasal polyps, or other allergic symptoms in response to administration of ibuprofen, diclofenac, paracetamol, acetylsalicylic acid, or other nonsteroidal anti-inflammatory drugs (NSAIDs). 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. Blood coagulation disorders of unknown origin. Blood disorders, leukopenia, severe anemia. Conditions of increased excitability, sleep disturbances, epilepsy. Peripheral arterial diseases. Congenital hyperbilirubinemia. Glucose-6-phosphate dehydrogenase deficiency. Alcoholism. Treatment of postoperative pain following coronary artery bypass grafting (or use of artificial circulation).

Interaction with other medicinal products and other types of interactions.

Diclofenac.

Lithium, digoxin. The product may increase plasma concentrations of lithium and digoxin. Monitoring of lithium and digoxin plasma levels is recommended.

Diuretics and antihypertensive agents. The product, like other NSAIDs, may reduce the antihypertensive effect of diuretics or antihypertensive drugs, such as beta-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, combination of such drugs should be prescribed with caution, and patients (especially elderly) should have their blood pressure monitored periodically. Patients should consume sufficient amounts of water, and renal function should be monitored periodically, especially when diuretics and ACE inhibitors are used, due to increased risk of nephrotoxicity.

Medicinal products causing hyperkalemia. Concomitant use of potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, serum potassium levels should be monitored in patients receiving such drugs simultaneously.

Anticoagulants and antiplatelet agents. Concomitant use of the product with anticoagulants, particularly warfarin and other coumarins, and antiplatelet agents increases the risk of bleeding. Although clinical studies do not indicate an effect of diclofenac on anticoagulant activity, available data show an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously. To ensure that anticoagulant dosing does not require adjustment, careful monitoring of such patients is recommended. Like other nonsteroidal anti-inflammatory drugs, diclofenac at high doses may temporarily inhibit platelet aggregation.

Other NSAIDs, including selective cyclooxygenase-2 inhibitors, and corticosteroids. Concomitant use of the product with other NSAIDs or corticosteroids increases the risk of gastrointestinal bleeding or ulcers. Simultaneous use of two or more NSAIDs should be avoided.

Selective serotonin reuptake inhibitors (SSRIs). Concomitant use of systemic NSAIDs and SSRIs increases the risk of gastrointestinal bleeding.

Antidiabetic agents. Diclofenac, when used with oral antidiabetic agents, did not alter their therapeutic effect. However, there are individual reports of both hypoglycemia and hyperglycemia occurring in such cases, necessitating adjustment of antidiabetic drug dosage during treatment with the product. Therefore, blood glucose levels should be monitored during therapy with the product.

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

Metotrexate. Diclofenac may inhibit renal tubular clearance of methotrexate, leading to increased methotrexate levels. Caution should be exercised when prescribing NSAIDs, including diclofenac, less than 24 hours before or after methotrexate administration, as this may increase methotrexate blood concentration and enhance its toxic effects. Serious toxicity cases have been reported when the interval between methotrexate and NSAID (including diclofenac) administration was within 24 hours. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine. The effect of NSAIDs on prostaglandin synthesis in the kidneys may enhance cyclosporine nephrotoxicity; therefore, the product should be administered in lower doses when given to patients receiving cyclosporine.

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

Antibacterial agents – quinolone derivatives. Seizures may occur in patients receiving quinolone derivatives and NSAIDs concomitantly. This may occur in patients both with and without epilepsy or history of seizures. Therefore, caution should be exercised when considering quinolone use in patients already receiving NSAIDs.

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

Medicinal products that induce drug-metabolizing enzymes. Medicinal products that induce enzymes, such as rifampicin, carbamazepine, phenytoin, St. John's wort (Hypericum perforatum), etc., may theoretically reduce diclofenac plasma concentrations.

Cholestyramine and colestipol. Concomitant use of the product with cholestyramine or colestipol reduces diclofenac absorption by approximately 30% and 60%, respectively. Therefore, diclofenac should be administered at least 1 hour before or 4–6 hours after cholestyramine/colestipol administration.

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

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

CYP2C9 inhibitors. Caution is required when co-administering diclofenac with CYP2C9 inhibitors (e.g., voriconazole). This may lead to a significant increase in plasma maximum concentrations and enhanced effects of diclofenac.

CYP2C9 inducers. Caution is required when co-administering diclofenac with CYP2C9 inducers (e.g., rifampicin). This may lead to a significant decrease in plasma concentrations and reduced efficacy of diclofenac.

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 by long-term daily use of paracetamol, increasing the risk of bleeding. Occasional use has no significant effect.

Barbiturates reduce the antipyretic effect of paracetamol.

Concomitant use of paracetamol with chloramphenicol increases the plasma concentration of the latter.

Anticonvulsants (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effects of paracetamol due to increased formation of hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic agents increases the risk of liver toxicity.

Concomitant use of high-dose paracetamol with isoniazid or rifampicin increases the risk of hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics.

Do not use concomitantly with alcohol.

Special precautions for use.

General warnings regarding the use of systemic NSAIDs

Gastrointestinal ulcers, bleeding, or perforation may occur at any time during NSAID therapy, regardless of COX-2 selectivity, even in the absence of warning symptoms. To minimize this risk and the risk of other adverse reactions, treatment should be initiated at the lowest effective dose and continued for the shortest duration possible.

Concomitant use of Bol-Ran® with systemic NSAIDs, such as selective COX-2 inhibitors, should be avoided due to the lack of evidence for synergistic effects and the potential for additive adverse effects. There is an increased risk of thrombotic cardiovascular and cerebrovascular complications associated with the use of certain selective COX-2 inhibitors. It is unknown whether this risk is directly related to the COX-1/COX-2 selectivity of individual NSAIDs. Currently, there are no available data on long-term treatment with the maximum dose of diclofenac; therefore, the risk-benefit ratio of diclofenac use should be carefully considered in patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial occlusive disease, or significant risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Diclofenac should be prescribed to patients with significant cardiovascular risk factors only after careful clinical evaluation. Since cardiovascular risks associated with 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 response to therapy and the need for continued diclofenac use to relieve symptoms should be periodically reassessed.

Do not use concurrently with other medicinal products containing diclofenac.

This medicinal product contains paracetamol; therefore, it should not be used together with other products containing paracetamol, such as those used for fever reduction, pain relief, flu or cold symptoms, or insomnia. Concomitant use with other paracetamol-containing products may lead to overdose. Paracetamol overdose can cause liver failure, which may necessitate liver transplantation or result in death.

Outcomes are generally more severe in elderly patients.

If gastrointestinal bleeding or ulcers occur in patients, use of Bol-Ran® should be discontinued.

Cases of impaired liver function or liver failure have been reported in patients with reduced glutathione levels, such as those with severe malnutrition, anorexia, low body mass index, chronic alcoholism, or sepsis.

In patients with reduced glutathione levels, the risk of metabolic acidosis may increase during paracetamol use. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Medical attention should be sought immediately if these symptoms occur. If symptoms persist, medical advice should be sought.

Consult a physician before use if the patient is taking warfarin or similar anticoagulant agents.

Patients who take analgesics daily for mild forms of arthritis should consult a physician.

Caution is required when administering the product to patients over 65 years of age. In particular, the lowest effective dose should be used in elderly or debilitated patients or those with low body weight.

History of bronchial asthma

Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (e.g., nasal polyps), chronic obstructive pulmonary disease, or chronic respiratory tract infections (especially those associated with allergic, rhinitis-like symptoms) are more likely to experience reactions to NSAIDs, such as asthma exacerbation (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria. Therefore, special precautionary measures (emergency readiness) are recommended for such patients. This also applies to patients with allergic reactions to other substances (e.g., skin rash, pruritus, or urticaria).

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

Effects on the gastrointestinal tract

As with other NSAIDs, both COX-2 selective and non-selective, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported. These events can be fatal and may occur at any time during treatment, with or without preceding symptoms or a history of serious gastrointestinal events. These events generally have more serious consequences in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the medicinal product should be discontinued.

As with other NSAIDs, including diclofenac-containing products, medical monitoring and special caution are required for patients with symptoms suggesting gastrointestinal (GI) disorders or with a history of gastric or intestinal ulcers, bleeding, or perforation. The risk of GI bleeding increases with higher doses and is also elevated in patients with a history of ulcers, particularly those complicated by bleeding or perforation. Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal. To reduce the risk of such gastrointestinal toxicity, treatment should be initiated and maintained at the lowest effective doses. For such patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid (ASA/aspirin) or other drugs that increase the risk of gastrointestinal adverse effects, the use of combination therapy with protective agents (e.g., proton pump inhibitors or misoprostol) should be considered. Patients with a history of gastrointestinal toxicity, especially the elderly, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding). Caution is also required for patients receiving concomitant medications that increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., ASA), or selective serotonin reuptake inhibitors.

Effects on the liver

The risk of hepatotoxic effects of paracetamol is increased in patients with liver disease. Consult a physician before use.

Careful medical monitoring is required when administering the product to patients with impaired liver function, as their condition may worsen.

As with other NSAIDs, including diclofenac, the levels of one or more liver enzymes may increase. Elevated enzyme levels usually return to normal after discontinuation of the medicinal product.

During long-term treatment, monitoring of liver function and liver enzyme levels is recommended as a precautionary measure. If liver function abnormalities persist or worsen, if clinical symptoms suggest progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), the product should be discontinued.

In addition to elevated liver enzyme levels, severe hepatic reactions have been rarely observed, including jaundice, fulminant hepatitis, liver necrosis, and liver failure, which in some cases have led to death.

Diseases such as hepatitis may progress without prodromal symptoms. Caution is required when administering the product to patients with hepatic porphyria due to the potential to provoke an attack.

Effects on the kidneys

Consult a physician before use in patients with kidney disease.

Renal effects of NSAIDs, including diclofenac, often (1–10%) include fluid retention with edema and/or hypertension. Therefore, diclofenac should be used with caution in patients with cardiac dysfunction and other conditions leading to fluid retention, especially in patients with heart or kidney dysfunction, a history of arterial hypertension, elderly patients, patients receiving concomitant diuretic therapy, ACE inhibitors, or drugs that significantly affect kidney function, patients at increased risk of hypovolemia, and patients with significant reduction in extracellular fluid volume for any reason, such as before or after major surgery. In such cases, monitoring of kidney function is recommended. Discontinuation of therapy usually results in return to the pre-treatment state.

Effects on the skin

Serious skin reactions, some of which are fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported with the use of NSAIDs, including diclofenac. The highest risk of these reactions occurs at the beginning of therapy, and most cases develop within the first month of treatment. The product should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity. In rare cases, as with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur, even without prior exposure to diclofenac. Due to its pharmacodynamic properties, the product, like other NSAIDs, may mask symptoms of infection.

Systemic lupus erythematosus and mixed connective tissue diseases

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

Cardiovascular and cerebrovascular effects

Treatment with Bol-Ran® is generally not recommended in patients with diagnosed cardiovascular diseases (heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled arterial hypertension.

Diclofenac products may be prescribed to patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation and only at doses up to 100 mg daily for treatment courses not exceeding 4 weeks. Since cardiovascular risks associated with 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 need for diclofenac use to relieve symptoms and the response to therapy should be periodically reviewed, especially if treatment lasts longer than 4 weeks.

Appropriate monitoring and recommendations are necessary for patients with a history of arterial hypertension and/or mild to moderate congestive heart failure, as fluid retention and edema have been reported with the use of NSAIDs, including diclofenac.

Bol-Ran® should be used with caution in patients taking concomitant diuretics or ACE inhibitors, or in those at increased risk of hypovolemia.

Available data indicate that the use of diclofenac, particularly at high doses (150 mg/day) and during prolonged treatment, slightly increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke).

The medicinal product is contraindicated in patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

Patients should be informed about the possibility of developing serious antithrombotic symptoms (chest pain, dyspnea, weakness, speech disturbances) at any time. In such cases, immediate medical attention is required.

Effects on hematological parameters

Complete blood count is recommended during prolonged use of this product, as with other NSAIDs. Like other NSAIDs, the product may temporarily inhibit platelet aggregation. Patients with coagulation disorders, hemorrhagic diathesis, or hematological disorders should be closely monitored.

Diclofenac, an ingredient of the product, may adversely affect female fertility and is therefore not recommended for use in women attempting to conceive or undergoing infertility investigations.

The risk of hepatotoxic effects of paracetamol is increased in patients with alcoholic non-cirrhotic liver disease. The product may affect laboratory test results for blood glucose and uric acid levels.

Do not exceed the recommended doses.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy or breastfeeding.

If the product is used by a woman planning to become pregnant, the dose should be as low as possible and the duration of treatment as short as possible.

Ability to affect reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness, vertigo, somnolence, or other central nervous system disturbances during use of Bol-Ran® should refrain from driving or operating machinery.

Method of Administration and Dosage

The dose and duration of treatment are determined individually by a physician for each patient, depending on the patient's 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, taking into account the treatment goals for each individual patient.

For adults and children aged 14 years and older: 1 tablet 2–3 times daily after meals, with an interval of at least 4 hours between doses. Tablets should be taken whole, without chewing, with half a glass of water. Do not exceed the recommended dose.

The treatment duration should be minimal and not exceed 5–7 days. The maximum duration of use without consulting a physician is 3 days.

The maximum daily dose of the drug for adults and children aged 14 years and older is 3 tablets.

Do not take together with other medicinal products containing diclofenac or paracetamol.

Children

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

Overdose

Diclofenac

There is no typical clinical picture characteristic of diclofenac overdose. Overdose may cause 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

Treatment of acute poisoning with NSAIDs, including diclofenac, consists of supportive and symptomatic therapy. This includes management of manifestations such as arterial hypotension, renal failure, convulsions, gastrointestinal disorders, and respiratory depression. Specific interventions such as forced diuresis, dialysis, or hemoperfusion are unlikely to be effective in eliminating NSAIDs, including diclofenac, because the active substances are highly protein-bound and undergo extensive metabolism. Activated charcoal may be administered after ingestion of potentially toxic doses. Gastric decontamination (e.g., induced vomiting, gastric lavage) may be performed after ingestion of potentially life-threatening doses.

Paracetamol

Paracetamol overdose can lead to liver failure, which may necessitate liver transplantation or result in fatal outcome. Acute pancreatitis has been observed, usually in conjunction with liver function impairment and hepatotoxicity.

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 use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs that induce liver enzymes; alcohol abuse; glutathione system deficiency, e.g., due to malnutrition, HIV infection, fasting, cystic fibrosis, cachexia), ingestion of 5 g or more of paracetamol may lead to liver damage.

In case of overdose, immediate medical assistance is required. Treatment should be initiated immediately. The patient should be taken to a hospital even if early symptoms of overdose are absent.

Symptoms within the first 24 hours: pallor, nausea, vomiting, loss of appetite, abdominal pain. Experience shows that symptoms of liver damage may become apparent 12–48 hours after overdose and usually peak after 4–6 days. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, liver failure may progress to encephalopathy, hemorrhages, hypoglycemia, coma, and result in death. Acute renal failure with acute tubular necrosis may present as severe pain in the lumbar region, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias have also been reported.

With prolonged use of the drug in high doses, the following hematological disorders may develop: aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia. High-dose intake may also cause the following reactions: from the central nervous system – dizziness, psychomotor agitation, and disorientation; from the urinary system – nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis); from the digestive system – hepatic necrosis.

Treatment

Symptoms of overdose may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. Immediate medical assistance is required in case of overdose, even if no symptoms are observed. If overdose is confirmed or even suspected, the patient must be taken to the nearest medical facility where emergency medical care and qualified treatment can be provided. This should be done even in the absence of symptoms due to the risk of delayed liver damage. Administration of activated charcoal should be considered if the excessive dose of paracetamol was taken within the last hour. Plasma paracetamol 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 the maximum protective effect is achieved when administered within 8 hours after ingestion. The efficacy of the antidote decreases sharply after this time. If necessary, intravenous N-acetylcysteine should be administered according to current dosing recommendations. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside the hospital.

Supportive and symptomatic treatment is indicated for complications such as arterial hypotension, renal failure, convulsions, gastrointestinal disturbances, and respiratory depression. Forced diuresis, hemodialysis, or hemoperfusion are unlikely to be effective in eliminating nonsteroidal anti-inflammatory drugs (NSAIDs), as the active substances are highly protein-bound and undergo extensive metabolism.

Adverse Reactions

Blood and lymphatic system disorders: thrombocytopenia, neutropenia, leukopenia, anemia, including aplastic anemia, hemolytic anemia (especially in patients with glucose-6-phosphate dehydrogenase deficiency), sulfhemoglobinemia, and methemoglobinemia (cyanosis, dyspnea, chest pain), agranulocytosis, pancytopenia, bruising or bleeding.

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

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

Psychiatric disorders: disorientation, depression, nightmares, irritability, restlessness, fear, psychotic disorders, confusion, psychomotor agitation.

Nervous system disorders: headache, dizziness, somnolence, fatigue, paresthesia, sleep disturbances, insomnia, memory impairment, seizures, anxiety, tremor, aseptic meningitis, taste disturbances, cerebral circulation disorders, stroke, hallucinations, sensory disturbances, malaise.

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

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

Cardiovascular disorders: palpitations, tachycardia, dyspnea, chest pain, heart failure, myocardial infarction, arterial hypertension, arterial hypotension, hypertensive crisis, vasculitis.

Respiratory system disorders: bronchial asthma (including dyspnea), bronchospasm (especially in patients sensitive to aspirin and other NSAIDs), chest pain, pneumonitis.

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

Hepatobiliary disorders: liver function abnormalities, elevated transaminase levels; liver failure, hepatitis, liver necrosis, jaundice, liver disorders; fulminant hepatitis.

Renal and urinary system disorders: fluid retention, edema, hypertension, acute renal failure, hematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.

General disorders: edema, general weakness, increased sweating, hypoglycemia, up to hypoglycemic coma.

Reproductive system and breast disorders: impotence.

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.

Visual disturbances.

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

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

10 tablets in a blister, 1 blister in a cardboard package (package No. 10);

10 tablets in a blister, 10 blisters in a cardboard package (package No. 100 (10×10)).

Prescription status.

Prescription only.

Manufacturer.

Bafna Pharmaceuticals Ltd., India / Bafna Pharmaceuticals Ltd., India.

Manufacturer's address and location of its business activity.

147, Madhavaram Red Hills Road, Grantlyon Village, Vadakarai, Chennai, Tamil Nadu IN 600052, India / 147, Madhavaram Red Hills Road, Grantlyon Village, Vadakarai, Chennai, Tamil Nadu IN 600052, India.

Marketing Authorization Holder. JIVDHARA PHARMA PRIVATE LIMITED / JIVDHARA PHARMA PRIVATE LIMITED.

INSTRUCTIONS

for medical use of the medicinal product

BOL-RAN®

(BOL-RAN®)

Composition:

Active ingredients: paracetamol, sodium diclofenac;

1 tablet contains: paracetamol 500 mg, sodium diclofenac 50 mg;

Inactive ingredients: maize starch, microcrystalline cellulose, sodium starch glycolate (type A), sodium croscarmellose, povidone, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, flat tablets with a score line on one side.

Pharmacotherapeutic group: Nonsteroidal anti-inflammatory and antirheumatic drugs.

ATC code M01AB55.

Pharmacological properties.

Pharmacodynamics.

Bol-Ran® is a combined medication that exerts a pronounced anti-inflammatory, analgesic, and antipyretic effect. The pharmacological activity of the drug is determined by the properties of diclofenac and paracetamol, which are components of the preparation.

Sodium diclofenac exerts a pronounced anti-inflammatory and analgesic effect, as well as a moderate antipyretic effect. Paracetamol demonstrates a pronounced analgesic effect, mild antipyretic activity, and a slight anti-inflammatory effect. 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 the active ingredients show a linear dependence on the dose of the drug; maximum levels are reached within 60–90 minutes after administration.

Binding of diclofenac to plasma proteins (mainly to 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 via methoxylation, leading to the formation of several phenolic metabolites whose biological activity is significantly lower than that of the parent compound.

The total systemic plasma clearance of diclofenac is approximately 300 mL/min. The terminal elimination half-life is 1–2 hours. About 60% of the administered dose is excreted in the urine as glucuronide conjugates of unchanged diclofenac, and the remainder is excreted in bile and feces.

Paracetamol is metabolized in the liver and is primarily excreted in the urine.

With repeated administration, the pharmacokinetic parameters of the active ingredients do not change. When recommended dosing intervals are maintained, no drug accumulation occurs.

Clinical characteristics.

Indications.

Contraindications.

Hypersensitivity to diclofenac, paracetamol, or to any other component of the medicinal product. Active gastric or intestinal ulcer; gastrointestinal bleeding or perforation. Inflammatory bowel diseases (Crohn’s disease or ulcerative colitis). Gastrointestinal bleeding or perforation associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs) in medical history. Active peptic ulcer/bleeding or recurrent peptic ulcer/bleeding in history (two or more separate episodes of confirmed ulcer or bleeding). Third trimester of pregnancy. Severe hepatic insufficiency (Child–Pugh class C, cirrhosis or ascites). Renal insufficiency (creatinine clearance < 30 mL/min). Severe heart failure (NYHA functional class III–IV), congestive heart failure (NYHA II–IV), decompensated heart failure, marked increase in blood pressure, organic cardiovascular diseases, including severe atherosclerosis, severe hypertensive disease, acute myocardial infarction, paroxysmal tachycardia, hyperthyroidism. Acute pancreatitis. Severe forms of diabetes mellitus. Glaucoma. Contraindicated in patients who experience attacks of bronchial asthma ("aspirin-induced asthma"), angioneurotic edema, urticaria, or acute rhinitis, nasal polyps, or other allergic symptoms in response to ibuprofen, diclofenac, paracetamol, acetylsalicylic acid, or other nonsteroidal anti-inflammatory drugs (NSAIDs). 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. Blood dyscrasias of unknown origin. Blood disorders, leukopenia, severe anemia. Conditions of increased excitation, sleep disturbances, epilepsy. Peripheral arterial diseases. Congenital hyperbilirubinemia. Glucose-6-phosphate dehydrogenase deficiency. Alcoholism. Treatment of postoperative pain following coronary artery bypass grafting (or use of cardiopulmonary bypass).

Interaction with other medicinal products and other forms of interaction.

Diclofenac.

Lithium, digoxin. The product may increase plasma concentrations of lithium and digoxin. Monitoring of lithium and digoxin plasma levels is recommended.

Diuretics and antihypertensive agents. The product, like other NSAIDs, when used concomitantly with diuretics or antihypertensive agents, such as beta-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, may reduce their antihypertensive effect by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, such combinations should be prescribed with caution, and patients (especially elderly) should have their blood pressure monitored periodically. Patients should consume sufficient amounts of water, and renal function should be monitored periodically, particularly after initiation and after discontinuation of concomitant therapy, especially when diuretics and ACE inhibitors are used, due to an increased risk of nephrotoxicity.

Medicinal products causing hyperkalemia. Concomitant use of potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to elevated serum potassium levels; therefore, serum potassium levels should be monitored in patients receiving such drugs concurrently.

Anticoagulants and antiplatelet agents. Concomitant use of the product with anticoagulants, particularly warfarin and other coumarins, and antiplatelet agents increases the risk of bleeding. Although clinical studies do not indicate an effect of diclofenac on anticoagulant activity, available data show an increased risk of bleeding in patients receiving diclofenac and anticoagulants simultaneously. To ensure anticoagulant dosing does not require adjustment, careful monitoring of such patients is recommended. Like other nonsteroidal anti-inflammatory drugs, diclofenac at high doses may temporarily inhibit platelet aggregation.

Other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, and corticosteroids. Concomitant use of the product with other NSAIDs or corticosteroids increases the risk of gastrointestinal bleeding or ulceration. Concurrent use of two or more NSAIDs should be avoided.

Selective serotonin reuptake inhibitors (SSRIs). Concomitant use of systemic NSAIDs and SSRIs increases the risk of gastrointestinal bleeding.

Antidiabetic agents. Diclofenac, when used with oral antidiabetic agents, did not alter their therapeutic effect. However, there are isolated reports of both hypoglycemia and hyperglycemia occurring in such cases, necessitating dosage adjustments of antidiabetic agents during treatment with the product. Therefore, blood glucose levels should be monitored during therapy.

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

Methotrexate. Diclofenac may inhibit renal tubular clearance of methotrexate, leading to elevated methotrexate levels. Caution should be exercised when prescribing NSAIDs, including diclofenac, less than 24 hours before or after methotrexate administration, as this may increase methotrexate blood concentration and enhance its toxic effects. Cases of severe toxicity have been reported when the interval between methotrexate and NSAID (including diclofenac) administration was within 24 hours. This interaction is mediated via methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Cyclosporine. The effect of NSAIDs on prostaglandin synthesis in the kidneys may potentiate the nephrotoxicity of cyclosporine; therefore, the product should be administered in lower doses when given to patients receiving cyclosporine.

Tacrolimus. The concomitant use of NSAIDs with tacrolimus increases the risk of nephrotoxicity, which may be mediated via renal anti-prostaglandin effects of NSAIDs and the calcineurin inhibitor.

Antibacterial agents – quinolone derivatives. Seizures may occur in patients receiving quinolone derivatives and NSAIDs concomitantly. This may occur in patients both with and without a history of epilepsy or seizures. Therefore, caution should be exercised when considering quinolone use in patients already receiving NSAIDs.

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

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

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

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

CYP2C9 inhibitors. Caution is required when co-prescribing diclofenac with CYP2C9 inhibitors (e.g., voriconazole). This may lead to a significant increase in maximum plasma concentrations and enhanced effects of diclofenac.

CYP2C9 inducers. Caution is required when co-prescribing diclofenac with CYP2C9 inducers (e.g., rifampicin). This may lead to a significant decrease in plasma concentration and reduced efficacy of diclofenac.

Paracetamol.

The absorption rate of paracetamol may be increased when used with metoclopramide and domperidone, and decreased when used with cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by long-term daily use of paracetamol, increasing the risk of bleeding. Occasional use has no significant effect.

Barbiturates reduce the antipyretic effect of paracetamol.

Concomitant use of paracetamol with chloramphenicol increases the plasma concentration of the latter.

Concomitant use of high doses of paracetamol with isoniazid or rifampicin increases the risk of hepatotoxic syndrome. Paracetamol reduces the efficacy of diuretics.

Do not use concomitantly with alcohol.

Special precautions for use.

General warnings regarding the use of systemic NSAIDs

Gastrointestinal ulcers, bleeding, or perforation may occur at any time during NSAID therapy, regardless of COX-2 selectivity, even in the absence of warning symptoms. To minimize this risk, as well as the risk of other adverse reactions, treatment should be initiated with the lowest effective dose and administered for the shortest duration necessary.

Concomitant use of Bol-Ran® with systemic NSAIDs, such as selective COX-2 inhibitors, should be avoided due to lack of evidence for synergistic effect and potential for additive adverse effects. There is an increased risk of thrombotic cardiovascular and cerebrovascular complications associated with use of certain selective COX-2 inhibitors. It is unknown whether this risk is directly related to the COX-1/COX-2 selectivity of individual NSAIDs. Currently, there are no available data on long-term treatment with the maximum dose of diclofenac; therefore, the risk-benefit ratio of diclofenac use should be carefully considered in patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial occlusive disease, or significant risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Diclofenac should be prescribed to patients with significant cardiovascular risk factors only after careful clinical evaluation. Since cardiovascular risks associated with 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 response to therapy and need for continued diclofenac use for symptom relief should be periodically reassessed.

Do not use concurrently with other agents containing diclofenac.

This medicinal product contains paracetamol; therefore, it should not be used together with other medications containing paracetamol, such as those used for fever reduction, pain relief, flu and cold symptoms, or insomnia. Concomitant use with other paracetamol-containing products may lead to overdose. Paracetamol overdose can cause liver failure, which may necessitate liver transplantation or result in death.

Outcomes are generally more severe in elderly patients.

If gastrointestinal bleeding or ulceration occurs in patients, use of Bol-Ran® should be discontinued.

In patients with reduced glutathione levels, the risk of developing metabolic acidosis during paracetamol intake is increased. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Immediate medical attention should be sought if these symptoms occur. If symptoms persist, medical advice should be sought.

Consult a physician before use if the patient is taking warfarin or similar anticoagulant agents.

Patients who take analgesics daily for mild forms of arthritis should consult a physician.

Caution is required when administering the drug to patients over 65 years of age. In particular, the lowest effective dose should be used in elderly or underweight patients.

History of bronchial asthma

Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (i.e., nasal polyps), chronic obstructive pulmonary disease, or chronic respiratory tract infections (especially those associated with allergic, rhinitis-like symptoms) are more likely to experience reactions to NSAIDs, such as asthma exacerbation (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria. Therefore, special precautionary measures (readiness for emergency intervention) are recommended for such patients. This also applies to patients with allergic reactions to other substances (e.g., rash, pruritus, or urticaria).

Effects on the gastrointestinal tract

As with other NSAIDs, both COX-2 selective and non-selective, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation—some of which may be fatal—have been reported. These events may occur at any time during treatment, with or without warning symptoms or a history of serious gastrointestinal events. These effects generally have more serious consequences in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.

As with other NSAIDs, including diclofenac-containing products, medical supervision and special caution are mandatory in patients with symptoms suggesting gastrointestinal (GI) tract disorders or with a history of gastric or intestinal ulcers, bleeding, or perforation. The risk of GI bleeding increases with higher doses and is elevated in patients with a history of ulcers, especially those complicated by bleeding or perforation. Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal. To reduce the risk of GI toxicity, treatment should be initiated and maintained at the lowest effective doses. For such patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid (ASA/aspirin) or other drugs increasing GI risk, consideration should be given to co-therapy with protective agents (e.g., proton pump inhibitors or misoprostol). Patients with a history of gastrointestinal toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding). Caution is also required in patients receiving concomitant medications that increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., ASA), or selective serotonin reuptake inhibitors.

Effects on the liver

The risk of hepatotoxic effects of paracetamol is increased in patients with liver disease. Consult a physician before use.

Close medical monitoring is required when administering the drug to patients with impaired liver function, as their condition may worsen.

As with other NSAIDs, including diclofenac, the levels of one or more liver enzymes may increase. Elevated enzyme levels usually return to normal after discontinuation of the drug.

During long-term treatment, monitoring of liver function and liver enzyme levels is recommended as a precautionary measure. If liver function abnormalities persist or worsen, or if clinical symptoms suggest progressive liver disease or other manifestations (e.g., eosinophilia, rash), the drug should be discontinued.

In addition to elevated liver enzymes, severe hepatic reactions have been rarely observed, including jaundice, fulminant hepatitis, liver necrosis, and liver failure, some of which have resulted in death.

Diseases such as hepatitis may progress without prodromal symptoms. Caution is required when administering the drug to patients with hepatic porphyria, due to the potential to provoke an attack.

Effects on the kidneys

Consult a physician before use in patients with kidney disease.

Renal effects of NSAIDs, including diclofenac, frequently (1–10%) include fluid retention with edema and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with cardiac dysfunction and other conditions leading to fluid retention, particularly in patients with impaired cardiac or renal function, history of arterial hypertension, elderly patients, those receiving concomitant diuretic therapy, angiotensin-converting enzyme (ACE) inhibitors, or drugs significantly affecting renal function, patients at increased risk of hypovolemia, and those with significantly reduced extracellular fluid volume due to any cause, such as before or after major surgery. In such cases, monitoring of renal function is recommended. Discontinuation of therapy usually results in return to the pre-treatment state.

Effects on the skin

Serious skin reactions, some of which are fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported with NSAIDs, including diclofenac. The highest risk for these reactions occurs early in therapy, with most cases developing within the first month of treatment. The drug should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity. Rarely, as with other NSAIDs, allergic reactions including anaphylactic/anaphylactoid reactions may occur, even without prior exposure to diclofenac. Due to its pharmacodynamic properties, the drug, like other NSAIDs, may mask symptoms of infection.

Systemic lupus erythematosus and mixed connective tissue diseases

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

Cardiovascular and cerebrovascular effects

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

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

Bol-Ran® should be used with caution in patients taking concomitant diuretics or ACE inhibitors, or those at increased risk of hypovolemia.

Available data indicate that diclofenac use, particularly at high doses (150 mg/day) and during prolonged treatment, slightly increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke).

The drug is contraindicated in patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

Effects on hematological parameters

Complete blood count is recommended during long-term use of this drug, as with other NSAIDs. Like other NSAIDs, the drug may temporarily inhibit platelet aggregation. Patients with coagulation disorders, hemorrhagic diathesis, or hematological disorders should be closely monitored.

Diclofenac, an ingredient of the drug, may adversely affect female fertility and is therefore not recommended for patients attempting to conceive or undergoing infertility investigations.

The risk of hepatotoxic effects of paracetamol is increased in patients with alcoholic non-cirrhotic liver disease. The drug may affect laboratory test results for blood glucose and uric acid levels.

Do not exceed the recommended doses.

Use during pregnancy or breastfeeding

The drug is contraindicated during pregnancy or breastfeeding.

If used by women attempting to conceive, the dose should be as low as possible and the duration of treatment as short as possible.

Ability to affect reaction speed when driving or operating machinery

Patients who experience visual disturbances, dizziness, vertigo, somnolence, or other central nervous system effects during Bol-Ran® use should refrain from driving or operating machinery.

Method of Administration and Dosage

For adults and children aged 14 years and older: 1 tablet 2–3 times daily after meals. The interval between doses should be at least 4 hours. Tablets should be taken whole, without chewing, with half a glass of water. Do not exceed the recommended dose.

The treatment duration should be as short as possible and should not exceed 5–7 days. The maximum duration of use without medical consultation is 3 days.

The maximum daily dose of the drug for adults and children aged 14 years and older is 3 tablets.

Do not take together with other medicinal products containing diclofenac or paracetamol.

Children

The medicinal product is contraindicated in children under 14 years of age.

Overdose

Diclofenac

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

Treatment

Treatment of acute poisoning with NSAIDs, including diclofenac, consists of supportive and symptomatic therapy. This includes management 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, because the active substances are highly protein-bound and undergo extensive metabolism. Activated charcoal may be administered after ingestion of potentially toxic doses. Gastric decontamination (e.g., induction of emesis, gastric lavage) may be performed after ingestion of potentially life-threatening doses.

Paracetamol

Paracetamol overdose may lead to liver failure, which may necessitate liver transplantation or result in death. Acute pancreatitis has been observed, usually in conjunction with liver dysfunction and hepatotoxicity.

Liver damage may occur in adults who ingest 10 g or more of paracetamol and in children who ingest more than 150 mg/kg body weight. In patients with risk factors (chronic use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs that induce liver enzymes; alcohol abuse; glutathione system deficiency, e.g., due to malnutrition, HIV infection, fasting, cystic fibrosis, cachexia), ingestion of 5 g or more of paracetamol may lead to liver damage.

Prompt medical attention is required in case of overdose. Treatment should be initiated immediately. The patient should be taken to a hospital even if early symptoms of overdose are absent.

Symptoms within the first 24 hours: pallor, nausea, vomiting, loss of appetite, abdominal pain. Experience shows that symptoms of liver damage may become apparent 12–48 hours after overdose and usually peak within 4–6 days. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, liver failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and may result in death. Acute renal failure with acute tubular necrosis may present as severe lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias have also been reported.

With prolonged use of the drug in high doses, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop from the hematopoietic system. High-dose intake may cause the following reactions: from the central nervous system – dizziness, psychomotor agitation, and disorientation; from the urinary system – nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis); from the digestive system – hepatic necrosis.

Treatment

Symptoms of overdose may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. Immediate medical assistance is required in case of overdose, even if no symptoms are observed. If overdose is confirmed or even suspected, the patient must be taken to the nearest medical facility where emergency medical care and qualified treatment can be provided. This should be done even if no symptoms of overdose are present—due to the risk of delayed liver damage. Administration of activated charcoal should be considered if the excessive dose of paracetamol was ingested within 1 hour. Plasma paracetamol 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 the maximum protective effect is achieved when administered within 8 hours after ingestion. The efficacy of the antidote decreases sharply after this time. If necessary, intravenous N-acetylcysteine should be administered according to current dosing recommendations. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside the hospital.

Side effects.

Blood and lymphatic system disorders: thrombocytopenia, neutropenia, leukopenia, anemia, including aplastic anemia and hemolytic anemia (especially in patients with glucose-6-phosphate dehydrogenase deficiency), sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), agranulocytosis, pancytopenia, bruising or bleeding.

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

Psychiatric disorders: disorientation, depression, nightmares, irritability, restlessness, fear, psychotic disorders, confusion, psychomotor agitation.

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

Ear and labyrinth disorders: vertigo, tinnitus, ear noise, hearing disorders.

Cardiovascular system disorders: palpitations, tachycardia, dyspnea, chest pain, heart failure, myocardial infarction, arterial hypertension, arterial hypotension, hypertensive crisis, vasculitis.

Respiratory system disorders: bronchial asthma (including dyspnea), bronchospasm (especially in patients sensitive to aspirin and other NSAIDs), chest pain, pneumonitis.

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

Hepatobiliary system disorders: liver function abnormalities, elevated transaminase levels; liver failure, hepatitis, liver necrosis, jaundice, hepatic disorders; fulminant hepatitis.

Renal and urinary system disorders: fluid retention, edema, hypertension, acute renal failure, hematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.

General disorders: edema, general weakness, increased sweating, hypoglycemia, up to hypoglycemic coma.

Reproductive system and breast disorders: impotence.

Visual disturbances.

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

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

10 tablets in a blister, 1 blister in a cardboard pack (pack size № 10);

10 tablets in a blister, 10 blisters in a cardboard pack (pack size № 100 (10×10)).

Prescription status.

By prescription only.

Manufacturer.

Vivimed Labs Ltd, India / Vivimed Labs Ltd, India.

Manufacturer's address and location of operations.

D-125 & 128, Phase-III, IDA, Jeedimetla, Medchal-Malkajgiri District - 500055, India

Marketing authorization holder. JIVDHARA PHARMA PRIVATE LIMITED / JIVDHARA PHARMA PRIVATE LIMITED.

Bol-ran

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BOL-RAN® (BOL-RAN®)

Composition:

Pharmacological Properties.

Clinical characteristics.

Special precautions for use.

Method of Administration and Dosage

Adverse Reactions

Composition:

Pharmacological properties.

Clinical characteristics.

Special precautions for use.

Method of Administration and Dosage

Side effects.