INSTRUCTION

for medical use of the medicinal product

BOL-RAN^®

Composition:

active substance: paracetamol, diclofenac sodium;

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

excipients: corn starch, microcrystalline cellulose, sodium starch glycolate (type A), croscarmellose sodium, povidone, magnesium stearate, anhydrous colloidal silica.

 

Pharmaceutical form. Tablets.

Basic physical and chemical properties: white, round, flat tablets with a scoreline on one side.

 

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and anti-rheumatic drugs.

ATC code  М01А В55.

 

Pharmacological properties.

Pharmacodynamics.

Bol-Ran^® is a combined drug that has pronounced anti-inflammatory, analgesic and antipyretic effects. The pharmacological activity of the drug is due to the properties of diclofenac and paracetamol, which are part of the drug.

Diclofenac sodium has pronounced anti-inflammatory, analgesic and moderate antipyretic effects. Paracetamol has pronounced analgesic, minor 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 drug’s absorption.

Concentrations of active substances in blood plasma have a linear dependence in the drug dose. The maximum levels are reached in 60-90 minutes after administration.

Diclofenac is bound to serum proteins at 99.7 %, mainly to albumin. The expected volume of distribution is 0.12-0.17 L/kg. Diclofenac penetrates the synovial fluid, where its maximum concentration is reached 2-4 hours later than in blood plasma. The half-life of diclofenac from synovial fluid is 3-6 hours.

Diclofenac is metabolized by glucuronidation of the unchanged molecule and by methoxylation, which leads to the formation of several phenolic metabolites, the biological activity of which is significantly inferior to the starting material activity.

The total systemic plasma clearance of diclofenac is approximately 300 ml/min. The terminal half-life in plasma is 1-2 hours. 60% of the administered dose is excreted in the urine in form of glucuronide conjugates of unchanged diclofenac. The remainder of the dose is eliminated through the bile in the faeces.

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

After repeated use of the drug, the pharmacokinetic parameters of the active substances do not change. Under the conditions of observance of the recommended intervals between receptions of tablets accumulation of drug is not noted. No accumulation of the drug occurs at the recommended dosage intervals.

 

Clinical particulars.

Indications.

Acute pain (muscular pain, headache, toothache, pain localized in the spine), pain in non-articular rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, acute gout attacks, primary dysmenorrhoea, otitiseritis, otitis media; post-traumatic and postoperative pain.

 

Contraindications.

Hypersensitivity to diclofenac, paracetamol or to any other component of the drug. Acute gastric or intestinal ulcer; gastrointestinal bleeding or perforation. Inflammatory bowel disease (Crohn's disease or ulcerative colitis). History of gastrointestinal bleeding or perforation associated with nonsteroidal anti-inflammatory drugs. Active form of peptic ulcer/bleeding or recurrent peptic ulcer/history of bleeding (two or more separate episodes of diagnosed ulcer or bleeding). The last trimester of pregnancy. Severe hepatic impairment (Child-Pugh C, cirrhosis or ascites). Renal insufficiency (creatinine clearance <30 ml/min). Severe heart failure (Class III-IV according to the Functional Classification of the New York Association of Cardiologists of Chronic Heart Failure (NYHA)), congestive heart failure (NYHA II-IV), decompensated heart failure, expressed blood pressure increase, cardiovascular system organic diseases, including severe atherosclerosis, severe hypertension, acute myocardial infarction, paroxysmal tachycardia, hyperthyroidism. Acute pancreatitis. Severe forms of diabetes. Glaucoma. Contraindicated in patients who, in response to ibuprofen, diclofenac, paracetamol, acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs), develop asthma attacks ("aspirin asthma"), angioneurotic oedema, polyps allergic symptoms. Ischemic heart disease in patients with angina, patients experienced myocardial infarction. Cerebrovascular disease in patients, who experienced a stroke or have episodes of transient ischemic attacks. Hematopoietic disorders of unknown origin. Blood diseases, leukopenia, severe anaemia. Increased arousal condition, sleep disorders, epilepsy. Diseased peripheral arteries. Congenital hyperbilirubinemia. Glucose-6-phosphate dehydrogenase deficiency. Alcoholism. Treatment of postoperative pain in coronary artery bypass grafting (or when using artificial circulation).

 

Interaction with other medicinal products and other forms of interaction.

Diclofenac.

Lithium, digoxin. If used concomitantly, diclofenac may raise plasma concentrations of lithium and digoxin. Monitoring of the serum lithium and digoxin level is recommended.

Diuretics and antihypertensive agents. Like other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors) may cause a decrease in their antihypertensive effect by inhibiting the synthesis of vasodilating prostaglandins. Therefore, the combination should be administered with caution and patients (especially the elderly) should have their blood pressure periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity.

Drugs known to cause hyperkalaemia. Concomitant use of potassium-sparing diuretics, cyclosporine, tacrolimus or trimethoprim may cause increased serum potassium, so serum potassium should be monitored in patients receiving such concomitant medications.

Anticoagulants and antiplatelet agents. Concomitant use of the drug with anticoagulants, especially warfarin and other coumarins, and antiplatelet drugs increases the risk of bleeding. Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there are reports of an increased risk of haemorrhage in patients receiving diclofenac and anticoagulants concomitantly. Careful monitoring of such patients is recommended to ensure that anticoagulant dosage does not require adjustment. Like other nonsteroidal anti-inflammatory drugs, diclofenac in high doses may temporarily inhibit platelet aggregation.

Other NSAIDs, including selective cyclooxygenase-2 inhibitors, and corticosteroids. Concomitant use of the drug and other NSAIDs or corticosteroids increases the risk of gastrointestinal bleeding or ulcers. Concomitant 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.

Antidiabetics. Diclofenac when used in combination with oral antidiabetic agents did not affect their therapeutic effect. However, there have been isolated reports of both hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose level in recommended during concomitant therapy.

There have also been isolated reports of metabolic acidosis when co-administered with diclofenac, especially in patients with pre-existing renal impairment.

Methotrexate. Diclofenac can inhibit the tubular renal clearance of methotrexate hereby increasing methotrexate levels. Caution is recommended when NSAIDs, including diclofenac, are administered less than 24 hours before or after treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increased. Cases of severe toxicity have been reported when the interval between methotrexate and NSAIDs, including diclofenac, was within 24 hours. This interaction is mediated through the accumulation of methotrexate as a result of impaired renal excretion in the presence of NSAIDs.

Cyclosporine. The effect of NSAIDs on the synthesis of prostaglandins in the kidneys may increase the nephrotoxicity of cyclosporine. Therefore the drug should be given at doses lower than those that would be used in patients not receiving cyclosporine.

Tacrolimus. The use of NSAIDs with tacrolimus increases the risk of nephrotoxicity, which may be mediated through the renal antiprostaglandin effects of NSAIDs and calcineurin inhibitor.

Quinolone antibacterials. Convulsions may occur in patients who have co-administered quinolone and NSAIDs. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSAID.

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

Agents that stimulate enzymes metabolizing medicinal products. Agents that stimulate enzymes, such as rifampicin, carbamazepine, phenytoin, St. John's wort (Hypericum perforatum), etc., are theoretically able to reduce plasma concentrations of diclofenac.

Colestipol and cholestyramine. Co-administration of colestipol or cholestyramine reduces the absorption of diclofenac by approximately 30% and 60%, respectively. Therefore, it is recommended to administer diclofenac at least one hour before or 4 to 6 hours after administration of colestipol/cholestyramine.

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

Mifepristone. NSAIDs should not be used for 8-12 days after taking mifepristone, since NSAIDs may reduce the effect of mifepristone.

CYP2C9 inhibitors. Caution should be exercised when co-administering diclofenac with CYP2C9 inhibitors (e.g. voriconazole). This may cause a significant increase in peak plasma concentrations and a potentiation of diclofenac.

CYP2C9 inductors. Caution should be exercised when co-administering diclofenac with CYP2C9 inducers (e.g. rifampicin). This may cause a significant decrease in plasma concentrations and a weakening of diclofenac.

Paracetamol.

The rate of absorption of paracetamol may increase with metoclopramide and domperidone and decrease with cholestyramine as well. The anticoagulant effect of warfarin and other coumarins may be enhanced in case of concomitant long-term daily use of paracetamol and the risk of bleeding may be increased. Periodic intake has no significant effect.

Barbiturates reduce the antipyretic effect of paracetamol.

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

Anticonvulsants (including phenytoin, barbiturates, carbamazepine), which stimulate the activity of liver microsomal enzymes, may increase the toxic effects of paracetamol on the liver by increasing the rate of conversion of the drug to hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic drugs increases the toxic effects of drugs on the liver.

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

Do not use with alcohol.

 

Precautions for use.

General precautions for the use of systemic NSAIDs

Gastrointestinal ulcers, bleeding or perforations may occur at any time during NSAID treatment, regardless of the selectivity of cyclooxygenase-2 (COX-2), 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 should be carried out within the shortest period of time.

Concomitant use of Bol-Ran^® with systemic NSAIDs, such as selective COX-2 inhibitors, should be avoided due to the lack of any evidence of a synergistic effect and due to potential additive side effects. There is an increased risk of thrombotic cardiovascular and cerebrovascular complications when used with certain selective COX-2 inhibitors. It is not known whether this risk is directly related to the selectivity of COX-1/COX-2 of individual NSAIDs. To date, no data on the long-term treatment with the maximum dose of diclofenac are available. Therefore the risk-benefit balance of diclofenac should be carefully considered in patients with clinically confirmed coronary heart disease, cerebrovascular disorders, peripheral arterial occlusive disease or significant risk factors for hyperberaemia, hypertension, smoking). Diclofenac should be prescribed to patients with significant risk factors for cardiovascular events only after careful clinical evaluation. Since the cardiovascular risks of diclofenac may be increased with increasing dose and duration of treatment, it should be used for as short a period as possible and at the lowest effective dose. Response to therapy and the patient's need to use diclofenac to relieve symptoms should be reconsidered periodically.

Do not use concomitantly with other drugs containing diclofenac.

This medicinal product contains paracetamol, therefore it should not be used with other paracetamol-containing medicinal products used, for example, to reduce fever, treat pain, flu and cold symptoms or insomnia. Concomitant use with other paracetamol-containing medicinal products may cause an overdose. The overdose of paracetamol may be fatal or may cause liver failure as a result the liver transplantation may be needed.

The consequences are usually more serious in elderly patients.

If patients experience gastrointestinal bleeding or ulcers, Bol-Ran^® should be discontinued.

Cases of hepatic impairment/liver insufficiency have been reported in patients with low glutathione levels, such as severe depletion, anorexia, low body mass index, chronic alcoholism or sepsis.

The increased risk of metabolic acidosis has patients with decreased glutathione levels when using paracetamol. Symptoms of metabolic acidosis are deep, rapid or difficult breathing, nausea, vomiting and loss of appetite. It is recommended to see a doctor immediately if these symptoms occurred. If symptoms persist, the patient should seek medical attention.

Before using the drug, consult a doctor if the patient is using warfarin or similar drugs having an anticoagulant effect.

Patients who take analgesics every day for mild arthritis should consult a doctor.

Caution should be exercised in patients over 65 years of age. In particular, it is recommended that the lowest effective dose to be used in debilitated elderly or patients with low body weight.

History of bronchial asthma

Patients with bronchial asthma, seasonal allergic rhinitis, oedema of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary disease or chronic respiratory infections (especially those associated with allergic, rhinitis-like symptoms) have more likely reactions to NSAIDs, such as asthma exacerbation (so-called intolerance to analgesics/analgesic asthma), angioedema or urticaria. Therefore, special precautions (preparedness for emergency care) are recommended for such patients. This also applies to patients with allergic reactions to other substances (such as rash, itching or urticaria).

Like other prostaglandinsynthetase inhibitors, diclofenac sodium and other NSAIDs may provoke the development of bronchospasm when used in patients with bronchial asthma or in patients with a history of bronchial asthma.

Gastrointestinal effects

As with any other COX-2-selective NSAIDs, including diclofenac, some cases of gastrointestinal bleeding (vomiting, melena), ulceration or perforation, which may be fatal and occur in any time in the course of treatment in the presence or absence of warning symptoms or serious phenomena of the gastrointestinal tract in the anamnesis have been reported. These phenomena usually have more serious consequences in elderly patients. If gastrointestinal bleeding or ulceration are observed in patients receiving diclofenac, the drug should be discontinued.

As with all NSAIDs, including diclofenac, close medical surveillance is imperative and particular caution should be exercised when prescribing diclofenac in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation. The risk of GI bleeding is higher with increasing NSAID doses and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation. The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal. To reduce the risk of GI toxicity, the treatment should be initiated and maintained at the lowest effective dose. Combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered for these patients, and also for patients requiring concomitant use of medicinal products containing low-dose acetylsalicylic acid (ASA/aspirin) or other medicinal products likely to increase gastrointestinal risk. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding). Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants such as warfarin, anti-platelet agents such as acetylsalicylic acid (ASA/aspirin) or selective serotonin-reuptake inhibitors.

Hepatic effects

It should be considered that patients with liver disease have the increased risk of hepatotoxic effects of paracetamol. It is recommended to consult your doctor before using this medicinal product.

Close medical surveillance is required when prescribing the drug to patients with impaired hepatic function, as their condition may be exacerbated.

As with other NSAIDs, including diclofenac, values of one or more liver enzymes may increase. The increased enzyme levels usually recover after discontinuation of the drug.

During prolonged treatment with the drug, regular monitoring of hepatic function and hepatic enzyme levels is indicated as a precautionary measure. If abnormal liver function tests persist or worsen, if clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash), the drug should be discontinued.

In addition to the increased liver enzymes, the severe liver reactions, including jaundice and fulminant hepatitis, liver necrosis and liver failure causing death in some cases have been reported rarely.

The course of diseases such as hepatitis may occur without prodromal symptoms. Caution should be exercised when using the drug in patients with hepatic porphyria, since it may trigger in attack.

Renal effects

In case of kidney diseases, it is recommended to consult a doctor before using the drug.

Renal effects of NSAIDs, including diclofenac, often (1–10%) include fluid retention with oedema and/or hypertension. Therefore, diclofenac should be used with caution in patients with cardiac dysfunction and other conditions causing fluid retention, especially in patients with cardiac or renal impairment, a history of hypertension, in elderly patients, in patients receiving concomitant therapy with diuretics, ACE inhibitors or drugs that significantly affect renal function, in patients at increased risk of hypovolaemia, and in those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery. Monitoring of renal function is recommended in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.

Skin effects

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. The drug should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign 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 drug, like other NSAIDs, can mask the symptoms of infection.

Systemic lupus erythematosus and mixed connective tissue diseases

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

Cardiovascular and cerebrovascular effects

 Bol-Ran^® treatment is generally not recommended for patients diagnosed with cardiovascular disease (heart failure, coronary heart disease, peripheral artery disease) or uncontrolled hypertension.

Diclofenac should be prescribed to patients with significant risk factors for cardiovascular events (such as hypertension, hyperlipidaemia, diabetes, smoking) only after careful clinical evaluation and only at doses up to 100 mg per day for a course of treatment not exceeding 4 weeks. Since the cardiovascular risks of diclofenac may be increased with increasing dose and duration of treatment, it should be used for as short a period as possible and at the lowest effective dose. The patient's need to use diclofenac to relieve symptoms and respond to therapy should be reconsidered periodically, especially if treatment lasts more than 4 weeks.

Patients with a history of hypertension and/or mild or moderate congestive heart failure should be monitored and advised, since fluid retention and oedema have been reported with NSAIDs, including diclofenac.

Bol-Ran^® should be used with caution in patients taking concomitant diuretics or ACE inhibitors or in those having the increased risk of hypovolaemia.

The available data suggest that the use of diclofenac, especially in high doses (150 mg/day) and with long-term treatment, slightly increases the risk of arterial thrombotic complications (e.g. myocardial infarction or stroke).

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

Patients should be informed of the possibility of serious antithrombotic symptoms at any time (chest pain, shortness of breath, weakness, speech disorders). In this case, it is necessary to see a doctor immediately.

Haematological effects

During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended. Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Patients with defects of haemostasis and patients treated with anticoagulants should be carefully monitored.

Diclofenac, which is part of the drug, may adversely affect women's fertility, therefore it is not recommended for use in patients trying to conceive or undergoing infertility testing.

It should be considered that the risk of hepatotoxic effects of paracetamol is increased in patients with alcoholic non-cirrhotic liver disease. The drug may affect the results of laboratory tests for blood glucose and uric acid.

Do not exceed these doses.

 

Pregnancy and Lactation.

The medicinal product is contraindicated during pregnancy or breastfeeding.

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

 

Effects on ability to drive and use machines.

Patients experiencing visual disturbances, dizziness, vertigo, somnolence or other central nervous system disturbances while taking diclofenac, should refrain from driving or using machines.

 

Method of administration and dosage.

The dose and duration of treatment is determined by the doctor for each patient individually, depending on the patient's age, nature and course of the disease, individual tolerability and therapeutic efficacy of the drug. The drug should be used in the lowest effective doses for the shortest period of time, taking into account the objectives of treatment in each individual patient.

Adults and children over 14 years of age – 1 tablet 2-3 times a day after meals, the interval between doses is at least 4 hours. It is recommended to take the tablets with a half of glass of water without chewing. Do not exceed the recommended dose.

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

The maximum daily dose for adults and children over 14 years of age is 3 tablets.

Do not take with other medicines containing diclofenac or paracetamol.

 

Children.

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

 

Overdose.

Diclofenac.

There is no typical clinical picture resulting from diclofenac over dosage. Overdose can cause symptoms such as vomiting, gastrointestinal haemorrhage, diarrhoea, dizziness, tinnitus or convulsions. In the event of significant poisoning, acute renal failure and liver damage are possible.

 

Therapeutic measures.

Management of acute poisoning with NSAIDs, including diclofenac, essentially consists of supportive measures and symptomatic treatment. Supportive measures and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal disorder, and respiratory depression.

Special measures such as forced diuresis, dialysis or haemo-perfusion are probably of no help in eliminating NSAIDs, including diclofenac, due to the high protein binding and extensive metabolism. Activated charcoal may be considered after ingestion of a potentially toxic overdose, and gastric decontamination (e.g. vomiting, gastric lavage) after ingestion of a potentially life threatening overdose.

Paracetamol.

The overdose of paracetamol may be fatal or may cause liver failure as a result the liver transplantation may be needed. Acute pancreatitis was usually observed with hepatic impairment and hepatotoxicity.

Liver damage is possible in adults who have taken 10 g or more of paracetamol and in children who received more than 150 mg/kg body weight. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (long-term use of carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St. John's wort or other drugs that induce liver enzymes; alcohol abuse; glutathione system deficiency, e.g. malnutrition, HIV infection, starvation, cystic fibrosis, cachexia).

Immediate treatment is essential in the management of paracetamol overdose. Treatment should be started immediately. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention.

Symptoms of paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Experience has shown that symptoms of liver damage may become apparent 12 to 48 hours after administration and usually reach a maximum after 4 to 6 days. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

With long-term use of the drug at high doses, aplastic anaemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia may develop in hematopoietic organs. At high doses, the following reactions may occur: the central nervous system disorders- dizziness, psychomotor agitation and disorientation; the urinary system disorders - nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis); the digestive system disorders - hepatonecrosis.

Management.

Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Immediate medical attention is required in case of overdose, even if symptoms of overdose are not observed. If the overdose is confirmed or even suspected, the patient should be taken to the nearest medical facility where he or she will be able to receive emergency medical care and qualified treatment. This should be done even if there are no symptoms of overdose - due to the risk of delayed liver damage. Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable).  Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol however, the maximum protective effect is obtained up to 8 hours post ingestion. The effectiveness of the antidote decreases sharply after this time. If required the patient should be given intravenous-N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital.

Supportive and symptomatic treatment is indicated for complications such as hypotension, renal failure, convulsions, gastrointestinal disorders and respiratory depression. Forced diuresis, hemodialysis or hemoperfusion are unlikely to be effective in the elimination of non-steroidal anti-inflammatory drugs (NSAIDs), since the active substances of the drug are highly bound to plasma proteins and undergo extensive metabolism.

 

Adverse reactions.

Blood system and lymphatic system disorders: thrombocytopenia, neutropenia, leukopenia, anaemia, including aplastic anaemia, haemolytic anaemia (especially for patients with glucose-6-phosphate dehydrogenase deficiency), sulfhemoglobinemia and methemoglobinemia (cyanosis, shortness of breath, heart pain), agranulocytosis, pancytopenia, bruising or bleeding.

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

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

Psychiatric disorders: disorientation, depression, night terrors, irritability, anxiety, fear, psychotic disorders, confusion, psychomotor agitation.

Nervous system disorders: headache, dizziness, drowsiness, fatigue, paraesthesiae, sleep disturbances, insomnia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular disorders, stroke, hallucinations, taste disturbances, general malaise.

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

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

Cardiovascular system disorders: palpitations, tachycardia, shortness of breath, heart pain, heart failure, myocardial infarction, hypertension, hypotension, hypertensive crisis, vasculitis.

Respiratory, thoracic and mediastinal disorders: bronchial asthma (including shortness of breath), bronchospasm (especially in patients sensitive to aspirin and other NSAIDs), chest pain, pneumonitis.

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

Hepatobiliary disorders: liver dysfunction, transaminases increased; liver failure, hepatitis, liver necrosis, jaundice, liver disorders; fulminant hepatitis.

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

General disorders: oedema, general weakness, increased sweating, hypoglycaemia, hypoglycaemic coma.

Reproductive system and breast disorders: impotence.

Clinical trial and epidemiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high dose (150 mg daily) and in long term treatment.

Eye disorders.

Eye disorders such as visual disturbances, visual impairment and diplopia are effects of the NSAID class and, generally, they are reversible after drug withdrawal. The most likely mechanism of visual impairment is inhibition of the synthesis of prostaglandins and other related compounds, which, by disrupting the regulation of retinal blood flow, contribute to the development of visual disturbances. If such symptoms occur during treatment with diclofenac, an ophthalmologic 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.

Keep out of reach of children.

 

Packaging.

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

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

 

Terms of dispensing.

On prescription.

 

Manufacturer.

Vivimed labs Ltd., India.

 

Manufacturer’s registered address.

D-125 & 128, Phase-III, IDA, Jeedimetla, Hyderabad-500055, Telangana State, India.

 

Applicant. SCAN BIOTECH LTD, India.