Flamides®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLAMIDASE® (FLAMIDASE®)

Composition:

Active substances: paracetamol, diclofenac potassium, serratiopeptidase;

One film-coated tablet contains: paracetamol 500 mg, potassium diclofenac 50 mg, serratiopeptidase in the form of granules with enteric coating, containing 15 mg of serratiopeptidase, equivalent to an enzymatic activity of 30,000 IU per tablet;

Excipients: microcrystalline cellulose; maize starch; povidone (K-30); lactose monohydrate; hypromellose; polyethylene glycols (PEG 6000); titanium dioxide (E 171); talc; polysorbates (80); tartrazine (E 102); Opadry White 58901 (hypromellose; lactose monohydrate; titanium dioxide (E 171); polyethylene glycol; talc);

Excipients of serratiopeptidase granules: sodium croscarmellose, magnesium stearate, colloidal anhydrous silicon dioxide, microcrystalline cellulose.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: yellow, oval, biconvex tablets with a score line on one side, film-coated.

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

ATC code M01AB55.

Pharmacological Properties

Pharmacodynamics

Paracetamol acts as an analgesic and antipyretic agent. The analgesic and antipyretic effects of paracetamol are associated with its influence on the thermoregulatory center in the hypothalamus and its ability to inhibit prostaglandin synthesis.

Potassium diclofenac exhibits anti-inflammatory, analgesic, antipyretic, antirheumatic, and antiaggregatory effects. It inhibits cyclooxygenase, thereby blocking reactions of the arachidonic acid cascade and disrupting the synthesis of prostaglandins PGE2, PGE2a, thromboxane A2, prostacyclin, leukotrienes, and the release of lysosomal enzymes; it suppresses platelet aggregation; in vitro, it slows down proteoglycan biosynthesis in cartilage at concentrations corresponding to those observed in humans.

Serratiopeptidase is a proteolytic enzyme isolated from the non-pathogenic intestinal bacterium Serratia E15. It demonstrates fibrinolytic, anti-inflammatory, and anti-edematous activity. In addition to reducing inflammation, serratiopeptidase alleviates pain by blocking the release of pain-inducing amines from inflamed tissues.

Serratiopeptidase binds in a 1:1 ratio with alpha-2-macroglobulin in blood, which masks its antigenicity while preserving its enzymatic activity. It slowly migrates into the exudate at the site of inflammation, and its blood levels gradually decrease. By hydrolyzing bradykinin, histamine, and serotonin, serratiopeptidase directly reduces capillary dilation and controls capillary permeability. Serratiopeptidase blocks plasmin inhibitors, thereby promoting the fibrinolytic activity of plasmin. Therefore, Flamidez® can be used in all pathological conditions associated with edema.

Pharmacokinetics

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration; maximum plasma concentration is reached within 10–60 minutes. Plasma protein binding is approximately 10%. It is metabolized in the liver primarily into pharmacologically inactive metabolites—glucuronide (60–80%) and paracetamol sulfate (20–30%). Less than 4% is metabolized via oxidation to form cysteine and mercapturic acid (mediated by cytochrome P450). The elimination half-life is approximately 2–2.5 hours. It is excreted in urine, mainly as metabolites, with about 5% excreted unchanged. Paracetamol metabolism is not altered in hepatic insufficiency.

Potassium diclofenac is rapidly absorbed after oral administration; food may slow the rate of absorption without affecting its completeness. Maximum plasma concentration is achieved within 1–2 hours. Bioavailability is 50%; it undergoes extensive presystemic elimination. Plasma protein binding exceeds 99%. It penetrates well into tissues and synovial fluid, where its concentration rises more slowly, reaching higher levels than in plasma after 4 hours. Approximately 35% is excreted in feces as metabolites; about 65% is metabolized in the liver and excreted by the kidneys as inactive derivatives (less than 1% is excreted unchanged). The elimination half-life is about 2 hours; in synovial fluid, it is 3–6 hours. When the recommended dosing interval is maintained, potassium diclofenac does not accumulate.

Serratiopeptidase passes through the gastric wall unchanged and is absorbed in the intestine. It is detected in urine in negligible amounts.

Clinical characteristics.

Indications.

Acute pain (myositis, myalgia, headache, toothache, radicular syndrome), in rheumatic soft tissue disorders, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, acute gout attacks, primary dysmenorrhea, adnexitis, pharyngotonsillitis, otitis.

Contraindications.

Hypersensitivity to the components of the drug.

Angioneurotic edema.

Contraindicated in patients who experience attacks of bronchial asthma («aspirin-induced asthma»), urticaria, or acute rhinitis in response to acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs).

Congestive heart failure (NYHA II–IV).

Ischemic heart disease in patients with angina pectoris or history of myocardial infarction.

Cerebrovascular disorders in patients who have experienced stroke or transient ischemic attacks.

Peripheral arterial disease.

Treatment of perioperative pain in aortocoronary bypass surgery (or use of cardiopulmonary bypass apparatus).

High risk of postoperative bleeding, coagulation disorders, hemostatic disorders, hematopoietic disorders, or cerebrovascular hemorrhage.

History of gastrointestinal bleeding or perforation associated with previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).

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

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

Severe hepatic insufficiency.

Severe renal insufficiency.

Blood disorders.

Leukopenia.

Marked anemia.

Congenital hyperbilirubinemia.

Glucose-6-phosphate dehydrogenase deficiency.

Alcoholism.

Interaction with other medicinal products and other forms of interaction.

Diclofenac.

Alcohol: Do not use Flamidex® together with alcohol.

Lithium: the drug may increase lithium plasma concentrations. Monitoring of serum lithium levels is recommended.

Phenytoin: when used concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to possible increased phenytoin effects.

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

Digoxin: the drug may increase digoxin plasma concentrations. Monitoring of serum digoxin levels is recommended.

Diuretics and antihypertensive agents: as with other NSAIDs, concomitant use of Flamidex® with diuretics or antihypertensive agents (e.g., beta-blockers, angiotensin-converting enzyme (ACE) inhibitors) may reduce their antihypertensive effect. Therefore, such combinations should be used with caution, and patients, especially elderly patients, should be closely monitored for blood pressure. Adequate hydration is recommended, and monitoring of renal function is also advised both after initiation and on a regular basis during concomitant therapy, particularly with diuretics and ACE inhibitors due to increased risk of nephrotoxicity. Concomitant treatment with potassium-sparing agents may lead to increased serum potassium levels, requiring continuous monitoring of patients.

Other NSAIDs and corticosteroids: concomitant use of Flamidex® with other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal adverse reactions. Concomitant use of the drug with other NSAIDs, including selective COX-2 inhibitors, should be avoided.

Anticoagulants and antithrombotic agents: regular, simultaneous, and prolonged use of the drug with anticoagulants, particularly warfarin and other coumarins, and antiplatelet agents may increase the risk of bleeding. Occasional use has no significant effect. Seratopeptidase enhances the effect of anticoagulants when used concomitantly; therefore, careful and regular monitoring of the patient is recommended when these drugs are combined.

Selective serotonin reuptake inhibitors (SSRIs): concomitant administration of systemic NSAIDs and SSRIs increases the risk of gastrointestinal bleeding.

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

Antidiabetic agents: the drug can be used together with oral antidiabetic agents without affecting their efficacy; however, isolated cases of both hypoglycemic and hyperglycemic effects have been reported, requiring dosage adjustments of antidiabetic agents during Flamidex® treatment. Monitoring of blood glucose levels is recommended as a precaution during concomitant therapy.

Cholestyramine and colestipol: concomitant use of Flamidex® with colestipol or cholestyramine reduces diclofenac absorption by approximately 30% and 60%, respectively. These agents should be administered with several hours' interval.

Drugs that induce drug-metabolizing enzymes: drugs that induce enzymes, such as rifampicin, carbamazepine, phenytoin, barbiturates, and St. John's wort (Hypericum perforatum), may theoretically reduce diclofenac plasma concentrations.

Methotrexate: caution is recommended when administering NSAIDs less than 24 hours before or less than 24 hours after methotrexate treatment, as this may increase methotrexate blood concentrations and enhance its toxicity.

Drugs causing hyperkalemia: concomitant treatment with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may be associated with increased serum potassium levels; therefore, more frequent monitoring of patients is required.

Cyclosporine and tacrolimus: NSAIDs may increase cyclosporine nephrotoxicity by affecting renal prostaglandin synthesis. Therefore, it should be used at lower doses than in patients not receiving cyclosporine. This risk also applies to treatment with tacrolimus.

Quinolone antibiotics: there are isolated reports of seizures that may result from concomitant use of quinolones and NSAIDs.

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

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.

Barbiturates: reduce the antipyretic effect of paracetamol.

Drugs that induce drug-metabolizing enzymes: drugs that induce enzymes, such as rifampicin, carbamazepine, phenytoin, barbiturates, and St. John's wort (Hypericum perforatum), may enhance the hepatotoxic effect of paracetamol by increasing its conversion into hepatotoxic metabolites.

Concomitant use of paracetamol with hepatotoxic agents increases the hepatotoxic potential of the drugs.

Isoniazid: concomitant use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome.

Metoclopramide and domperidone: may increase the rate of paracetamol absorption.

Diuretics: paracetamol reduces the effectiveness of diuretics.

Coumarin derivatives (warfarin): prolonged use of paracetamol increases the risk of bleeding. Single-dose administration has no significant effect.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as this combination 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.

Do not exceed the recommended doses.

The medicinal product contains paracetamol; therefore, it should not be taken concomitantly with other medicinal products containing paracetamol used, for example, 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.

Cases of liver dysfunction/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 use of paracetamol increases the risk of metabolic acidosis. 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.

Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, as well as in patients with inadequate nutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who received paracetamol at therapeutic doses for prolonged periods or a combination of paracetamol and flucloxacillin. If high anion gap metabolic acidosis due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring of the patient. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

Concomitant use of Flamidex® with systemic NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided due to the potential for additional adverse effects.

NSAIDs increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which may be fatal. Therefore, the medicinal product is not recommended for the treatment of postoperative pain or during coronary artery bypass graft (CABG) surgery.

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation. Clinical trial data and epidemiological evidence indicate that the use of diclofenac, particularly at high doses (150 mg/day) and for prolonged periods, is associated with a certain increase in the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke).

A careful risk-benefit assessment should be performed before prescribing Flamidex® to patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial occlusive diseases, or significant risk factors (e.g., hypertension, hyperglycemia, diabetes mellitus, smoking).

Diclofenac is not recommended for patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial diseases, and/or cerebrovascular disease. If necessary, treatment may be considered only after a thorough risk-benefit assessment and at a daily dose not exceeding 100 mg. A similar assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

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

Patients should be informed about the possibility of serious complications (chest pain, shortness of breath, weakness, speech disturbances), which may occur at any time. In such cases, immediate medical attention is required.

Since cardiovascular risks of diclofenac increase with higher doses and longer duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The patient's need for diclofenac and response to therapy should be periodically reassessed.

Caution should be exercised when administering the medicinal product to patients with hepatic porphyria.

Use with caution in patients with a history of liver, kidney, or gastrointestinal disorders, dyspeptic symptoms, after surgical procedures, elderly patients, bronchial asthma, or congestive heart failure. In patients with a history of allergic reactions, the medicinal product should be prescribed only in emergency situations.

When using all NSAIDs, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported, which may be fatal and may occur at any time during treatment, with or without warning symptoms, and even in patients with a history of serious gastrointestinal events. These events usually have more severe consequences in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the medicinal product should be discontinued.

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

Very rarely, serious skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have occurred with the use of NSAIDs. The risk of such reactions is highest at the beginning of treatment, and most cases occur within the first month of therapy. The medicinal product should be discontinued at the first sign of skin rash, mucosal lesions, or any other signs of hypersensitivity.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur even after the first dose.

Like other NSAIDs, Flamidex® may mask symptoms of infection. If symptoms of the underlying condition do not resolve, medical advice should be sought.

With prolonged use, peripheral blood parameters and liver function should be monitored.

General warnings

Avoid concomitant use of the medicinal product with systemic NSAIDs, including selective cyclooxygenase-2 inhibitors, due to the lack of synergistic benefit and the potential for additional adverse effects.

Due to the risk of thrombotic cardiovascular and cerebrovascular complications, gastrointestinal ulcers, bleeding, or perforation, the lowest effective doses of the medicinal product should be used for the shortest possible duration.

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

Caution is required when prescribing the medicinal product to elderly individuals. In particular, the lowest effective doses are recommended for elderly patients and those with low body weight.

The medicinal product contains lactose. If intolerance to certain sugars has been diagnosed, consultation with a physician is necessary before taking this medicinal product.

Hypersensitivity reactions may progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction. Symptoms of such reactions may include chest pain occurring in combination with an allergic reaction to diclofenac.

History of bronchial asthma

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

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 symptoms similar to rhinitis) are more likely than others to experience NSAID-related reactions resembling asthma exacerbations (also associated with analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria. Therefore, special precautionary measures (preparedness for emergency care) are recommended for such patients. This also applies to patients allergic to other substances, for example, those with skin reactions, itching, or urticaria.

Gastrointestinal effects

As with other NSAIDs, medical supervision and special caution are mandatory when prescribing the medicinal product to patients with symptoms indicating gastrointestinal tract (GIT) disorders or with a history of gastric or intestinal ulcers, bleeding, or perforations. The risk of gastrointestinal bleeding increases with higher doses and in patients with a history of ulcers, especially complicated by bleeding or perforation, and in elderly patients.

To reduce the risk of GIT toxicity in patients with a history of ulcers, particularly complicated by bleeding or perforation, and in elderly patients, treatment should be initiated and maintained at the lowest effective doses.

For such patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid (ASA) or other medicinal products that increase the risk of adverse GIT effects, consideration should be given to combined therapy with protective agents (e.g., proton pump inhibitors).

Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding).

Caution is also required when treating patients receiving concomitant medications that increase the risk of ulcers or bleeding, such as systemic corticosteroids, anticoagulants, antiplatelet agents, or selective serotonin reuptake inhibitors.

The use of NSAIDs, including diclofenac, is associated with an increased risk of gastrointestinal anastomosis failure. Close monitoring and caution are recommended when using diclofenac after gastrointestinal surgery.

Hepatic effects

Careful medical supervision is required when prescribing Flamidex® to patients with impaired liver function, as their condition may worsen.

As with other NSAIDs, levels of one or more liver enzymes may increase. During long-term treatment, regular monitoring of liver function is recommended as a precautionary measure. If liver function abnormalities persist or worsen, if clinical signs or symptoms may be related to progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), the medicinal product should be discontinued. The course of diseases such as hepatitis may proceed without prodromal symptoms.

In patients with alcoholic liver disease, the risk of hepatotoxic effects of paracetamol is increased.

Renal effects

The effect of NSAIDs on the kidneys may lead to fluid retention, edema, and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with cardiac disorders or other conditions predisposing to fluid retention. The medicinal product should be used cautiously in patients concurrently using diuretics or angiotensin-converting enzyme (ACE) inhibitors or those at increased risk of hypovolemia. Since fluid retention and edema have been reported during NSAID treatment, particular attention should be paid to patients with heart or kidney dysfunction (including functional renal failure due to hypovolemia, nephrotic syndrome, lupus nephritis, and decompensated liver cirrhosis), a history of arterial hypertension, elderly patients, patients receiving concomitant diuretic therapy or drugs significantly affecting 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.

Hematological effects

With prolonged use of the medicinal product, as with other NSAIDs, monitoring of blood parameters is recommended.

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

Like other NSAIDs, the medicinal product may temporarily inhibit platelet aggregation. Careful monitoring is required in patients with coagulation disorders.

Use during pregnancy or breastfeeding.

The medicinal product should not be used.

Use of Flamidex® from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after the start of treatment and is usually reversible upon discontinuation of therapy.

During the third trimester, all inhibitors of prostaglandin synthesis cause:

risks for the fetus:

• cardiopulmonary toxicity (with premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction (see above);

risks for the woman at the end of pregnancy and for the newborn:

• prolonged bleeding time, antiaggregatory effect, which may occur even with very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, Flamidex® is contraindicated during pregnancy.

Female fertility.

The use of the medicinal product may impair fertility in women and is not recommended for women attempting to conceive. If a woman experiences difficulties in conceiving or is undergoing infertility evaluation, discontinuation of the medicinal product should be considered.

Ability to affect reaction speed when driving or operating machinery.

Flamidex® may impair psychomotor performance; therefore, patients should refrain from driving or operating complex machinery during treatment.

Method of Administration and Dosage

If intolerance to certain sugars is established, consult a physician before taking this medicinal product.

The drug should be used at the lowest effective doses for the shortest possible duration, taking into account the individual treatment goals for each patient.

The dosage is determined individually by a physician depending on the patient's age, nature and course of the disease, as well as the drug's tolerability and therapeutic efficacy.

The drug is taken orally, after meals, with a small amount of liquid (200 ml).

Adults: 1 tablet 2–3 times daily, depending on the severity of the disease.

Children aged 14 years and older: 1 tablet 1–2 times daily.

Maximum daily dose – 3 tablets.

The duration of treatment is determined individually by a physician based on symptom dynamics and should not exceed 5–7 days.

Maximum duration of use without medical consultation – 3 days.

Children.

The drug is indicated for children aged 14 years and older.

Overdose.

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

Symptoms within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become evident 12–48 hours after overdose.

Acute paracetamol overdose may cause reversible or irreversible necrosis of liver cells, leading to impaired glucose metabolism and metabolic acidosis, hepatocellular failure, encephalopathy, hemorrhage, hypoglycemia, coma, and potentially fatal outcomes. It is believed that an increased amount of the paracetamol metabolite (normally neutralized by glutathione when standard doses are used) binds irreversibly to liver tissues.

Acute renal failure with acute tubular necrosis may manifest as severe lumbar pain, hematuria, and proteinuria, and may develop even in the absence of severe liver damage. Concurrently, increased levels of liver transaminases (AST, ALT), lactate dehydrogenase, bilirubin, and prolonged prothrombin time may occur 12–48 hours after ingestion.

In cases of overdose, the following may also occur: arterial hypotension, respiratory depression, seizures, gastrointestinal bleeding, tinnitus, cardiac arrhythmia, and pancreatitis.

With prolonged use of the drug in high doses, hematological side effects may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Central nervous system (CNS) effects from high doses may include dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

In cases of diclofenac overdose, arterial hypotension, respiratory depression, seizures, renal failure, diarrhea, gastrointestinal bleeding, dizziness, and tinnitus may occur.

In case of overdose, immediate medical assistance is required. The patient should be taken to a hospital immediately, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of the overdose or risk of organ damage. Administration of activated charcoal should be considered if the excessive dose of paracetamol was taken within the past hour. Plasma paracetamol concentration should be measured 4 hours or more after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours after ingestion. The efficacy of the antidote decreases sharply after this time. If necessary, intravenous N-acetylcysteine should be administered according to the established dosage regimen. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Supportive measures and symptomatic treatment are necessary to manage complications such as hypotension, renal failure, seizures, gastrointestinal disturbances, and respiratory depression.

Forced diuresis, dialysis, or hemoperfusion cannot reliably eliminate nonsteroidal anti-inflammatory drugs due to their high plasma protein binding and extensive metabolism.

Adverse Reactions

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

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

Psychiatric disorders: disorientation, depression, sleep disturbances, insomnia, nightmares, irritability, anxiety, fear, psychiatric disorders, confusion, psychomotor agitation, hallucinations.

Nervous system disorders: headache, dizziness, drowsiness, paresthesia, memory impairment, seizures, anxiety, tremor, aseptic meningitis, taste disturbances, cerebral circulation disorders, sensory disturbances.

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

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

Cardiac disorders: palpitations, tachycardia, chest pain, dyspnea, heart failure, myocardial infarction, Kounis syndrome.

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

Vascular disorders: arterial hypertension, arterial hypotension, vasculitis.

Respiratory, thoracic and mediastinal disorders: asthma (including dyspnea), bronchospasm (especially in patients sensitive to acetylsalicylic acid), chest pain, pneumonitis, blood-tinged sputum, acute eosinophilic pneumonia.

Gastrointestinal disorders: nausea, vomiting, diarrhea, dyspepsia, epigastric pain, abdominal pain, flatulence, anorexia, gastritis, gastrointestinal bleeding, vomiting with blood, hemorrhagic diarrhea, melena, gastric or intestinal ulcer (with or without bleeding or perforation), colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis, glossitis, esophageal disorders, diaphragm-like intestinal strictures, pancreatitis.

Hepatobiliary disorders: increased transaminase levels, hepatitis, jaundice, liver function abnormalities; fulminant hepatitis, hepatonecrosis (with high-dose intake), liver failure.

Skin and subcutaneous tissue disorders: rashes (usually generalized, erythematous rashes, mucosal rashes), urticaria, pruritus, bullous eruptions, exfoliative dermatitis, eczema, erythema, exudative multiform erythema, alopecia, photosensitivity reaction, purpura, allergic purpura, itching, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

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

Endocrine disorders: hypoglycemia (up to hypoglycemic coma).

Reproductive system disorders: impotence.

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

General disorders: fluid retention, edema, general weakness, increased fatigue, excessive sweating, bruising, bleeding.

Description of selected adverse reactions

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

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 2.5 years.

Storage conditions.

Store in the original packaging, in a place inaccessible to children, at a temperature not exceeding 30 °C.

Packaging.

10 tablets per blister; 1, 3, or 10 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Evertogen Life Sciences Limited /
Evertogen Life Sciences Limited.

Saga Lifesciences Limited /
Saga Lifesciences Limited.

Manufacturer's address and place of business.

Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India /
Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India.

Survey No. 198/2 & 198/3, Chachrawadi Vasna, Ta Sannand District, Ahmedabad, Gujarat, 382210, India /
Survey No. 198/2 & 198/3, Chachrawadi Vasna, Ta Sannand District, Ahmedabad, Gujarat, 382210, India.