Doloxene

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOLOXEN (DOLOXEN)

Composition:

Active substances: paracetamol, diclofenac sodium;

1 tablet contains 500 mg of paracetamol and 50 mg of diclofenac sodium;

Excipients: sodium croscarmellose, microcrystalline cellulose, povidone, methacrylic acid copolymer dispersion, magnesium stearate, sodium starch glycolate (type A), hydroxypropylmethylcellulose, macrogol 4000, titanium dioxide (E 171), purified talc, dichloromethane, isopropyl alcohol, purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped, biconvex, film-coated tablets of white or almost white color, with a score line on one side.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01AB55.

Pharmacological properties.

Pharmacodynamics.

Doloxen is a combination drug that has pronounced anti-inflammatory, analgesic, and antipyretic effects. The pharmacological activity of the drug is determined by the properties of diclofenac and paracetamol, which are components of Doloxen. The main mechanism of action of diclofenac is inhibition of the synthesis of prostaglandins—endogenous substances that play an important role in the pathogenesis of inflammation, pain, and fever. Paracetamol belongs to nonsteroidal anti-inflammatory drugs (NSAIDs) from the group of para-aminophenol derivatives. The analgesic and antipyretic effects of paracetamol are due to its influence on hypothalamic centers of the brain.

In rheumatic diseases, the anti-inflammatory and analgesic properties of Doloxen provide a clinical effect characterized by reduction in joint pain intensity, morning stiffness, joint swelling, and improvement in joint function.

In post-traumatic and postoperative inflammatory conditions, Doloxen rapidly relieves pain and reduces inflammatory swelling of postoperative wounds.

Doloxen also has an analgesic effect in pain syndromes of non-rheumatic origin, including primary algodysmenorrhea and migraine attacks.

Pharmacokinetics.

After oral administration of Doloxen, diclofenac and paracetamol are rapidly and completely absorbed. Food does not affect the absorption of the drug.

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

Protein binding of diclofenac to plasma proteins (mainly to albumin) reaches 99.7%. The apparent 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 is metabolized via glucuronidation of the unchanged molecule and via oxidative metabolism (hydroxylation and 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. 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 via bile and feces.

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

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

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to diclofenac, paracetamol, or any other component of the medicinal product.

Acute peptic ulcer of the stomach or intestine; gastrointestinal bleeding or perforation.

Active peptic ulcer disease/bleeding or recurrent peptic ulcer disease/bleeding in history (two or more separate episodes of diagnosed ulcer or bleeding).

Hepatic failure.

Renal failure.

Established congestive heart failure [functional class II–IV according to NYHA (New York Heart Association) classification], ischemic heart disease, peripheral arterial disease, cerebrovascular diseases.

Contraindicated in patients who have experienced attacks of bronchial asthma ("aspirin-induced asthma"), angioneurotic edema, urticaria, or acute rhinitis, nasal polyps, or other allergic symptoms in response to administration of diclofenac, paracetamol, acetylsalicylic acid, ibuprofen, or other nonsteroidal anti-inflammatory drugs (NSAIDs).

History of gastrointestinal bleeding or perforation associated with the use of nonsteroidal anti-inflammatory drugs.

Severe heart failure (functional class III–IV).

Blood dyscrasias of unknown origin.

Leukopenia.

Moderate to severe anemia.

Congenital hyperbilirubinemia.

Glucose-6-phosphate dehydrogenase deficiency.

Inflammatory bowel diseases (Crohn's disease or ulcerative colitis).

Alcoholism.

Do not use for treatment of postoperative pain following coronary artery bypass graft (CABG) surgery (or use of cardiopulmonary bypass machine).

The medicinal product is contraindicated during pregnancy or breastfeeding.

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 plasma levels of lithium and digoxin is recommended.

Diuretics and antihypertensive agents. Like other NSAIDs, the product may reduce the antihypertensive effect of diuretics or antihypertensive agents, such as beta-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors. Therefore, combination therapy should be prescribed with caution, and patients (especially elderly) should have periodic monitoring of blood pressure. Patients should consume adequate amounts of fluid, and renal function should be monitored periodically, particularly when diuretics and ACE inhibitors are used, due to increased risk of nephrotoxicity.

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

Other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, and corticosteroids. Concomitant use of diclofenac with other NSAIDs or corticosteroids may increase the frequency of gastrointestinal adverse events. Concomitant use of this product with other NSAIDs, including selective COX-2 inhibitors, should be avoided due to lack of evidence for any synergistic benefit. Like other NSAIDs, diclofenac at high doses may temporarily inhibit platelet aggregation.

Anticoagulants and antiplatelet agents. Regular concomitant use of diclofenac with anticoagulants, particularly warfarin and other coumarins, and antiplatelet agents increases the risk of bleeding.

Although clinical studies have not demonstrated that diclofenac affects the efficacy of anticoagulants, data indicate an increased risk of bleeding in patients who concurrently use diclofenac and anticoagulants. Therefore, careful monitoring of patients concurrently using diclofenac and anticoagulants is recommended, and dosage adjustment of anticoagulants may be necessary.

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

Antidiabetic agents. The efficacy of antidiabetic agents is not altered when used concomitantly with this product. However, isolated reports of both hypoglycemia and hyperglycemia have been documented, necessitating dosage adjustments of antidiabetic agents during treatment. Therefore, blood glucose levels should be monitored during therapy with Doloxen. Isolated cases of metabolic acidosis have also been reported with concomitant use of antidiabetic agents and diclofenac, particularly in patients with pre-existing renal impairment.

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

Methotrexate. Diclofenac may inhibit tubular renal clearance of methotrexate, leading to elevated methotrexate levels. NSAIDs, including diclofenac, should be used with caution if administered less than 24 hours before methotrexate, as methotrexate blood levels may rise and toxicity may be enhanced. Cases of severe toxicity have been reported when methotrexate and NSAIDs, including diclofenac, were administered within 24 hours of each other. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

Agents stimulating drug-metabolizing enzymes. Agents that stimulate enzymes, such as rifampicin, carbamazepine, phenytoin, and St. John's wort (Hypericum perforatum), may theoretically reduce diclofenac plasma concentrations.

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

Cyclosporine. The effect of NSAIDs on renal prostaglandin synthesis may potentiate cyclosporine nephrotoxicity; therefore, the product should be administered at lower doses than in patients not receiving cyclosporine.

Antibacterial agents – quinolone derivatives. Due to interaction between quinolone antibiotics and NSAIDs, seizures may occur. This may occur in patients with epilepsy or history of seizures, as well as in patients without such history. Therefore, caution should be exercised when considering quinolone use in patients already receiving NSAIDs.

Potent CYP2C9 inhibitors. Diclofenac should be used with caution when administered concomitantly with potent CYP2C9 inhibitors (e.g., voriconazole), as significant increases in maximum plasma concentration and exposure of diclofenac may occur due to inhibition of diclofenac metabolism.

Inducers of CYP2C9. Caution is required when administering diclofenac concomitantly with CYP2C9 inducers (e.g., rifampicin), as significant decreases in plasma concentration and exposure of diclofenac may occur.

Tacrolimus. When NSAIDs are administered concomitantly with tacrolimus, the risk of nephrotoxicity increases. This may be mediated through inhibition of renal prostaglandins by both NSAIDs and calcineurin inhibitors; therefore, diclofenac should be used at lower doses than in patients not receiving tacrolimus.

Cardiac glycosides. Concomitant use of cardiac glycosides and NSAIDs may promote worsening of heart failure, decreased glomerular filtration rate (GFR), and increased plasma concentration of glycosides.

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

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

Probenecid. Medicinal products containing probenecid may delay elimination 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, regular daily use of paracetamol, increasing the risk of bleeding. Occasional use has no significant effect.

Barbiturates reduce the antipyretic effect of paracetamol.

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 hepatotoxicity.

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

Concomitant use of paracetamol and ethanol increases the risk of hepatotoxic effects and acute pancreatitis.

Do not use concomitantly with alcohol.

Barbiturates, rifampicin, salicylamide, antiepileptic drugs, carbamazepine, phenytoin, ethanol, phenylbutazone, tricyclic antidepressants, and other stimulators of microsomal oxidation increase the production of hydroxylated active metabolites, affecting liver function and potentially causing severe intoxication even with minor overdoses.

Paracetamol may reduce the bioavailability of lamotrigine, decreasing its effect, likely due to induction of hepatic metabolism.

Concomitant use of paracetamol and zidovudine increases the risk of neutropenia.

Inhibitors of microsomal oxidation (cimetidine) reduce the risk of hepatotoxic effects of Doloxen.

Metoclopramide and domperidone increase the absorption of paracetamol.

Prolonged concomitant use of the medicinal product with acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs may lead to kidney damage.

Coumarin derivatives (warfarin) – long-term use of paracetamol increases the risk of bleeding. Occasional use has no significant effect.

Cholestyramine reduces the absorption of paracetamol.

Under the influence of paracetamol, the elimination time of chloramphenicol increases fivefold.

Probenecid affects the plasma concentration and excretion of paracetamol.

Caution is required when using paracetamol concomitantly with flucloxacillin, as concomitant administration has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

Special precautions for use.

The medicinal product contains paracetamol; therefore, it should not be used concomitantly with other medicinal products containing paracetamol and used, for example, to reduce fever, relieve pain, treat flu or cold symptoms, or insomnia. Concurrent 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.

Patients with liver or kidney disease should consult a physician before using this medicinal product.

It should be noted that patients with liver disease have an increased risk of hepatotoxic effects of paracetamol; the product may affect laboratory test results for blood glucose and uric acid levels. Patients who take analgesics daily for mild forms of arthritis should consult a physician before using paracetamol.

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

Cases of metabolic acidosis with high anion gap due to pyroglutamic acidosis have been reported in patients with severe conditions, such as severe renal impairment or sepsis, as well as in patients with inadequate nutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who received prolonged treatment with paracetamol at therapeutic doses or a combination of paracetamol and flucloxacillin.

If metabolic acidosis with high anion gap due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and close monitoring of the patient are recommended. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

In patients with reduced glutathione levels, such as those with severe infections like sepsis, the risk of developing metabolic acidosis increases during paracetamol use. 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, consult a physician.

If headache becomes persistent, consult a physician.

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

Do not exceed the recommended doses.

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

There is an increased risk of thrombotic cardiovascular and cerebrovascular complications with certain selective COX-2 inhibitors. It is unknown whether this risk directly depends on 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; the possibility of a similarly increased risk cannot be excluded. Until such data become available, careful assessment of the risk-benefit ratio is required when using diclofenac 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). Therefore, the lowest effective dose should be used for the shortest possible treatment duration.

Renal effects of NSAIDs 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. Caution is also required in patients receiving concomitant diuretics or angiotensin-converting enzyme (ACE) inhibitors, or those at increased risk of hypovolemia. Consequences are generally more severe in elderly patients. If gastrointestinal bleeding or ulcers occur in patients during NSAID treatment, the medicinal product should be discontinued. Treatment should be prescribed cautiously in patients aged 65 years and older, following recommendations for this patient group. In particular, the lowest effective doses are recommended for frail elderly patients and those with low body weight.

Allergic reactions, including anaphylactic/anaphylactoid reactions, may occur during diclofenac use, as with other NSAIDs, even without prior exposure to diclofenac. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may cause myocardial infarction. Symptoms of such reactions may include chest pain occurring in combination with an allergic reaction to diclofenac.

Serious skin reactions, some of which have been 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. Due to its pharmacodynamic properties, the product, like other NSAIDs, may mask signs and symptoms of infection.

Patients with impaired kidney or liver function should consult a physician regarding the possibility of using the medicinal product.

It should be noted that patients with liver disease have an increased risk of hepatotoxic effects of paracetamol.

Alcoholic beverages should not be consumed during treatment. Paracetamol may be hepatotoxic at doses exceeding 6–8 g per day; however, adverse effects on the liver may occur even at significantly lower doses when alcohol is consumed, when hepatic enzyme inducers are used, or when other substances with hepatotoxic effects are taken. The risk is also higher in patients with non-cirrhotic alcoholic liver disease. Chronic alcohol consumption significantly increases the risk of hepatotoxic effects of paracetamol. In patients with impaired liver function, as well as in those taking high doses of paracetamol for prolonged periods, regular liver function tests are recommended.

Patients should consult a physician before using the medicinal product if they are taking warfarin or similar anticoagulant agents. Restrictions on using the medicinal product in such patients are primarily due to the presence of paracetamol.

When oral anticoagulants are used concomitantly with high doses of paracetamol, monitoring of prothrombin time is required.

The medicinal product may affect laboratory test results for blood glucose and uric acid levels.

Cases of impaired liver function/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 developing metabolic acidosis increases during paracetamol use. 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.

Warnings
Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control (relieve) symptoms.

Concomitant use of the medicinal product 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.

Caution is required in elderly patients. In particular, the lowest effective dose is recommended for frail elderly patients or those with low body weight.

Bronchial asthma in medical history

In patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (i.e., nasal polyps), chronic obstructive pulmonary diseases, or chronic respiratory tract infections (especially those associated with allergic, rhinitis-like symptoms), reactions to NSAIDs, such as exacerbation of bronchial asthma (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria, occur more frequently. Therefore, special precautions (readiness for emergency care) are recommended. This also applies to patients with allergic reactions (e.g., rash, itching, or urticaria) to other substances. Medicinal products that inhibit prostaglandin synthetase activity, including sodium diclofenac and other NSAIDs, may provoke bronchospasm in patients with bronchial asthma or those with a history of bronchial asthma.

Gastrointestinal effects

Cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported during NSAID use, including diclofenac. These events may be fatal and can occur at any time during treatment, regardless of warning 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 taking diclofenac, use of the medicinal product should be discontinued.

Patients taking NSAIDs, including diclofenac, who have symptoms indicating gastrointestinal (GI) tract disorders or a history of gastric or intestinal ulcers, bleeding, or perforation, require medical supervision and special caution. The risk of GI bleeding increases with higher doses and in patients with a history of ulcers, especially those complicated by bleeding or perforation, and in elderly patients.

Elderly patients have a higher frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal.

To reduce the risk of such GI toxicity in patients with a history of ulcers, especially those complicated by hemorrhage or perforation, and in elderly patients, treatment should be initiated and maintained at the lowest effective doses.

For such patients, as well as those requiring concomitant use of medicinal products containing low-dose acetylsalicylic acid (ASA) or other medicinal products that may increase the risk of GI adverse effects, consideration should be given to using combination therapy with protective agents (e.g., proton pump inhibitors or misoprostol). Patients with a history of gastrointestinal toxicity, especially elderly patients, should be informed to report any unusual abdominal symptoms (particularly GI bleeding). Caution is also required for patients receiving concomitant medicinal products that increase the risk of ulcers or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid), or selective serotonin reuptake inhibitors.

Careful medical supervision and special caution are required in patients with ulcerative colitis or Crohn's disease, as these conditions may worsen. Use of NSAIDs, including diclofenac, is associated with an increased risk of gastrointestinal anastomotic bleeding. Careful medical monitoring and caution are recommended when prescribing diclofenac after gastrointestinal surgery.

Hepatic effects

Careful medical supervision is required when diclofenac is prescribed 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 product.

During long-term treatment, regular monitoring of liver function and liver enzyme levels is recommended as a precautionary measure. If liver function impairment persists or worsens, and if clinical signs or symptoms may be related to progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), the product should be discontinued.

The course of diseases such as hepatitis may proceed without prodromal symptoms. Caution is required when the product is used in patients with hepatic porphyria due to the potential risk of provoking an attack.

Renal effects

Long-term treatment with high doses of NSAIDs, including diclofenac, frequently (1–10%) leads to edema and arterial hypertension. Particular attention should be paid to patients with impaired cardiac or renal function, a history of arterial hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs that significantly affect renal function, and patients with significant reduction in extracellular fluid volume for any reason, such as before or after major surgery. In such cases, monitoring of renal function is recommended. Discontinuation of therapy usually leads to return to the pre-treatment state.

Skin effects

Serious skin reactions (some of which have been fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and generalized bullous fixed drug eruption, have been very rarely reported with the use of diclofenac. The highest risk of these reactions occurs at the beginning of therapy, in most cases within the first month of treatment.

Diclofenac use should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Systemic lupus erythematosus (SLE) and mixed connective tissue 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 treatment in patients with congestive heart failure (NYHA functional class I) and patients with significant cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking) should only be initiated after careful risk-benefit assessment.

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

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

Since cardiovascular risks increase with higher doses and longer duration of diclofenac use, it should be used for the shortest possible duration and at the lowest effective dose.

The need for symptomatic relief and response to therapy should be periodically re-evaluated.

Patients should be informed about the necessity to monitor for symptoms of serious arterial thromboembolic events (chest pain, dyspnea, weakness, speech disturbances). In case such an event occurs, patients should seek immediate medical attention.

Hematological effects

The medicinal product is recommended only for short-term treatment.

With prolonged use of this product, as with other NSAIDs, monitoring of complete blood count is recommended.

Like other NSAIDs, the medicinal product may temporarily inhibit platelet aggregation. Patients with coagulation disorders, hemorrhagic diathesis, or hematological disorders should be carefully monitored.

Do not exceed the recommended doses.

Consider that patients with non-cirrhotic alcoholic liver disease have an increased risk of hepatotoxic effects of paracetamol; the product may affect laboratory test results for blood glucose and uric acid levels.

Do not take the product simultaneously with other products containing paracetamol or diclofenac.

Use during pregnancy or breastfeeding.

A large amount of data in pregnant women does not indicate teratogenic or fetal/neonatal toxicity. Epidemiological data on neurodevelopment in children exposed to paracetamol in utero are inconclusive. The medicinal product is contraindicated during pregnancy or breastfeeding. From the 20th week of pregnancy, use of sodium diclofenac may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of the product. Additionally, cases of arterial duct constriction after treatment during the second trimester of pregnancy have been reported, most of which resolved after discontinuation of treatment.

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

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

Method of Administration and Dosage.

The dose is determined by a physician individually for each patient, depending on the patient's age, the nature and course of the disease, individual tolerance, and therapeutic efficacy of the drug.

For adults and children aged 14 years and older: 1 tablet 2–3 times daily after meals.

The duration of treatment should not exceed 5–7 days and depends on the course of the disease.

The maximum daily dose of the drug for adults and children aged 14 years and older is no more than 3 tablets.

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 vomiting, gastrointestinal bleeding, diarrhea, dizziness, tinnitus, and seizures. Acute renal failure and liver damage are possible in cases of severe intoxication.

Paracetamol.

Liver damage may occur in adults who have ingested 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight. In patients with risk factors (long-term 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, AIDS, fasting, cystic fibrosis, cachexia), ingestion of 5 g or more of paracetamol may lead to liver damage.

Symptoms of overdose within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12–48 hours after overdose. Glucose metabolism 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 and pancreatitis have also been reported.

With prolonged use of the drug in high doses, blood-forming organs may develop aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia. With high-dose intake, the nervous system may exhibit dizziness, psychomotor agitation, and disorientation; the urinary system may show nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis); the digestive system may develop hepatonecrosis.

Treatment: urgent supportive and symptomatic therapy measures.

If an excessive dose was ingested within the past hour, administration of activated charcoal should be considered. 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 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, N-acetylcysteine is administered intravenously according to the established dosage regimen. 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, seizures, gastrointestinal disturbances, and respiratory depression. Forced diuresis, hemodialysis, or hemoperfusion are unlikely to be effective for eliminating nonsteroidal anti-inflammatory drugs (NSAIDs), as the active substances of the drug are highly bound to plasma proteins and undergo extensive metabolism.

Adverse Reactions

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

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

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

Nervous system disorders: headache; dizziness; sensory disturbances, including paresthesia; sleep disturbances; nightmares; somnolence; insomnia; memory impairment; disorientation; seizures; depression; increased irritability; anxiety; tremor; aseptic meningitis; taste disturbances; cerebral circulation disorders; psychotic reactions; increased fatigue; confusion; hallucinations; sensory disturbances; general malaise.

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

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

Cardiovascular system disorders: palpitations, tachycardia, dyspnea, chest pain, heart failure, myocardial infarction, arterial hypertension; arterial hypotension; vasculitis; Kounis syndrome.

Respiratory system disorders: bronchial asthma (including dyspnea), bronchospasm (particularly in patients sensitive to acetylsalicylic acid), chest pain, pneumonitis.

Gastrointestinal disorders: nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia, gastritis, gastrointestinal bleeding, vomiting with blood, hemorrhagic diarrhea, melena, gastric or intestinal ulcer (with/without bleeding or perforation), colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including aphthous), glossitis, esophageal disorders, diaphragm-like intestinal strictures, intestinal spasms, pancreatitis, gastrointestinal stenosis or perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis, proctitis, ischemic colitis.

Hepatobiliary system disorders: elevated transaminase levels, liver failure, hepatitis, liver necrosis, jaundice, liver disorders, fulminant hepatitis.

Skin and subcutaneous tissue disorders: pruritus, skin rashes, erythema, mucosal rashes, urticaria, bullous rashes, eczema, exudative polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), erythroderma, exfoliative dermatitis, allergic dermatitis, hair loss, photosensitivity reactions, purpura, allergic purpura, itching, Schönlein-Henoch purpura; frequency unknown – fixed drug eruption, generalized bullous fixed drug eruption.

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

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

Diclofenac, particularly at high doses (150 mg/day) and with prolonged use, increases the risk of arterial thromboembolism (e.g., myocardial infarction or stroke).

Reproductive system and breast disorders: impotence.

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

*Information based on long-term use at high doses (150 mg/day). Clinical trial data and epidemiological evidence indicate an increased risk of thrombotic complications (e.g., myocardial infarction or stroke) associated with diclofenac use, particularly at high therapeutic doses (150 mg/day) and with prolonged treatment.

**Reported in the post-marketing period during concomitant use of paracetamol with flucloxacillin; usually in the presence of risk factors.

Description of selected adverse reactions

Visual disturbances

Visual disturbances such as blurred 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 these disturbances. If such symptoms occur during treatment with diclofenac, an ophthalmological examination should be performed to rule out other possible causes.

If severe adverse effects occur, treatment should be discontinued.

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap due to pyroglutamic acidosis have been observed during paracetamol use in patients with risk factors (see section "Special precautions"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

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 per blister; 2 or 10 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Galpharm Laboratories Ltd. Unit 1.

Manufacturer's address and location of business operations.

Village-Thana (Baddi), Tehsil-Nalagarh, District-Solan, Himachal Pradesh, 173205, India.

INSTRUCTION

for medical use of medicinal product

DOLOXEN

(DOLOXEN)

Composition:

Active substances: paracetamol, sodium diclofenac;

1 tablet contains 500 mg of paracetamol and 50 mg of sodium diclofenac;

Excipients: sodium croscarmellose, microcrystalline cellulose, povidone, methacrylic acid copolymer dispersion, magnesium stearate, sodium starch glycolate (type A), hydroxypropylmethylcellulose, macrogol 4000, titanium dioxide (E 171), purified talc, dichloromethane, isopropyl alcohol, purified water.

Dosage form. Film-coated tablets.

Main physicochemical characteristics: capsule-shaped, biconvex, film-coated tablets of white or almost white color, with a score line on one side.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01AB55.

Pharmacological Properties

Pharmacodynamics

Doloxene is a combined medication that has pronounced anti-inflammatory, analgesic, and antipyretic effects. The pharmacological activity of the drug is determined by the properties of diclofenac and paracetamol, which are components of Doloxene. The main mechanism of action of diclofenac is inhibition of the synthesis of prostaglandins—endogenous substances that play an important role in the development of inflammation, pain, and fever. Paracetamol belongs to non-steroidal anti-inflammatory drugs (NSAIDs) from the group of para-aminophenol derivatives. The analgesic and antipyretic effects of paracetamol are due to its influence on hypothalamic centers of the brain.

In rheumatic diseases, the anti-inflammatory and analgesic properties of Doloxene provide a clinical effect characterized by reduction in joint pain intensity, morning stiffness, and joint swelling, as well as improvement in joint function.

In post-traumatic and postoperative inflammatory conditions, Doloxene rapidly relieves pain and reduces inflammatory swelling of postoperative wounds.

Doloxene also has an analgesic effect in pain syndromes of non-rheumatic origin, particularly in primary algomenorrhea and migraine attacks.

Pharmacokinetics

After oral administration of Doloxene, diclofenac and paracetamol are rapidly and completely absorbed. Food does not affect the absorption of the drug.

Plasma concentrations of the active substances show a linear relationship with the dose of the drug; maximum levels are reached within 60–90 minutes after administration of Doloxene.

Binding of diclofenac to plasma proteins (mainly to albumin) reaches 99.7%. The apparent 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 blood plasma. The elimination half-life from synovial fluid is 3–6 hours.

Diclofenac is metabolized via glucuronidation of the unchanged molecule and via oxidative metabolism 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. 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 via bile and feces.

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

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

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to diclofenac, paracetamol, or to any other component of the medicinal product.

Acute gastric or intestinal ulcer; gastrointestinal bleeding or perforation.

Active peptic ulcer/gastrointestinal bleeding, or recurrent peptic ulcer/bleeding in history (two or more separate episodes of diagnosed ulcer or bleeding).

Hepatic failure.

Renal failure.

Established congestive heart failure [functional class II–IV according to NYHA (New York Heart Association) classification], ischemic heart disease, peripheral arterial disease, cerebrovascular disease.

Contraindicated in patients who experience attacks of bronchial asthma (‘aspirin-induced asthma’), angioedema, urticaria, or acute rhinitis, nasal polyps, or other allergic symptoms in response to administration of diclofenac, paracetamol, acetylsalicylic acid, ibuprofen, or other nonsteroidal anti-inflammatory drugs (NSAIDs).

History of gastrointestinal bleeding or perforation related to previous use of nonsteroidal anti-inflammatory drugs.

Severe heart failure (functional class III–IV).

Hematopoietic disorders of unknown origin.

Leukopenia.

Moderate to severe anemia.

Congenital hyperbilirubinemia.

Glucose-6-phosphate dehydrogenase deficiency.

Inflammatory bowel diseases (Crohn’s disease or ulcerative colitis).

Alcoholism.

Do not use for postoperative pain treatment following coronary artery bypass graft (CABG) surgery (or use of cardiopulmonary bypass).

The medicinal product is contraindicated during pregnancy or breastfeeding.

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 plasma lithium and digoxin levels is recommended.

Diuretics and antihypertensive agents. The product, like other NSAIDs, may reduce the antihypertensive effect when used concomitantly with diuretics or antihypertensive agents, such as beta-blockers, calcium channel blockers, or angiotensin-converting enzyme (ACE) inhibitors. Therefore, such combinations should be prescribed with caution, and blood pressure should be monitored periodically in patients (especially elderly). Patients should maintain adequate hydration, and renal function should be monitored periodically before and after initiation of concomitant therapy, particularly when using diuretics and ACE inhibitors due to increased risk of nephrotoxicity.

Medicinal products causing hyperkalemia. Concomitant use of potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may increase serum potassium levels, which should be monitored.

Other NSAIDs, including selective cyclooxygenase-2 inhibitors, and corticosteroids. Concomitant use of diclofenac with other NSAIDs or corticosteroids may increase the frequency of adverse gastrointestinal events. Simultaneous use of the product with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided due to lack of evidence of synergistic benefit. Like other NSAIDs, diclofenac at high doses may temporarily inhibit platelet aggregation.

Anticoagulants and antiplatelet agents. Regular concomitant use of diclofenac with anticoagulants, particularly warfarin and other coumarins, and antiplatelet agents increases the risk of bleeding.

Although clinical studies have not demonstrated that diclofenac affects the efficacy of anticoagulants, data indicate an increased risk of bleeding in patients who concurrently used diclofenac and anticoagulants. Therefore, careful monitoring of patients receiving diclofenac and anticoagulants is recommended, and dose adjustment of anticoagulants may be necessary.

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

Antidiabetic agents. The efficacy of antidiabetic agents is not altered when used concomitantly with the product. However, isolated reports describe both hypoglycemia and hyperglycemia, necessitating dose adjustments of antidiabetic agents during treatment with Doloxen. Therefore, blood glucose levels should be monitored during therapy with Doloxen. Isolated cases of metabolic acidosis have also been reported with concomitant use of antidiabetic agents and diclofenac, particularly in patients with pre-existing renal impairment.

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

Metotrexate. Diclofenac may inhibit renal tubular clearance of methotrexate, increasing methotrexate levels. NSAIDs, including diclofenac, should be used with caution when administered less than 24 hours before methotrexate, as blood methotrexate levels may rise and toxicity may increase. Cases of severe toxicity have been reported when methotrexate and NSAIDs, including diclofenac, were administered within 24 hours of each other. This interaction is mediated by methotrexate accumulation due to impaired renal excretion in the presence of NSAIDs.

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

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

Cyclosporine. The effect of NSAIDs on prostaglandin synthesis in the kidneys may potentiate the nephrotoxicity of cyclosporine; therefore, the product should be administered at lower doses than in patients not receiving cyclosporine.

Quinolone antibacterial agents. Due to interaction between quinolone antibiotics and NSAIDs, seizures may occur. This may be observed both in patients with epilepsy or history of seizures and in those without such history. Therefore, caution should be exercised when considering quinolone use in patients already receiving NSAIDs.

Potent CYP2C9 inhibitors. Diclofenac should be used with caution concomitantly with potent CYP2C9 inhibitors (e.g., voriconazole), as significant increases in maximum plasma concentration and exposure of diclofenac may occur due to inhibition of diclofenac metabolism.

CYP2C9 inducers. Caution is required when diclofenac is used concomitantly with CYP2C9 inducers (e.g., rifampicin), as significant reduction in plasma concentration and exposure of diclofenac may occur.

Tacrolimus. When NSAIDs are used concomitantly with tacrolimus, the risk of nephrotoxicity increases. This may be mediated through inhibition of renal prostaglandins by both NSAIDs and calcineurin inhibitors; therefore, diclofenac should be used at lower doses than in patients not receiving tacrolimus.

Cardiac glycosides. Concomitant use of cardiac glycosides and NSAIDs may promote worsening of heart failure, decreased glomerular filtration rate (GFR), and increased plasma concentration of glycosides.

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

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

Probenecid. Medicinal products containing probenecid may delay elimination 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, regular daily use of paracetamol, increasing the risk of bleeding. Occasional use has no significant effect.

Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsants (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol due to increased conversion of the drug into hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic agents increases the hepatotoxic potential of the drugs.

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

Concomitant intake of paracetamol and ethanol increases the risk of hepatotoxic effects and acute pancreatitis.

Do not use concomitantly with alcohol.

Barbiturates, rifampicin, salicylamide, antiepileptic drugs, carbamazepine, phenytoin, ethanol, phenylbutazone, tricyclic antidepressants, and other microsomal oxidation stimulants – these medicinal products increase the production of hydroxylated active metabolites affecting liver function, increasing the risk of severe intoxication even with minor overdoses.

Paracetamol may reduce lamotrigine bioavailability, decreasing its effect, possibly due to induction of its hepatic metabolism.

Concomitant use of paracetamol and zidovudine increases the risk of neutropenia.

Microsomal oxidation inhibitors (cimetidine) – reduce the risk of hepatotoxicity of Doloxen.

Metoclopramide and domperidone – increase paracetamol absorption.

Prolonged concomitant use of the medicinal product with acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs may lead to kidney damage.

Coumarin derivatives (warfarin) – long-term use of paracetamol increases the risk of bleeding. Occasional dosing has no significant effect.

Cholestyramine – reduces paracetamol absorption.

Under the influence of paracetamol, the elimination time of chloramphenicol increases fivefold.

Probenecid affects paracetamol plasma concentration and its excretion.

Caution is required when paracetamol is used concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

Special precautions for use.

The medicinal product contains paracetamol; therefore, it should not be used concomitantly with other medicinal products containing paracetamol, such as those used for fever reduction, pain relief, flu and cold symptoms, or insomnia. Concurrent 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.

Patients with liver or kidney disease should consult a physician before using this medicinal product.

It should be noted that patients with liver disease have an increased risk of hepatotoxic effects of paracetamol; the product may affect laboratory test results for blood glucose and uric acid levels. Patients who take analgesics daily for mild forms of arthritis should consult a physician before using paracetamol.

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

Cases of metabolic acidosis with a high anion gap due to pyroglutamic acidosis have been reported in patients with severe conditions, such as severe renal impairment and sepsis, as well as in patients with inadequate nutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who have been treated long-term with therapeutic doses of paracetamol or a combination of paracetamol and flucloxacillin.

If metabolic acidosis with a high anion gap due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and close monitoring of the patient are recommended. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

In patients with reduced glutathione levels, such as those with severe infections like sepsis, the risk of developing metabolic acidosis increases during paracetamol use. 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, consult a physician.

If headaches become persistent, consult a physician.

Patients should consult a physician before using the product if they are taking warfarin or similar anticoagulant agents.

Do not exceed the recommended doses.

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, the lowest effective dose should be used for the shortest possible duration.

There is an increased risk of thrombotic cardiovascular and cerebrovascular complications with certain selective COX-2 inhibitors. It is unknown whether this risk is directly related to the COX-1/COX-2 selectivity of individual NSAIDs. There are currently no data available on long-term treatment with the maximum dose of diclofenac, and the possibility of a similarly increased risk cannot be excluded. Until such data become available, careful assessment of the risk-benefit ratio is required when using diclofenac in patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial occlusive diseases, or significant risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Therefore, the lowest effective dose should be used for the shortest possible treatment duration.

Renal effects of NSAIDs include fluid retention with edema and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with heart dysfunction and other conditions leading to fluid retention. Particular attention is also required for patients receiving concomitant diuretics or ACE inhibitors, or those at increased risk of hypovolemia. Consequences are generally more serious in elderly patients. If gastrointestinal bleeding or ulcers occur in patients during NSAID therapy, the medicinal product should be discontinued. Treatment should be prescribed cautiously to patients aged 65 years and older, following recommendations for this patient group. In particular, the lowest effective doses are recommended for frail elderly patients and those with low body weight.

Allergic reactions, including anaphylactic/anaphylactoid reactions, may occur with diclofenac, as with other NSAIDs, even without prior exposure to diclofenac. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may cause myocardial infarction. Symptoms of such reactions may include chest pain occurring in combination with an allergic reaction to diclofenac.

Serious skin reactions, some of which have been fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have very rarely been 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. Due to its pharmacodynamic properties, the product, like other NSAIDs, may mask signs and symptoms of infection.

Patients with kidney or liver dysfunction should consult a physician regarding the possibility of using the medicinal product.

It should be noted that patients with liver disease have an increased risk of hepatotoxic effects of paracetamol.

Alcoholic beverages should not be consumed during treatment. Paracetamol doses exceeding 6–8 g per day may be hepatotoxic; however, adverse effects on the liver may also occur at significantly lower doses when alcohol is consumed, when hepatic enzyme inducers are used, or when other substances with hepatotoxic effects are taken. This effect is also higher in patients with non-cirrhotic alcoholic liver disease. Chronic alcohol consumption significantly increases the risk of hepatotoxic effects of paracetamol. In patients with impaired liver function, as well as in those taking high doses of paracetamol for prolonged periods, regular liver function tests are recommended.

Patients should consult a physician before using the product if they are taking warfarin or similar anticoagulant agents. Restrictions on using the medicinal product in such patients are primarily due to the presence of paracetamol.

When treating with oral anticoagulants and concomitant high-dose paracetamol, monitoring of prothrombin time is required.

The medicinal product may affect laboratory test results for blood glucose and uric acid levels.

Cases of impaired liver function/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 developing metabolic acidosis increases during paracetamol use. 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.

Warning
Adverse effects can be minimized by using the lowest effective dose for the shortest possible duration required to control (relieve) symptoms.

Concomitant use of the medicinal product 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.

Caution is required for elderly patients. In particular, the lowest effective dose is recommended for frail elderly patients or those with low body weight.

Bronchial asthma in medical history

Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal swelling (i.e., nasal polyps), chronic obstructive lung diseases, or chronic respiratory tract infections (especially those associated with allergic, rhinitis-like symptoms) more frequently experience reactions to NSAIDs, such as exacerbation of bronchial asthma (so-called analgesic intolerance/analgesic asthma), Quincke's edema, or urticaria. Therefore, special precautions (readiness for emergency care) are recommended. This also applies to patients with allergic reactions (e.g., rash, itching, or urticaria) to other substances. Medicinal products that inhibit prostaglandin synthetase activity, including sodium diclofenac and other NSAIDs, may provoke bronchospasm in patients suffering from bronchial asthma or those with a history of bronchial asthma.

Gastrointestinal effects

Cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported with the use of NSAIDs, including diclofenac, which may be fatal and can occur at any time during treatment, regardless of the presence of warning 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 taking diclofenac, use of the medicinal product should be discontinued.

Patients with symptoms indicating gastrointestinal (GI) tract disorders or with a history of gastric or intestinal ulcers, bleeding, or perforation require medical supervision and special caution when using NSAIDs, including diclofenac. The risk of gastrointestinal bleeding increases with higher doses and in patients with a history of ulcers, especially those complicated by bleeding or perforation, as well as in elderly patients.

Elderly patients have a higher frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal.

To reduce the risk of such toxic effects on the gastrointestinal tract in patients with a history of ulcers, especially those complicated by hemorrhage or perforation, and in elderly patients, treatment should be initiated and maintained with the lowest effective doses.

For such patients, as well as those requiring concomitant use of medicinal products containing low-dose acetylsalicylic acid (ASA) or other medicinal products likely to increase the risk of adverse GI effects, consideration should be given to using combination therapy with protective agents (e.g., proton pump inhibitors or misoprostol). Patients with a history of gastrointestinal toxicity, especially elderly patients, should be informed to report any unusual abdominal symptoms (particularly gastrointestinal bleeding). Caution is also required for patients receiving concomitant medicinal products that increase the risk of ulcers or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antithrombotic agents (e.g., acetylsalicylic acid), or selective serotonin reuptake inhibitors.

Careful medical supervision and special caution are required for patients with ulcerative colitis or Crohn's disease, as these conditions may worsen. The use of NSAIDs, including diclofenac, is associated with an increased risk of gastrointestinal anastomotic bleeding. Careful medical monitoring and caution are recommended when prescribing diclofenac after gastrointestinal surgery.

Hepatic effects

Careful medical supervision is required when diclofenac is prescribed 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 product.

Regular monitoring of liver function and liver enzyme levels is recommended during long-term treatment as a precautionary measure. If liver function impairment persists or worsens, and if clinical signs or symptoms may be related to progressive liver disease or other manifestations (e.g., eosinophilia, rash) occur, use of the product should be discontinued.

Diseases such as hepatitis may progress without prodromal symptoms. Caution is required when the product is used in patients with hepatic porphyria, due to the potential risk of provoking an attack.

Renal effects

Long-term treatment with high doses of NSAIDs, including diclofenac, frequently (1–10%) leads to edema and arterial hypertension. Particular attention should be paid to patients with impaired cardiac or renal function, a history of arterial hypertension, elderly patients, patients receiving concomitant diuretic therapy or medications that significantly affect renal function, and patients with significant extracellular fluid volume depletion due to any cause, e.g., before or after major surgery. In such cases, monitoring of renal function is recommended. Discontinuation of therapy usually leads to a return to the pre-treatment state.

Skin effects

Serious skin reactions (some of which have been fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and generalized bullous fixed drug eruption, have very rarely been reported with the use of diclofenac. The highest risk of these reactions occurs at the beginning of therapy, in most cases within the first month of treatment.

Diclofenac use should be discontinued at the first appearance of skin rashes, mucosal lesions, or any other signs of hypersensitivity.

Systemic lupus erythematosus (SLE) 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 treatment in patients with congestive heart failure (NYHA functional class I) and patients with significant cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking) should only be initiated after careful evaluation.

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

Clinical trial data and epidemiological evidence indicate that the use of diclofenac, particularly at high doses (150 mg/day) and during long-term treatment, somewhat increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke).

Since cardiovascular risks associated with diclofenac use increase with dose and duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose.

The patient's need for symptomatic relief and response to therapy should be periodically re-evaluated.

Patients should be informed about the need to monitor for symptoms of serious arterial thromboembolic events (chest pain, shortness of breath, weakness, speech disturbances). If such an event occurs, patients should seek immediate medical attention.

Hematological effects

The medicinal product is recommended only for short-term treatment.

With prolonged use of this product, as with other NSAIDs, monitoring of a complete blood count is recommended.

Like other NSAIDs, the medicinal product may temporarily inhibit platelet aggregation. Careful monitoring is required for patients with hemostasis disorders, hemorrhagic diathesis, or hematological disorders.

Do not exceed the recommended doses.

Consider that patients with non-cirrhotic alcoholic liver disease have an increased risk of hepatotoxic effects of paracetamol; the product may affect laboratory test results for blood glucose and uric acid levels.

Do not take the product simultaneously with other products containing paracetamol or diclofenac.

Use during pregnancy or breastfeeding.

A large amount of data in pregnant women does not indicate teratogenic or fetal/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero have yielded inconclusive results. The medicinal product is contraindicated during pregnancy or breastfeeding. From the 20th week of pregnancy, the use of sodium diclofenac may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after initiation of treatment and is usually reversible upon discontinuation of the product. Additionally, cases of arterial duct constriction after treatment in the second trimester have been reported, most of which resolved after discontinuation of treatment.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

The dose is determined by a physician individually for each patient, depending on the patient's age, the nature and course of the disease, individual tolerance, and therapeutic efficacy of the drug.

For adults and children aged 14 years and older: 1 tablet 2–3 times daily after meals.

The duration of treatment should not exceed 5–7 days and depends on the course of the disease.

The maximum daily dose of the drug for adults and children aged 14 years and older is no more than 3 tablets.

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 vomiting, gastrointestinal bleeding, diarrhea, dizziness, tinnitus, and seizures. Acute renal failure and liver damage are possible in cases of severe intoxication.

Paracetamol.

Liver damage may occur in adults who have ingested 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight. In patients with risk factors (long-term 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, AIDS, fasting, cystic fibrosis, cachexia), ingestion of 5 g or more of paracetamol may lead to liver damage.

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

With prolonged use of the drug in high doses, hematological disorders may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Nervous system effects from high doses include dizziness, psychomotor agitation, and disorientation; urinary system effects include nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis); gastrointestinal system effects include hepatonecrosis.

Treatment: urgent supportive and symptomatic therapy.

If an excessive dose was taken within the past hour, administration of activated charcoal should be considered. 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 ingestion, but maximum protective effect is achieved when administered within 8 hours after ingestion. The efficacy of the antidote decreases sharply after this time. If necessary, N-acetylcysteine is administered intravenously according to the established dosage regimen. 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, seizures, gastrointestinal disturbances, and respiratory depression. Forced diuresis, hemodialysis, or hemoperfusion are unlikely to be effective for eliminating nonsteroidal anti-inflammatory drugs (NSAIDs), as the active substances of the drug are highly protein-bound and undergo extensive metabolism.

Adverse Reactions

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

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

Psychiatric disorders: disorientation, depression, sleep disturbances, insomnia, night terrors, irritability, restlessness, fear, psychotic disorders, confusion, psychomotor agitation.

Nervous system disorders: headache; dizziness; sensory disturbances, including paresthesia; sleep disturbances; night terrors; somnolence; insomnia; memory impairment; disorientation; seizures; depression; increased irritability; anxiety; tremor; aseptic meningitis; taste disturbances; cerebral circulation disorders; psychotic reactions; increased fatigue; confusion; hallucinations; sensory disturbances; general malaise.

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

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

Cardiovascular system disorders:* palpitations, tachycardia, dyspnea, chest pain, heart failure, myocardial infarction, arterial hypertension; arterial hypotension; vasculitis; Kounis syndrome.

Respiratory system disorders: bronchial asthma (including dyspnea), bronchospasm (particularly in patients sensitive to acetylsalicylic acid), chest pain, pneumonitis.

Gastrointestinal disorders: nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia, gastritis, gastrointestinal bleeding, vomiting with blood, hemorrhagic diarrhea, melena, gastric or intestinal ulcer (with/without bleeding or perforation), colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including aphthous stomatitis), glossitis, esophageal disorders, diaphragm-like intestinal strictures, intestinal spasms, pancreatitis, gastrointestinal stenosis or perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis, proctitis, ischemic colitis.

Hepatobiliary disorders: elevated transaminase levels, liver failure, hepatitis, hepatic necrosis, jaundice, liver disorders, fulminant hepatitis.

Skin and subcutaneous tissue disorders: pruritus, skin rashes, erythema, mucosal rashes, urticaria, bullous eruptions, eczema, exudative polymorphic erythema, Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), erythroderma, exfoliative dermatitis, allergic dermatitis, hair loss, photosensitivity reactions, purpura, allergic purpura, itching, Schönlein–Henoch purpura; frequency not known – fixed drug eruption, generalized bullous fixed drug eruption.

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

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

Diclofenac, especially at high doses (150 mg/day) and with prolonged use, increases the risk of arterial thromboembolic events (e.g., myocardial infarction or stroke).

Reproductive system and breast disorders: impotence.

Metabolism and nutrition disorders: metabolic acidosis with high anion gap (frequency not known)**.

*Information is based on data from long-term use at high doses (150 mg/day). Clinical trial data and epidemiological evidence indicate an increased risk of thrombotic complications (e.g., myocardial infarction or stroke) associated with diclofenac use, particularly at high therapeutic doses (150 mg per day) and with prolonged treatment.

**Reported in the post-marketing period during concomitant use of paracetamol with flucloxacillin; usually in the presence of risk factors.

Description of selected adverse reactions

Visual disturbances

Visual disturbances such as blurred 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 these disturbances. If such symptoms occur during treatment with diclofenac, an ophthalmological examination should be performed to rule out other possible causes.

If severe adverse effects occur, treatment should be discontinued.

Metabolic acidosis with high anion gap

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

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; 2 or 10 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Indoco Remedies Limited.

Manufacturer's address and place of business.

L-14, Verna Industrial Area, Verna, Goa IN-403 722, India.