Fanigan

INSTRUCTION for medical use of the medicinal product Fanigan (Fanigan®)

Composition:

Active substances: paracetamol, sodium diclofenac;

One tablet contains 500 mg of paracetamol, 50 mg of sodium diclofenac;

Excipients: maize starch, povidone K-30, sodium croscarmellose, microcrystalline cellulose, magnesium stearate, Yellow FCF (E 110).

Pharmaceutical form. Tablets.

Main physicochemical properties: capsule-shaped tablets, orange-colored with white specks.

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

ATC code M01AB55.

Pharmacological Properties

Pharmacodynamics

Fanigan is a combination drug that exerts a pronounced anti-inflammatory, analgesic, and antipyretic effect. The pharmacological activity of the drug is due to the properties of diclofenac and paracetamol, which are components of the formulation.

Sodium diclofenac produces a pronounced anti-inflammatory and analgesic effect, as well as a moderate antipyretic action. It is an inhibitor of prostaglandin synthetase (cyclooxygenase).

In vitro, diclofenac at concentrations equivalent to those achieved during patient treatment does not inhibit proteoglycan biosynthesis in cartilage tissue. Paracetamol exhibits a pronounced analgesic effect, mild antipyretic activity, and a slight anti-inflammatory effect. Its mechanism of action is associated with inhibition of prostaglandin synthesis in the central nervous system.

Pharmacokinetics

Diclofenac.

Sodium diclofenac is rapidly absorbed into the bloodstream—the maximum plasma concentration is reached within 1–2 hours. Plasma protein binding exceeds 99%. It penetrates well into tissues and synovial fluid, where its concentration increases slowly and reaches higher levels than in plasma after 4 hours. Food may slow the rate of absorption but does not affect the extent of absorption. Bioavailability is approximately 5%.

The elimination half-life from plasma is 1–2 hours and from synovial fluid is 3–6 hours. Approximately 35% is excreted in feces as metabolites; about 65% is metabolized in the liver and excreted by the kidneys as inactive derivatives, and about 1% is excreted unchanged.

Paracetamol.

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 30–60 minutes. The elimination half-life ranges from 1 to 4 hours. It is uniformly distributed throughout all body fluids. Plasma protein binding is variable. Paracetamol is metabolized in the liver and primarily excreted by the kidneys in the form of conjugated metabolites.

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

Clinical characteristics.

Indications.

• Acute pain (muscular, headache, toothache, spinal pain), 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 to any other component of the drug.

Acute gastric or intestinal ulcer; gastrointestinal bleeding or perforation.

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

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

High risk of postoperative bleeding, coagulopathy, hemostasis disorders, hematopoietic disorders, or cerebrovascular bleeding.

Hepatic insufficiency.

Renal insufficiency (glomerular filtration rate < 15 ml/min/1.73 m²).

Congestive heart failure (functional class II–IV according to NYHA criteria).

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

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

Blood disorders, unexplained disturbances of hematopoiesis, leukopenia, severe anemia.

Congenital hyperbilirubinemia, Gilbert's syndrome.

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 grafting (or when using cardiopulmonary bypass apparatus).

Peripheral arterial disease.

Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks.

Interaction with other medicinal products and other forms of interaction.

Diclofenac.

Lithium. Diclofenac may increase plasma lithium concentrations when administered concomitantly. Monitoring of serum lithium levels is recommended.

Digoxin. Diclofenac may increase plasma digoxin concentrations when administered concomitantly. Monitoring of serum digoxin levels is recommended.

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g., β-blockers, angiotensin-converting enzyme [ACE] inhibitors) may reduce their antihypertensive effect by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, such combinations should be used with caution, and patients, especially elderly, should be closely monitored for blood pressure. Adequate hydration should be ensured, and renal function should be monitored after initiation and regularly during concomitant therapy, particularly with diuretics and ACE inhibitors, due to increased risk of nephrotoxicity.

Medicinal products causing hyperkalemia. Concomitant use with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may be associated with increased serum potassium levels; therefore, more frequent monitoring of patients is recommended.

Anticoagulants and antithrombotic agents. Concomitant use may increase the risk of bleeding; therefore, precautionary measures are recommended. Although there are no convincing data on the effect of diclofenac on anticoagulant activity, evidence exists of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously. Therefore, to ensure that no dosage adjustments of anticoagulants are needed, careful monitoring of such patients is recommended. Like other nonsteroidal anti-inflammatory drugs, diclofenac at high doses may transiently inhibit platelet aggregation.

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

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

Antidiabetic agents. Diclofenac has been shown to be used together with oral antidiabetic agents without altering their therapeutic effect. However, there are some reports of both hypoglycemia and hyperglycemia requiring dose adjustments of antidiabetic agents during diclofenac use. For this reason, blood glucose monitoring is recommended during combination therapy.

Isolated cases of metabolic acidosis have also been reported with concomitant use of diclofenac, particularly in patients with pre-existing renal function impairment.

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

Cyclosporine. The effect of diclofenac, as with other NSAIDs, on prostaglandin synthesis in the kidneys may potentiate the nephrotoxicity of cyclosporine; therefore, diclofenac should be administered at lower doses in patients receiving cyclosporine.

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

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

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

Cholestyramine and colestipol. These agents may delay or reduce absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least 1 hour before or 4–6 hours after cholestyramine/colestipol.

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

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

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

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

Paracetamol.

The absorption rate of paracetamol may be increased when co-administered with metoclopramide and domperidone, and decreased 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.

Caution should be exercised when using paracetamol concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with high anion gap, particularly in patients with risk factors (see section "Special precautions").

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

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

Do not use concomitantly with alcohol.

Special precautions for use.

General

To minimize adverse effects, treatment should be initiated at the lowest effective dose for the shortest duration necessary to control symptoms.

For diclofenac.

Concomitant use of diclofenac with systemic NSAIDs, such as selective cyclooxygenase-2 inhibitors, should be avoided due to lack of evidence for synergistic effect and potential for additive adverse effects.

An increased risk of thrombotic cardiovascular and cerebrovascular complications has been observed with the use of certain selective COX-2 inhibitors. A direct correlation between this risk and the COX-1/COX-2 selectivity of individual NSAIDs has not been established. Due to the lack of clinical data on long-term treatment with maximum doses of diclofenac, this increased risk cannot be excluded. Therefore, a careful benefit-risk assessment should be performed before prescribing diclofenac to patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial occlusive diseases, or significant risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). The lowest effective dose should be used for the shortest possible duration of treatment.

The effects of NSAIDs on the kidneys include fluid retention with edema and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with impaired cardiac function and other conditions predisposing to fluid retention. Caution is also advised in patients who are concurrently taking diuretics or angiotensin-converting enzyme (ACE) inhibitors, or who have an increased risk of hypovolemia.

Consequences are usually more serious in elderly patients. The drug should be prescribed with caution to elderly individuals. Particular caution is required when administering to patients over 65 years of age. Specifically, the lowest effective dose is recommended for frail elderly patients and those with low body weight.

If gastrointestinal bleeding or ulcers occur in patients undergoing treatment with diclofenac, its use should be discontinued.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur even in the absence of prior exposure to diclofenac.

Hypersensitivity reactions may also 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.

Due to its pharmacodynamic properties, diclofenac, like other NSAIDs, may mask signs and symptoms of infection.

Gastrointestinal effects.

Cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported with the use of all NSAIDs, whether COX-2 selective or not, including diclofenac. These events may be fatal and may occur at any time during treatment, with or without warning symptoms or prior history of serious gastrointestinal events. These events usually have more serious consequences in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.

As with other NSAIDs, including diclofenac, medical supervision and special caution are mandatory in patients with symptoms indicating gastrointestinal (GI) tract disorders. The risk of GI bleeding, ulceration, or perforation increases with higher NSAID doses, including diclofenac.

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

To reduce the risk of such GI toxicity, treatment should be initiated and maintained at the lowest effective dose. For such patients, as well as those requiring concomitant low-dose acetylsalicylic acid (ASA/aspirin) or other drugs that may increase the risk of GI adverse effects, consideration should be given to combined therapy with protective agents (e.g., proton pump inhibitors or misoprostol). Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly GI bleeding). Caution is also required in patients receiving concomitant medications that increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., ASA), or selective serotonin reuptake inhibitors.

NSAIDs, including diclofenac, are associated with an increased risk of gastrointestinal anastomosis failure. Careful medical monitoring and caution are recommended when using diclofenac after gastrointestinal surgery.

Hepatic effects.

Close medical supervision is required when diclofenac is prescribed to patients with impaired liver function, as their condition may worsen.

With the use of NSAIDs, including diclofenac, the levels of one or more liver enzymes may increase. Such increases have usually been reversible upon discontinuation of the drug. Elevated liver enzymes were very frequently observed during clinical trials with diclofenac (approximately in 15% of patients), but rarely associated with clinical symptoms. In most cases, the increase did not exceed the normal range. Moderate increases (≥3 to <8 times the upper limit of normal) were frequently observed (in 2.5% of cases), while marked increases (≥8 times the upper limit of normal) occurred in approximately 1% of cases. Clinically apparent liver injury occurred in 0.5% of cases in the aforementioned clinical trials.

During long-term treatment, regular monitoring of liver function and liver enzyme levels is recommended. If liver function abnormalities persist or worsen, if clinical symptoms may be related to progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), the use of the medicinal product Fanigan should be discontinued.

In addition to elevated liver enzymes, isolated cases of severe hepatic reactions have been reported, including jaundice, fulminant hepatitis, hepatic necrosis, and liver failure, sometimes resulting in death.

The course of diseases such as hepatitis may occur without prodromal symptoms. Caution is required when Fanigan is used in patients with hepatic porphyria, due to the potential to provoke an attack.

Renal effects.

NSAIDs, including diclofenac, reduce prostaglandin levels, which are important for maintaining renal blood flow.

Since fluid retention, edema, and hypertension are frequently (1–10%) reported during treatment with NSAIDs, including diclofenac, 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 (e.g., before or after major surgery). In such cases, monitoring of renal function is recommended. Discontinuation of therapy usually results in return to the pre-treatment state.

Skin effects.

Serious skin reactions (some of which were 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 early in the course of therapy: most reactions occur within the first month of treatment. Use of Fanigan should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

SLE and mixed connective tissue diseases.

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

Cardiovascular and cerebrovascular effects.

Treatment with diclofenac is generally not recommended for patients with diagnosed cardiovascular diseases (heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled arterial hypertension.

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation and only at doses up to 100 mg daily if treatment exceeds 4 weeks. Since cardiovascular risks increase with higher doses and longer duration of treatment, diclofenac should be used for the shortest possible time and at the lowest effective dose. The need for diclofenac and the patient's response to therapy should be periodically reassessed.

For patients with a history of arterial hypertension and/or mild to moderate congestive heart failure, appropriate monitoring and advice are necessary, as fluid retention and edema have been reported during treatment with NSAIDs, including diclofenac.

Diclofenac should be used with caution in patients who are concurrently taking diuretics or ACE inhibitors or who have an increased risk of hypovolemia.

Clinical and epidemiological data indicate that the use of diclofenac, particularly at high doses (150 mg/day) and during prolonged treatment, is associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

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

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

Hematological effects.

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

Diclofenac may temporarily inhibit platelet aggregation. Patients with coagulation disorders, hemorrhagic diathesis, or hematological disorders should be carefully monitored.

History of asthma.

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

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

Fertility.

Use of diclofenac, like other NSAIDs, may impair fertility in women and is therefore not recommended for women attempting to conceive. If a woman experiences difficulty conceiving or is undergoing infertility evaluation, discontinuation of the medicinal product Fanigan should be considered.

Based on animal studies, impairment of male reproductive function cannot be excluded. The relevance of these data to humans has not been established.

Effects on pregnancy and/or embryonic/fetal development.

Inhibition of prostaglandin synthesis by diclofenac may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and/or risk of cardiac defects and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. Animal studies have shown that administration of a prostaglandin synthesis inhibitor leads to increased pre- and post-implantation loss and embryonic/fetal mortality. Furthermore, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

From the 20th week of pregnancy, use of diclofenac may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of treatment.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may lead to fetal:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired renal function (see above).

In the mother and newborn at the end of pregnancy:

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

For paracetamol.

The medicinal product contains paracetamol; therefore, it should not be used together with other products containing paracetamol used, for example, to reduce fever, relieve pain, treat flu and cold symptoms, or for insomnia. Concomitant use with other paracetamol-containing products may lead to overdose. Paracetamol overdose may 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 product.

It should be noted that patients with liver disease have an increased risk of hepatotoxic effects of 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, chronic alcoholism, or sepsis.

Caution is recommended when using paracetamol concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis, especially in patients with severe renal insufficiency, sepsis, malnutrition, and other sources of glutathione deficiency (e.g., chronic alcoholism), as well as those taking maximum daily doses of paracetamol. Careful monitoring, including measurement of 5-oxoproline in urine, is recommended.

Patients with reduced glutathione levels have an increased risk of metabolic acidosis when taking paracetamol. 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. Do not exceed the recommended doses. Very prolonged use without medical supervision may be dangerous.

The medicinal product should be used only when clearly necessary.

If symptoms persist, a physician should be consulted.

Keep the product out of sight and reach of children.

The product contains the colorant sunset yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

The medicinal product Fanigan is contraindicated during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Do not exceed the recommended dose. The lowest effective dose should be used for the shortest duration necessary to achieve the treatment goal.

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

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

The interval between doses should be at least 4 hours.

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.

The maximum duration of use without medical consultation is 3 days.

Do not take together with other medicinal products containing paracetamol.

Elderly patients (aged 65 years and older).

Although the pharmacokinetics of diclofenac are not clinically significantly impaired in elderly patients, NSAIDs should be used with particular caution in this population, who are generally more susceptible to adverse reactions. In particular, for frail elderly patients or those with low body weight, the lowest effective doses are recommended. Patients should also be monitored for gastrointestinal bleeding during NSAID therapy.

Cardiovascular diseases or significant cardiovascular risk factors.

The medicinal product may be prescribed to patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation. Since cardiovascular risks increase with higher doses and longer duration of treatment, diclofenac should be used for the shortest possible duration and at the lowest effective dose. The patient's need for diclofenac to relieve symptoms and response to therapy should be reviewed periodically.

Patients with renal impairment.

The medicinal product is contraindicated in patients with renal insufficiency (glomerular filtration rate < 15 ml/min/1.73 m²; see section "Contraindications").

Specific studies in patients with renal impairment have not been conducted; therefore, no dosage recommendations can be provided. Diclofenac should be used with caution in patients with renal impairment (see section "Special Warnings and Precautions for Use").

Patients with hepatic impairment.

The medicinal product is contraindicated in patients with hepatic insufficiency (see section "Contraindications").

Specific studies in patients with hepatic impairment have not been conducted; therefore, no dosage recommendations can be provided. Diclofenac should be used with caution in patients with mild to moderate hepatic impairment (see section "Special Warnings and Precautions for Use").

Children.

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

Overdose.

Diclofenac.

Symptoms.

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

Treatment.

Management of acute poisoning with NSAIDs, including diclofenac, consists of supportive and symptomatic therapy. This includes treatment of manifestations such as arterial hypotension, renal failure, convulsions, gastrointestinal disturbances, and respiratory depression. Specific interventions such as forced diuresis, dialysis, or hemoperfusion are unlikely to be effective in eliminating NSAIDs, including diclofenac, because these drugs are highly protein-bound and undergo extensive metabolism. After ingestion of potentially toxic doses, activated charcoal is recommended. After ingestion of potentially life-threatening doses, gastric decontamination (e.g., induction of emesis, gastric lavage) should be performed.

Paracetamol.

Paracetamol overdose can cause liver failure, which may necessitate liver transplantation or lead to fatal outcomes. Clinical signs of liver damage after paracetamol overdose typically appear within 24–48 hours and peak at 4–6 days.

There is an increased risk of paracetamol poisoning, particularly in elderly patients, children, patients with liver disease, chronic alcoholism, or chronic malnutrition.

Symptoms within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Overdose may also be asymptomatic initially. A single overdose of paracetamol in adults and children may cause reversible or irreversible necrosis of liver cells, leading to disturbances in glucose metabolism, metabolic acidosis, hepatocellular failure, encephalopathy, hemorrhage, hypoglycemia, coma, and death. Elevated levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, bilirubin, and prothrombin time are observed 12–48 hours after ingestion. Liver injury is likely in adults who have taken more than the recommended amount of paracetamol. It is believed that an increased amount of a paracetamol metabolite (normally neutralized by glutathione at therapeutic doses) binds irreversibly to liver tissue.

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 injury. Cardiac arrhythmias and acute pancreatitis, usually associated with liver function abnormalities and hepatotoxicity, have also been reported.

With prolonged use of the drug in high doses, hematological disorders such as aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop. Neurological side effects may include dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis). Gastrointestinal effects may include hepatonecrosis.

Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage.

Risk factors for paracetamol overdose include:

• prolonged treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, and other drugs that induce liver enzyme synthesis;
• chronic alcohol abuse;
• reduced glutathione levels, e.g., due to malnutrition, fasting, cachexia, cystic fibrosis, HIV.

Treatment: urgent supportive and symptomatic therapy.

In cases of overdose, immediate medical assistance is required. Treatment for overdose or even suspected overdose should be initiated immediately. The patient should be taken to the hospital even if early symptoms are absent, as liver damage may not develop immediately. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier concentrations are unreliable).

If an excessive dose of paracetamol (>150 mg/kg) was ingested within 1 hour, administration of activated charcoal should be considered. Treatment with N-acetylcysteine or methionine may be beneficial. Symptomatic treatment should also be provided.

Adverse reactions.

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, agranulocytosis, anemia, including aplastic and hemolytic anemia (particularly in patients with glucose-6-phosphate dehydrogenase deficiency).

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

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

Psychiatric disorders: confusion, depression, insomnia, nightmares, irritability, psychiatric disorders; hallucinations.

Nervous system disorders: headache, dizziness; somnolence, fatigue; paresthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular disorders, stroke; confusion, sensory disturbances, malaise.

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

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

Cardiac and vascular disorders: palpitations, chest pain, heart failure, myocardial infarction, arterial hypertension, arterial hypotension, vasculitis; Kounis syndrome.

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

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

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

Renal and urinary disorders: fluid retention, edema; acute kidney injury (acute renal failure), hematuria, proteinuria, interstitial nephritis, nephrotic syndrome, renal papillary necrosis.

Reproductive system and breast disorders: impotence.

General disorders: edema.

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

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

Also, the following adverse reactions may occur after paracetamol intake: epigastric pain, hypoglycemia up to hypoglycemic coma, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruises or bleeding, increased activity of liver enzymes, usually without development of jaundice.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

4 tablets per blister, 25 blisters per cardboard pack.

10 tablets per blister, 10 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's address and place of business.

40020, Ukraine, Sumy region, Sumy city, Davydovskoho Hryhoriya St., 54.

INSTRUCTION

for medical use of the medicinal product

Phanigan

(Fanigan®)

Composition:

Active substances: paracetamol, sodium diclofenac;

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

Excipients: maize starch, povidone K-30, sodium croscarmellose, microcrystalline cellulose, magnesium stearate, Yellow West FCF (E 110).

Pharmaceutical form. Tablets.

Main physicochemical properties: capsule-shaped tablets, orange-colored with white specks.

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

ATC code M01AB55.

Pharmacological Properties.

Pharmacodynamics.

Fanigan is a combination drug that exerts pronounced anti-inflammatory, analgesic, and antipyretic effects. The pharmacological activity of the drug is due to the properties of diclofenac and paracetamol contained in the formulation.

Sodium diclofenac exerts pronounced anti-inflammatory and analgesic effects, as well as moderate antipyretic action. It is an inhibitor of prostaglandin synthetase (cyclooxygenase).

In vitro, diclofenac at concentrations equivalent to those achieved during patient treatment does not suppress proteoglycan biosynthesis in cartilage tissue. Paracetamol demonstrates a pronounced analgesic effect, with slight antipyretic and anti-inflammatory activity. Its mechanism of action is associated with inhibition of prostaglandin synthesis in the central nervous system.

Pharmacokinetics.

Diclofenac.

Sodium diclofenac is rapidly absorbed into the bloodstream—the maximum plasma concentration is reached within 1–2 hours. Plasma protein binding exceeds 99%. It penetrates well into tissues and synovial fluid, where its concentration increases gradually, reaching higher levels than in plasma after 4 hours. Food may slow the rate of absorption without affecting the extent of absorption. Bioavailability is approximately 5%.

The elimination half-life from plasma is 1–2 hours and from synovial fluid is 3–6 hours. Approximately 35% is excreted in feces as metabolites; about 65% is metabolized in the liver and excreted by the kidneys as inactive derivatives, and about 1% is excreted unchanged.

Paracetamol.

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is achieved within 30–60 minutes. The elimination half-life ranges from 1 to 4 hours. It is uniformly distributed throughout all body fluids. Plasma protein binding is variable. Paracetamol is metabolized in the liver and primarily excreted by the kidneys as conjugated metabolites.

After repeated administration, the pharmacokinetic parameters of the active substances do not change. When the recommended intervals between tablet doses are observed, drug accumulation does not occur.

Clinical characteristics.

Indications.

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

Contraindications.

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

Active gastric or intestinal ulcer; gastrointestinal bleeding or perforation.

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

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

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

Hepatic failure.

Renal failure (glomerular filtration rate < 15 ml/min/1.73 m²).

Congestive heart failure (functional class II–IV according to NYHA criteria).

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

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

Blood disorders, unexplained hematopoietic disorders, leukopenia, severe anemia.

Congenital hyperbilirubinemia, Gilbert's syndrome.

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 grafting (or when using cardiopulmonary bypass apparatus).

Peripheral arterial disease.

Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks.

Interaction with other medicinal products and other forms of interaction.

Diclofenac.

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

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

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g., β-blockers, angiotensin-converting enzyme [ACE] inhibitors) may reduce their antihypertensive effect by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, such combinations should be used with caution, and patients, especially elderly ones, should be closely monitored for blood pressure. Adequate hydration is recommended, and renal function should be monitored after initiation of concomitant therapy and regularly thereafter, particularly when using diuretics and ACE inhibitors, due to increased risk of nephrotoxicity.

Agents causing hyperkalemia. Concomitant therapy with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, more frequent monitoring of patients is advised.

Anticoagulants and antithrombotic agents. Concomitant use may increase the risk of bleeding; therefore, precautionary measures are recommended. Although convincing data on the effect of diclofenac on anticoagulant activity are lacking, evidence exists of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended to ensure no dosage adjustments of anticoagulants are needed. Like other nonsteroidal anti-inflammatory drugs, diclofenac at high doses may transiently inhibit platelet aggregation.

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

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

Antidiabetic agents. It has been demonstrated that diclofenac can be used together with oral antidiabetic agents without altering their therapeutic effect. However, there are reports of both hypoglycemia and hyperglycemia requiring dosage adjustments of antidiabetic agents during diclofenac use. Therefore, blood glucose monitoring is recommended during combination therapy.

Isolated reports also exist of metabolic acidosis during concomitant use with diclofenac, especially in patients with pre-existing renal impairment.

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

Cyclosporine. The effect of diclofenac, like other NSAIDs, on renal prostaglandin synthesis may potentiate the nephrotoxicity of cyclosporine. Therefore, diclofenac should be administered at lower doses in patients receiving cyclosporine compared to those not receiving cyclosporine.

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

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

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

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 administration.

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

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

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

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

Caution should be exercised when using paracetamol concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with high anion gap, particularly in patients with risk factors (see section "Special precautions for use").

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

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

Do not use concomitantly with alcohol.

Special precautions for use.

General

To minimize adverse effects, treatment should be initiated at the lowest effective dose for the shortest duration necessary to control symptoms.

For diclofenac.

Concomitant use of diclofenac with systemic NSAIDs, such as selective cyclooxygenase-2 inhibitors, should be avoided due to lack of evidence for synergistic effect and due to potential additive adverse effects.

An increased risk of thrombotic cardiovascular and cerebrovascular complications has been observed with the use of certain selective COX-2 inhibitors. A direct correlation between this risk and the selectivity of individual NSAIDs for COX-1/COX-2 has not been established. Due to the lack of clinical trial data on long-term treatment with maximum doses of diclofenac, this increased risk cannot be excluded. Therefore, a careful risk-benefit assessment should be performed before prescribing diclofenac to patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial occlusive diseases, or significant risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). The lowest effective dose should be used for the shortest possible duration of treatment.

The effects of NSAIDs on the kidneys include fluid retention with edema and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with impaired cardiac function and other conditions predisposing to fluid retention. Caution is also advised in patients who are concurrently taking diuretics or angiotensin-converting enzyme (ACE) inhibitors or who have an increased risk of hypovolemia.

Adverse effects are usually more severe in elderly patients. The drug should be prescribed with caution to elderly individuals. Particular caution is required when using the drug in patients aged over 65 years. The lowest effective dose is recommended for frail elderly patients and patients with low body weight.

If gastrointestinal bleeding or ulcers occur in patients undergoing treatment with diclofenac, its use should be discontinued.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur, 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.

Due to its pharmacodynamic properties, diclofenac, like other NSAIDs, may mask signs and symptoms of infection.

Gastrointestinal effects.

Cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported with all NSAIDs, whether COX-2 selective or not, including diclofenac. These events may be fatal and may occur at any time during treatment, with or without warning symptoms or prior history of serious gastrointestinal events. These events usually have more serious consequences in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.

As with other NSAIDs, including diclofenac, medical supervision and special caution are mandatory for patients with symptoms indicating gastrointestinal (GI) disorders. The risk of GI bleeding, ulceration, or perforation increases with higher NSAID doses, including diclofenac.

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

To reduce the risk of such GI toxicity, treatment should be initiated and maintained at the lowest effective doses. For such patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid (ASA/aspirin) or other drugs that may increase the risk of GI adverse effects, consideration should be given to combined therapy with protective agents (e.g., proton pump inhibitors or misoprostol). Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly GI bleeding). Caution is also required for patients receiving concomitant medications that increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., ASA), or selective serotonin reuptake inhibitors.

NSAIDs, including diclofenac, are associated with an increased risk of gastrointestinal anastomotic dehiscence. Careful medical monitoring and caution are recommended when using diclofenac after gastrointestinal surgery.

Hepatic effects.

Close medical supervision is required when diclofenac is prescribed to patients with impaired liver function, as their condition may worsen.

With the use of NSAIDs, including diclofenac, the levels of one or more liver enzymes may increase. Such elevations were usually reversible upon discontinuation of the drug. This elevation was very frequently observed in clinical trials with diclofenac (approximately in 15% of patients), but rarely associated with clinical symptoms. In most cases, it did not exceed the upper limit of normal. Moderate elevations (≥ 3 to < 8 times the upper limit of normal) were frequently observed (in 2.5% of cases), while marked elevations (≥ 8 times the upper limit of normal) remained at approximately 1%. In the aforementioned clinical trials, elevated liver enzyme levels were associated with clinically evident liver injury in 0.5% of cases.

During long-term treatment, regular monitoring of liver function and liver enzyme levels is recommended. If liver function abnormalities persist or worsen, and if clinical symptoms may be related to progressive liver disease or if other manifestations occur (e.g., eosinophilia, rash), treatment with the medicinal product Fanigan should be discontinued.

In addition to elevated liver enzyme levels, isolated cases of severe hepatic reactions have been reported, including jaundice and fulminant hepatitis, hepatic necrosis, and liver failure, which have occasionally led to death.

The course of diseases such as hepatitis may occur without prodromal symptoms. Caution is necessary if Fanigan is used in patients with hepatic porphyria, due to the potential risk of provoking an attack.

Renal effects.

NSAIDs, including diclofenac, reduce prostaglandin levels, which are important for maintaining renal blood flow.

Since fluid retention, edema, and hypertension are frequently (1–10%) reported during treatment with NSAIDs, including diclofenac, 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 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 results in return to the pre-treatment state.

Skin effects.

Serious skin reactions (some of which were fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis) have been very rarely reported with the use of NSAIDs, including diclofenac. The highest risk of these reactions occurs early in the course of therapy: most cases occur within the first month of treatment. Treatment with Fanigan must be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

SLE and mixed connective tissue disorders.

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

Cardiovascular and cerebrovascular effects.

Treatment with diclofenac is generally not recommended for patients with diagnosed cardiovascular diseases (heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled arterial hypertension.

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation and only at doses up to 100 mg daily for treatment courses longer than 4 weeks. Since cardiovascular risks increase with higher doses and longer duration of treatment, diclofenac should be used for the shortest possible time and at the lowest effective dose. The need for diclofenac use to relieve symptoms and the patient's response to therapy should be periodically reviewed.

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

Diclofenac should be used with caution in patients who are concurrently taking diuretics or ACE inhibitors or who have an increased risk of hypovolemia.

Clinical trial data and epidemiological evidence indicate that the use of diclofenac, particularly at high doses (150 mg/day) and during prolonged treatment, is associated with a slight increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Diclofenac is not recommended for patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, and/or cerebrovascular disease. If use is necessary, it should be possible only after careful risk/benefit assessment at a dosage not exceeding 100 mg per day. A similar assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g., patients with arterial hypertension, hyperlipidemia, diabetes mellitus, and smokers).

Patients should be informed about the possibility of serious thromboembolic events (chest pain, dyspnea, weakness, speech disturbances) at any time. In such cases, immediate medical attention should be sought.

Hematological effects.

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

Diclofenac may temporarily inhibit platelet aggregation. Careful monitoring is required in patients with hemostatic disorders, hemorrhagic diathesis, or hematological disorders.

History of asthma.

In patients with 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 asthma exacerbation (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria occur more frequently. Therefore, special precautions (readiness for emergency intervention) are recommended for such patients. This also applies to patients with allergic reactions to other substances, such as rash, pruritus, or urticaria.

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

Fertility.

Use of diclofenac, like other NSAIDs, may impair fertility in women and is therefore not recommended for women attempting to conceive. If a woman experiences difficulty conceiving or is undergoing infertility evaluation, discontinuation of the medicinal product Fanigan should be considered.

Based on animal studies, impairment of male reproductive function cannot be excluded. The relevance of these data to humans has not been established.

Effects on pregnancy and/or embryonic/fetal development.

Inhibition of prostaglandin synthesis by diclofenac may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and/or risk of cardiac malformations and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. Animal studies have shown that administration of a prostaglandin synthesis inhibitor leads to increased pre- and post-implantation loss and embryonic/fetal mortality. Furthermore, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, was observed.

From the 20th week of pregnancy, the use of diclofenac may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of treatment.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may lead to the following in the fetus:

• cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
• impaired renal function (see above).

In the mother and newborn at the end of pregnancy:

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

For paracetamol.

The medicinal product contains paracetamol; therefore, it should not be used together with other products containing paracetamol used, for example, to reduce fever, relieve pain, treat flu and cold symptoms, or for insomnia. Concomitant use with other paracetamol-containing products may lead to overdose. Paracetamol overdose may cause liver failure, which may necessitate liver transplantation or lead to death.

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

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

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

Caution is recommended when paracetamol is used concomitantly with flucloxacillin due to an increased risk of metabolic acidosis with high anion gap, especially in patients with severe renal impairment, sepsis, malnutrition, and other sources of glutathione deficiency (e.g., chronic alcoholism), as well as those taking maximum daily doses of paracetamol. Careful monitoring, including measurement of 5-oxoproline in urine, is recommended.

Patients with reduced glutathione levels have an increased risk of developing metabolic acidosis when taking paracetamol. 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. Do not exceed the recommended doses. Very prolonged use without medical supervision may be dangerous.

The medicinal product should be used only when clearly necessary.

If symptoms persist, a physician should be consulted.

Keep the product out of the sight and reach of children.

The product contains the colorant yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

The medicinal product Fanigan is contraindicated during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness (vertigo), somnolence, lethargy, fatigue, or other central nervous system disturbances during treatment with the product should refrain from driving or operating machinery.

Method of Administration and Dosage.

Do not exceed the recommended dose. The lowest effective dose should be used for the shortest duration necessary to achieve the treatment goal.

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

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

The interval between doses should be at least 4 hours.

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.

The maximum duration of use without medical consultation is 3 days.

Do not take together with other medicinal products containing paracetamol.

Elderly patients (aged 65 years and older).

Although the pharmacokinetics of diclofenac is not clinically significantly impaired in elderly patients, NSAIDs should be used with particular caution in such patients, who are generally more susceptible to adverse reactions. In particular, for frail elderly patients or those with low body weight, the lowest effective doses are recommended. Patients should also be monitored for gastrointestinal bleeding during NSAID treatment.

Cardiovascular diseases or significant cardiovascular risk factors.

The medicinal product may be prescribed to patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation. Since cardiovascular risks increase with higher doses and longer treatment duration, diclofenac should be used for the shortest possible time and at the lowest effective dose. The patient's need for diclofenac to relieve symptoms and response to therapy should be reviewed periodically.

Patients with impaired renal function.

The medicinal product is contraindicated in patients with renal insufficiency (glomerular filtration rate < 15 ml/min/1.73 m²; see section "Contraindications").

Specific studies in patients with impaired renal function have not been conducted; therefore, no dosage recommendations can be provided. Diclofenac should be used with caution in patients with impaired renal function (see section "Special Warnings and Precautions for Use").

Patients with impaired hepatic function.

The medicinal product is contraindicated in patients with hepatic insufficiency (see section "Contraindications").

Specific studies in patients with impaired hepatic function have not been conducted; therefore, no dosage recommendations can be provided. Diclofenac should be used with caution in patients with mild to moderate hepatic impairment (see section "Special Warnings and Precautions for Use").

Children.

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

Overdose.

Diclofenac.

Symptoms.

There is no typical clinical picture specific to diclofenac overdose. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, excitement, coma, somnolence, tinnitus, or convulsions. Acute renal failure and liver damage are possible in cases of severe intoxication.

Treatment.

Management of acute poisoning with NSAIDs, including diclofenac, involves supportive and symptomatic therapy. This includes treatment of manifestations such as arterial hypotension, renal failure, convulsions, gastrointestinal disturbances, and respiratory depression. Specific interventions such as forced diuresis, dialysis, or hemoperfusion are unlikely to be effective in eliminating NSAIDs, including diclofenac, because these drugs are highly protein-bound and undergo extensive metabolism. After ingestion of potentially toxic doses, administration of activated charcoal is recommended; after ingestion of potentially life-threatening doses, gastric decontamination (e.g., induction of emesis, gastric lavage) should be performed.

Paracetamol.

Paracetamol overdose may cause liver failure, which may necessitate liver transplantation or result in death. Clinical signs of liver damage after paracetamol overdose typically appear 24–48 hours after ingestion and peak at 4–6 days.

There is an increased risk of paracetamol poisoning, particularly in elderly patients, children, patients with liver disease, chronic alcoholism, or chronic malnutrition.

Symptoms within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Overdose may also be asymptomatic. A single overdose of paracetamol in adults and children may cause reversible or irreversible necrosis of liver cells, leading to impaired glucose metabolism, metabolic acidosis, hepatocellular failure, encephalopathy, hemorrhage, hypoglycemia, coma, and death. Elevated levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, bilirubin, and prothrombin time are observed 12–48 hours after ingestion. Liver damage is likely in adults who have ingested more than the recommended amount of paracetamol. It is believed that an increased amount of a paracetamol metabolite (normally neutralized by glutathione at therapeutic doses) irreversibly binds to liver tissue. Acute renal failure with acute tubular necrosis may present as severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and acute pancreatitis have also been reported, usually accompanied by liver function abnormalities and hepatotoxicity.

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

Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage.

Risk factors for paracetamol overdose include:

• Long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, and other drugs that induce liver enzyme synthesis;
• Chronic alcohol abuse;
• Reduced glutathione levels, for example, in malnutrition, fasting, cachexia, cystic fibrosis, HIV.

Treatment: Urgent supportive and symptomatic therapy is required.

In case of overdose, immediate medical assistance is necessary. Treatment for overdose or even suspected overdose should be initiated immediately, and the patient should be taken to hospital, even in the absence of early symptoms, because liver damage may not develop immediately. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier concentrations are unreliable).

If an excessive dose of paracetamol (>150 mg/kg) was ingested within 1 hour, administration of activated charcoal should be considered. Treatment with N-acetylcysteine or methionine may be beneficial. Symptomatic treatment should also be provided.

Adverse Reactions

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, agranulocytosis, anemia, including aplastic and hemolytic anemia (especially in patients with glucose-6-phosphate dehydrogenase deficiency).

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

Skin and subcutaneous tissue disorders: skin rashes; urticaria; erythema, bullous eruptions, eczema, erythema, exudative polymorphous erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), exfoliative dermatitis, hair loss, photosensitivity reactions, purpura, including allergic purpura, pruritus.

Psychiatric disorders: disorientation, depression, insomnia, nightmares, irritability, psychotic disorders; hallucinations.

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

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

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

Cardiac and vascular disorders: palpitations, chest pain, heart failure, myocardial infarction, arterial hypertension, arterial hypotension, vasculitis; Kounis syndrome.

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

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

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

Renal and urinary disorders: fluid retention, edema; acute kidney injury (acute renal failure), hematuria, proteinuria, interstitial nephritis, nephrotic syndrome, renal papillary necrosis.

Reproductive system and breast disorders: impotence.

General disorders: edema.

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

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

Additionally, the following adverse reactions may occur after paracetamol intake: epigastric pain, hypoglycemia up to hypoglycemic coma, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruises or bleeding, increased activity of liver enzymes, usually without development of jaundice.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

4 tablets per blister, 25 blisters per cardboard pack.

10 tablets per blister, 10 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and location of business activity.

54 Skryabina Street, Sumy, 40020, Ukraine.

INSTRUCTION

for medical use of the medicinal product

Fanigan

(Fanigan®)

Composition:

Active substances: paracetamol, sodium diclofenac;

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

Excipients: maize starch, povidone K-30, sodium croscarmellose, microcrystalline cellulose, magnesium stearate, Yellow Sunset FCF (E 110).

Pharmaceutical form. Tablets.

Main physico-chemical properties: capsule-shaped tablets, orange-colored with white specks.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents.

ATC code M01AB55.

Pharmacological properties.

Pharmacodynamics.

Fanigan is a combination drug that exerts a pronounced anti-inflammatory, analgesic, and antipyretic effect. The pharmacological activity of the drug is due to the properties of diclofenac and paracetamol, which are components of the preparation.

Sodium diclofenac produces a pronounced anti-inflammatory and analgesic effect, as well as a moderate antipyretic action. It is an inhibitor of prostaglandin synthetase (cyclooxygenase).

In vitro, diclofenac at concentrations equivalent to those achieved during patient treatment does not inhibit proteoglycan biosynthesis in cartilage tissue. Paracetamol exhibits a pronounced analgesic effect, mild antipyretic and anti-inflammatory activity. Its mechanism of action is associated with inhibition of prostaglandin synthesis in the central nervous system.

Pharmacokinetics.

Diclofenac.

Sodium diclofenac is rapidly absorbed into the bloodstream – maximum plasma concentration is reached within 1–2 hours. Plasma protein binding exceeds 99%. It penetrates well into tissues and synovial fluid, where its concentration increases slowly, reaching higher levels than in plasma after 4 hours. Food may slow the rate of absorption without affecting the extent of absorption. Bioavailability is approximately 5%.

The elimination half-life from plasma is 1–2 hours and from synovial fluid is 3–6 hours. Approximately 35% is excreted in feces as metabolites; about 65% is metabolized in the liver and excreted by the kidneys as inactive derivatives, and about 1% is excreted unchanged.

Paracetamol.

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 30–60 minutes. The elimination half-life ranges from 1 to 4 hours. It is evenly distributed throughout all body fluids. Plasma protein binding is variable. Paracetamol is metabolized in the liver and primarily excreted by the kidneys as conjugated metabolites.

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

Clinical characteristics.

Indications.

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

Contraindications.

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

Active gastric or intestinal ulcer; gastrointestinal bleeding or perforation.

History of gastrointestinal bleeding or perforation related to previous treatment with non-steroidal anti-inflammatory drugs (NSAIDs).

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

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

Hepatic failure.

Renal failure (glomerular filtration rate < 15 ml/min/1.73 m²).

Congestive heart failure (functional class II–IV according to NYHA criteria).

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

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

Blood disorders, unexplained disturbances of hematopoiesis, leukopenia, severe anemia.

Congenital hyperbilirubinemia, Gilbert’s syndrome.

Glucose-6-phosphate dehydrogenase deficiency.

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

Alcoholism.

Should not be used for treatment of postoperative pain following coronary artery bypass grafting (or when using cardiopulmonary bypass machine).

Peripheral arterial disease.

Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks.

Interaction with other medicinal products and other forms of interaction.

Diclofenac.

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

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

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g., β-blockers, angiotensin-converting enzyme [ACE] inhibitors) may reduce their antihypertensive effect by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, such combinations should be used with caution, and patients, especially elderly, should be closely monitored for blood pressure. Adequate hydration is recommended, and monitoring of renal function should be performed after initiation and on a regular basis during concomitant therapy, particularly with diuretics and ACE inhibitors, due to increased risk of nephrotoxicity.

Agents causing hyperkalemia. Concomitant use with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, more frequent monitoring of patients is recommended.

Anticoagulants and antithrombotic agents. Concomitant use may increase the risk of bleeding; therefore, precautionary measures are recommended. Although there are no convincing data on the effect of diclofenac on anticoagulant activity, evidence exists of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended to ensure no dosage adjustments of anticoagulants are needed. Like other non-steroidal anti-inflammatory drugs, high-dose diclofenac may transiently inhibit platelet aggregation.

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

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

Antidiabetic agents. Diclofenac has been shown to be used together with oral antidiabetic agents without altering their therapeutic effect. However, there are some reports of both hypoglycemia and hyperglycemia requiring dosage adjustments of antidiabetic agents during diclofenac use. Therefore, blood glucose monitoring is recommended during combination therapy.

Isolated cases of metabolic acidosis have also been reported with concomitant use of diclofenac, particularly in patients with pre-existing renal impairment.

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

Cyclosporine. The effect of diclofenac, as with other NSAIDs, on prostaglandin synthesis in the kidneys may potentiate the nephrotoxicity of cyclosporine; therefore, diclofenac should be used at lower doses in patients receiving cyclosporine.

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

Quinolone antibiotics. Seizures may occur in patients receiving quinolone derivatives and NSAIDs concomitantly. This may occur in patients both with and without a history of epilepsy or seizures. Therefore, caution should be exercised when administering quinolones to patients already receiving NSAIDs.

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

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.

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

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

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

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

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

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 increases the risk of hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics.

Do not use concomitantly with alcohol.

Special precautions for use.

General

To minimize adverse effects, treatment should be initiated with the lowest effective dose for the shortest duration necessary to control symptoms.

For diclofenac.

Concomitant use of diclofenac with systemic NSAIDs, such as selective cyclooxygenase-2 inhibitors, should be avoided due to lack of evidence for synergistic effect and potential additive adverse effects.

An increased risk of thrombotic cardiovascular and cerebrovascular complications has been observed with the use of certain selective COX-2 inhibitors. A direct correlation between this risk and the selectivity of individual NSAIDs for COX-1/COX-2 has not been established. Due to the lack of clinical data on long-term treatment with maximum doses of diclofenac, this increased risk cannot be excluded. Therefore, careful risk-benefit assessment should be performed before prescribing diclofenac to patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial disease, or significant risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). The lowest effective dose should be used for the shortest possible duration of treatment.

The effect of NSAIDs on the kidneys includes fluid retention with edema and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with impaired cardiac function and other conditions predisposing to fluid retention. Caution is also advised in patients who are concurrently taking diuretics or angiotensin-converting enzyme (ACE) inhibitors or who have an increased risk of hypovolemia.

Adverse effects are generally more serious in elderly patients. Diclofenac should be prescribed with caution in elderly individuals. Particular caution is required when administering the drug to patients over 65 years of age. The lowest effective dose is recommended for frail elderly patients and those with low body weight.

If gastrointestinal bleeding or ulcers occur in patients undergoing treatment with diclofenac, the drug should be discontinued.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur, even without prior exposure to diclofenac.

Hypersensitivity reactions may also 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.

Due to its pharmacodynamic properties, diclofenac, like other NSAIDs, may mask signs and symptoms of infection.

Gastrointestinal effects.

Cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation, which may be fatal and may occur at any time during treatment, with or without warning symptoms or prior history of serious gastrointestinal events, have been reported with all NSAIDs, whether COX-2 selective or not, including diclofenac. These events are generally more serious in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.

As with other NSAIDs, including diclofenac, medical supervision and special caution are mandatory in patients with symptoms suggesting gastrointestinal (GI) tract disorders. The risk of GI bleeding, ulceration, or perforation increases with higher NSAID doses, including diclofenac.

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

To reduce the risk of such GI toxicity, treatment should be initiated and maintained at the lowest effective doses. For these patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid (ASA/aspirin) or other drugs that may increase the risk of GI adverse effects, consideration should be given to combination therapy with protective agents (e.g., proton pump inhibitors or misoprostol). Patients with a history of gastrointestinal toxicity, especially the elderly, should report any unusual abdominal symptoms (particularly GI bleeding). Caution is also required in patients receiving concomitant medications that increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., ASA), or selective serotonin reuptake inhibitors.

NSAIDs, including diclofenac, are associated with an increased risk of gastrointestinal anastomotic dehiscence. Close medical monitoring and caution are recommended when using diclofenac after gastrointestinal surgery.

Hepatic effects.

Careful medical monitoring is required when diclofenac is prescribed to patients with impaired liver function, as their condition may worsen.

With the use of NSAIDs, including diclofenac, the levels of one or more liver enzymes may increase. Such elevations are usually reversible upon discontinuation of the drug. Elevated liver enzymes were very frequently observed during clinical trials with diclofenac (approximately in 15% of patients), but rarely associated with clinical symptoms. In most cases, the elevations did not exceed normal limits. Moderate increases (≥3 to <8 times the upper limit of normal) were frequently observed (in 2.5% of cases), while marked increases (≥8 times the upper limit of normal) occurred in approximately 1% of cases. Clinically apparent liver injury occurred in 0.5% of cases in the aforementioned clinical trials.

Regular monitoring of liver function and liver enzyme levels is recommended during long-term treatment. If liver function abnormalities persist or worsen, if clinical symptoms suggest progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), treatment with Fanigan should be discontinued.

In addition to elevated liver enzymes, rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis, hepatic necrosis, and liver failure, sometimes resulting in death, have been reported.

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

Renal effects.

NSAIDs, including diclofenac, reduce prostaglandin levels, which are important for maintaining renal blood flow.

Since fluid retention, edema, and hypertension have been frequently reported (1–10%) during treatment with NSAIDs, including diclofenac, 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 extracellular fluid volume depletion due to any cause, such as before or after major surgery. In such cases, monitoring of renal function is recommended. Discontinuation of therapy usually leads to reversal to the pre-treatment state.

Skin effects.

Serious skin reactions (some of which were fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported with the use of NSAIDs, including diclofenac. The risk of these reactions is highest at the beginning of therapy, with most cases occurring within the first month of treatment. Fanigan 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 disorders.

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

Cardiovascular and cerebrovascular effects.

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

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation and only at doses up to 100 mg daily for treatment courses exceeding 4 weeks. Since cardiovascular risks increase with higher doses and longer duration of treatment, diclofenac should be used for the shortest possible time and at the lowest effective dose. The need for continued diclofenac use for symptom relief and response to therapy should be periodically reviewed.

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

Diclofenac should be used with caution in patients who are concurrently taking diuretics or ACE inhibitors or who have an increased risk of hypovolemia.

Clinical and epidemiological data indicate that the use of diclofenac, particularly at high doses (150 mg/day) and during prolonged treatment, is associated with a slight increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

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

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

Hematological effects.

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

Diclofenac may temporarily inhibit platelet aggregation. Close monitoring is required in patients with coagulation disorders, hemorrhagic diathesis, or hematological disorders.

History of asthma.

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

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

Fertility.

The use of diclofenac, like other NSAIDs, may impair fertility in women and is therefore not recommended for women wishing to conceive. If a woman experiences difficulty conceiving or is undergoing infertility evaluation, discontinuation of Fanigan should be considered.

Based on animal studies, impairment of male reproductive function cannot be excluded. The relevance of these findings to humans has not been established.

Effects on pregnancy and/or embryonic/fetal development.

Inhibition of prostaglandin synthesis by diclofenac may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and/or congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. In animal studies, administration of prostaglandin synthesis inhibitors resulted in increased pre- and post-implantation loss and embryonic/fetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, was observed.

From the 20th week of pregnancy, the use of diclofenac may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may lead to fetal:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired renal function (see above).

In the mother and newborn at the end of pregnancy:

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

For paracetamol.

The medicinal product contains paracetamol; therefore, it should not be used together with other products containing paracetamol, such as those used for fever reduction, pain relief, flu and cold symptoms, or insomnia. Concomitant use with other paracetamol-containing products may lead to overdose. Paracetamol overdose may 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 product.

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

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

Caution is recommended when paracetamol is used concomitantly with flucloxacillin due to an increased risk of metabolic acidosis with high anion gap, especially in patients with severe renal impairment, sepsis, malnutrition, and other sources of glutathione deficiency (e.g., chronic alcoholism), as well as those taking maximum daily doses of paracetamol. Careful monitoring, including measurement of urinary 5-oxoproline, is recommended.

Patients with reduced glutathione levels are at increased risk of developing metabolic acidosis when taking paracetamol. 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. Do not exceed the recommended doses. Very prolonged use without medical supervision may be dangerous.

The medicinal product should be used only when clearly necessary.

If symptoms persist, a physician should be consulted.

Keep the product out of sight and reach of children.

The product contains the colorant sunset yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Fanigan is contraindicated during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness (vertigo), somnolence, lethargy, fatigue, or other central nervous system disturbances during treatment should refrain from driving or operating machinery.

Method of Administration and Dosage

Do not exceed the recommended dose. The lowest effective dose should be used for the shortest duration necessary to achieve the treatment goal.

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

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

The interval between doses should be at least 4 hours.

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.

The maximum duration of use without consulting a physician is 3 days.

Do not take together with other medicinal products containing paracetamol.

Elderly patients (aged 65 years and older).

Although the pharmacokinetics of diclofenac are not clinically significantly impaired in elderly patients, NSAIDs should be used with particular caution in such patients, who are generally more susceptible to adverse reactions. Specifically, for frail elderly patients or patients with low body weight, the lowest effective doses are recommended; patients should also be monitored for gastrointestinal bleeding during NSAID therapy.

Presence of cardiovascular diseases or significant risk factors.

The medicinal product may be prescribed to patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical assessment. Since cardiovascular risks increase with higher doses and longer duration of treatment, diclofenac should be used for the shortest possible period and at the lowest effective dose. The patient's need for diclofenac to relieve symptoms and response to therapy should be reviewed periodically.

Patients with impaired renal function.

The medicinal product is contraindicated in patients with renal insufficiency (glomerular filtration rate < 15 mL/min/1.73 m²; see section "Contraindications").

Specific studies in patients with impaired renal function have not been conducted; therefore, no recommendations on dose adjustment can be provided. Diclofenac should be used with caution in patients with impaired renal function (see section "Special Warnings and Precautions for Use").

Patients with impaired hepatic function.

The medicinal product is contraindicated in patients with hepatic insufficiency (see section "Contraindications").

Specific studies in patients with impaired hepatic function have not been conducted; therefore, no recommendations on dose adjustment can be provided. Diclofenac should be used with caution in patients with mild to moderate hepatic impairment (see section "Special Warnings and Precautions for Use").

Children.

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

Overdose.

Diclofenac.

Symptoms.

There is no typical clinical picture characteristic of diclofenac overdose. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, excitement, coma, somnolence, tinnitus, or convulsions. Acute renal failure and hepatic injury are possible in cases of severe intoxication.

Treatment.

Management of acute poisoning with NSAIDs, including diclofenac, consists of supportive and symptomatic therapy. This includes treatment of manifestations such as arterial hypotension, renal failure, convulsions, gastrointestinal disturbances, and respiratory depression. Specific interventions such as forced diuresis, dialysis, or hemoperfusion are unlikely to be effective in eliminating NSAIDs, including diclofenac, because the active substances are highly protein-bound and undergo extensive metabolism. After ingestion of potentially toxic doses, activated charcoal is recommended; after ingestion of potentially life-threatening doses, gastric decontamination (e.g., induction of emesis, gastric lavage) should be performed.

Paracetamol.

Paracetamol overdose may cause hepatic failure, which may necessitate liver transplantation or lead to fatal outcomes. Clinical signs of liver injury after paracetamol overdose typically appear 24–48 hours after ingestion and peak at 4–6 days.

There is an increased risk of paracetamol poisoning, particularly in elderly patients, children, patients with liver disease, chronic alcoholism, or chronic malnutrition.

Symptoms of overdose within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Overdose may also be asymptomatic. A single overdose of paracetamol in adults and children may cause reversible or irreversible necrosis of liver cells, leading to disturbances in glucose metabolism, metabolic acidosis, hepatocellular failure, encephalopathy, hemorrhage, hypoglycemia, coma, and death. At the same time, elevated levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, bilirubin, and prolonged prothrombin time may be observed 12–48 hours after ingestion. Liver injury is likely in adults who have ingested more than the recommended amount of paracetamol. It is believed that an increased amount of a paracetamol metabolite (normally neutralized by glutathione at therapeutic doses) irreversibly binds to liver tissue. Acute renal failure with acute tubular necrosis may present as severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver injury. Cardiac arrhythmias and acute pancreatitis have also been reported, usually accompanied by liver function disturbances and hepatotoxicity.

With prolonged use of the drug in high doses, the following may occur: from the hematopoietic system—aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia; from the nervous system—dizziness, psychomotor agitation, disorientation; from the urinary system—nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis); from the digestive system—hepatic necrosis.

Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage.

Risk factors for paracetamol overdose include:

• prolonged treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, and other drugs that induce liver enzyme synthesis;
• chronic alcohol abuse;
• reduced glutathione levels, e.g., due to malnutrition, fasting, cachexia, cystic fibrosis, HIV.

Treatment: urgent supportive and symptomatic therapy.

In case of overdose, immediate medical assistance is required. Treatment for overdose or even suspected overdose should be initiated immediately; the patient should be taken to hospital, even if early symptoms are absent, because liver injury may not develop immediately. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable).

If an excessive dose of paracetamol (>150 mg/kg) was ingested within the past hour, administration of activated charcoal should be considered. Treatment with N-acetylcysteine or methionine may be beneficial. Symptomatic treatment should also be provided.

Adverse Reactions

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, agranulocytosis, anemia, including aplastic and hemolytic anemia (especially in patients with glucose-6-phosphate dehydrogenase deficiency).

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

Skin and subcutaneous tissue disorders: skin rashes; urticaria; erythema, bullous eruptions, eczema, erythema, exudative polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), exfoliative dermatitis, hair loss, photosensitivity reactions, purpura, including allergic purpura, pruritus.

Psychiatric disorders: confusion, depression, insomnia, nightmares, irritability, psychiatric disorders; hallucinations.

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

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

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

Cardiac and vascular disorders: palpitations, chest pain, heart failure, myocardial infarction, arterial hypertension, arterial hypotension, vasculitis; Kounis syndrome.

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

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

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

Renal and urinary disorders: fluid retention, edema; acute kidney injury (acute renal failure), hematuria, proteinuria, interstitial nephritis, nephrotic syndrome, renal papillary necrosis.

Reproductive system and breast disorders: impotence.

General disorders: edema.

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

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

Also, the following adverse reactions may occur after paracetamol intake: epigastric pain, hypoglycemia up to hypoglycemic coma, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruising or bleeding, increased activity of liver enzymes, usually without development of jaundice.

Reporting suspected adverse reactions.

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

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

4 tablets per blister, 25 blisters per cardboard pack.

10 tablets per blister, 10 blisters per cardboard pack.

Prescription category. Prescription only.

Manufacturer.

Kusum Healthcare Pvt Ltd.

Manufacturer's address and location of business activity.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

INSTRUCTIONS

for medical use of the medicinal product

Fanigan

(Fanigan®)

Composition:

Active ingredients: paracetamol, sodium diclofenac;

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

Excipients: maize starch, povidone K-30, sodium croscarmellose, microcrystalline cellulose, magnesium stearate, sunset yellow FCF (E 110).

Pharmaceutical form. Tablets.

Main physico-chemical properties: capsule-shaped tablets, orange-colored with white specks.

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

ATC code M01AB55.

Pharmacological Properties.

Pharmacodynamics.

Fanigan is a combination drug that exerts pronounced anti-inflammatory, analgesic, and antipyretic effects. The pharmacological activity of the drug is due to the properties of diclofenac and paracetamol, which are components of the preparation.

Sodium diclofenac exerts pronounced anti-inflammatory and analgesic effects, as well as a moderate antipyretic effect. It is an inhibitor of prostaglandin synthetase (cyclooxygenase).

In vitro, diclofenac at concentrations equivalent to those achieved during treatment of patients does not inhibit proteoglycan biosynthesis in cartilage tissue. Paracetamol exhibits a pronounced analgesic effect, with slight antipyretic and anti-inflammatory activity. The mechanism of action is associated with inhibition of prostaglandin synthesis in the central nervous system.

Pharmacokinetics.

Diclofenac.

Sodium diclofenac is rapidly absorbed into the bloodstream – maximum plasma concentration is reached within 1–2 hours. Plasma protein binding exceeds 99%. It penetrates well into tissues and synovial fluid, where its concentration increases gradually, reaching higher levels than in plasma after 4 hours. Food may slow the rate of absorption without affecting the extent of absorption. Bioavailability is approximately 5%.

The elimination half-life from plasma is 1–2 hours and from synovial fluid is 3–6 hours. Approximately 35% is excreted in feces as metabolites; about 65% is metabolized in the liver and excreted by the kidneys as inactive derivatives, and about 1% is excreted unchanged.

Paracetamol.

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is achieved within 30–60 minutes. The elimination half-life ranges from 1 to 4 hours. It is uniformly distributed throughout body fluids. Plasma protein binding is variable. Paracetamol is metabolized in the liver and primarily excreted by the kidneys as conjugated metabolites.

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

Clinical characteristics.

Indications.

• Acute pain (muscular, headache, toothache, spinal pain), 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 to any other component of the drug.

Active gastric or intestinal ulcer; gastrointestinal bleeding or perforation.

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

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

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

Hepatic failure.

Renal failure (glomerular filtration rate < 15 ml/min/1.73 m²).

Congestive heart failure (functional class II–IV according to NYHA criteria).

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

Contraindicated in patients who experience attacks of bronchial asthma ("aspirin-induced asthma"), angioneurotic edema, urticaria, or acute rhinitis, nasal polyps, and other allergic symptoms in response to ibuprofen, diclofenac, paracetamol, acetylsalicylic acid, or other NSAIDs.

Blood disorders, unexplained disturbances of hematopoiesis, leukopenia, severe anemia.

Congenital hyperbilirubinemia, Gilbert's syndrome.

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 grafting (or when using cardiopulmonary bypass apparatus).

Peripheral arterial disease.

Cerebrovascular disorders in patients with history of stroke or transient ischemic attacks.

Interaction with other medicinal products and other forms of interaction.

Diclofenac.

Lithium. When used concomitantly, diclofenac may increase plasma lithium concentrations. Monitoring of serum lithium levels is recommended.

Digoxin. When used concomitantly, diclofenac may increase plasma digoxin concentrations. Monitoring of serum digoxin levels is recommended.

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g., β-blockers, angiotensin-converting enzyme [ACE] inhibitors) may reduce their antihypertensive effect by inhibiting the synthesis of vasodilatory prostaglandins. Therefore, such combinations should be used with caution, and patients, especially elderly ones, should be closely monitored for blood pressure. Adequate hydration should be ensured, and renal function should also be monitored after initiation and on a regular basis during concomitant therapy, particularly with diuretics and ACE inhibitors, due to increased risk of nephrotoxicity.

Agents causing hyperkalemia. Concomitant treatment with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, more frequent monitoring of patients is recommended.

Anticoagulants and antithrombotic agents. Concomitant use may increase the risk of bleeding; therefore, precautionary measures are recommended. Although there are no convincing data on the effect of diclofenac on anticoagulant activity, evidence exists of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously. Therefore, to ensure that no dosage adjustments of anticoagulants are needed, careful monitoring of such patients is recommended. Like other nonsteroidal anti-inflammatory drugs, high-dose diclofenac may transiently inhibit platelet aggregation.

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

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

Antidiabetic agents. It has been demonstrated that diclofenac can be used together with oral antidiabetic agents without altering their therapeutic effect. However, there are some reports of both hypoglycemia and hyperglycemia occurring in such cases, necessitating dosage adjustments of antidiabetic agents during diclofenac therapy. For this reason, blood glucose levels should be monitored during combination therapy.

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

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

Cyclosporine. The effect of diclofenac, as with other NSAIDs, on prostaglandin synthesis in the kidneys may potentiate the nephrotoxicity of cyclosporine; therefore, diclofenac should be administered at lower doses in patients receiving cyclosporine compared to those not receiving cyclosporine.

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

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

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

Cholestyramine and colestipol. These agents may delay or reduce absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least 1 hour before or 4–6 hours after administration of cholestyramine/colestipol.

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

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

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

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

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

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

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

Do not use concomitantly with alcohol.

Special precautions for use.

General

To minimize adverse effects, treatment should be initiated at the lowest effective dose for the shortest duration necessary to control symptoms.

For diclofenac.

Concomitant use of diclofenac with systemic NSAIDs, such as selective cyclooxygenase-2 inhibitors, should be avoided due to lack of evidence of synergistic effect and potential additive adverse effects.

An increased risk of thrombotic cardiovascular and cerebrovascular complications has been observed with the use of certain selective COX-2 inhibitors. A direct correlation between this risk and the COX-1/COX-2 selectivity of individual NSAIDs has not been established. Due to the lack of clinical data on long-term treatment with maximum doses of diclofenac, this increased risk cannot be excluded. Therefore, a careful benefit-risk assessment should be performed before prescribing diclofenac to patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial disease, or significant risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). The lowest effective dose should be used for the shortest possible duration of treatment.

The effect of NSAIDs on the kidneys includes fluid retention with edema and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with impaired cardiac function and other conditions predisposing to fluid retention. Caution is also advised in patients who are concurrently taking diuretics or angiotensin-converting enzyme (ACE) inhibitors or who have an increased risk of hypovolemia.

Adverse effects are generally more serious in elderly patients. Diclofenac should be prescribed with caution in elderly individuals. Particular caution is required when using in patients over 65 years of age. The lowest effective dose is recommended for frail elderly patients and those with low body weight.

If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, treatment should be discontinued.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may occur even without prior exposure to diclofenac.

Hypersensitivity reactions may also 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.

Due to its pharmacodynamic properties, diclofenac, like other NSAIDs, may mask signs and symptoms of infection.

Gastrointestinal effects.

When using all NSAIDs, whether COX-2 selective or not, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation, which may be fatal, have been reported. These events can occur at any time during treatment, with or without 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 receiving diclofenac, the drug should be discontinued.

As with other NSAIDs, including diclofenac, medical supervision and special caution are mandatory in patients with symptoms indicating gastrointestinal (GI) tract disturbances. The risk of GI bleeding, ulceration, or perforation increases with higher NSAID doses, including diclofenac.

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

To reduce the risk of such GI toxicity, treatment should be initiated and maintained at the lowest effective doses. For such patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid (ASA/aspirin) or other drugs that may increase the risk of GI adverse effects, consideration should be given to combination therapy with protective agents (e.g., proton pump inhibitors or misoprostol). Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly GI bleeding). Caution is also required in patients receiving concomitant medications that increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., ASA), or selective serotonin reuptake inhibitors.

NSAIDs, including diclofenac, are associated with an increased risk of gastrointestinal anastomosis failure. Careful medical monitoring and caution are recommended when using diclofenac after gastrointestinal surgery.

Hepatic effects.

Close medical monitoring is required when diclofenac is prescribed to patients with impaired liver function, as their condition may worsen.

When using NSAIDs, including diclofenac, the levels of one or more liver enzymes may increase. Such increases were usually reversible upon discontinuation of the drug. Elevated liver enzymes were frequently observed during clinical trials with diclofenac (in approximately 15% of patients) but were rarely associated with clinical symptoms. In most cases, the elevations did not exceed the upper limit of normal. Moderate increases (≥ 3 to < 8 times the upper limit of normal) were observed in 2.5% of cases, while marked increases (≥ 8 times the upper limit of normal) occurred in approximately 1% of cases. In the aforementioned clinical trials, elevated liver enzymes were associated with clinically evident liver injury in 0.5% of cases.

During long-term treatment, regular monitoring of liver function and liver enzyme levels is recommended. If liver function abnormalities persist or worsen, if clinical symptoms may be related to progressive liver disease, or if other manifestations occur (e.g., eosinophilia, rash), use of the medicinal product Fanigan should be discontinued.

In addition to elevated liver enzymes, rare cases of severe hepatic reactions have been reported, including jaundice, fulminant hepatitis, hepatic necrosis, and liver failure, which in some cases led to death.

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

Renal effects.

NSAIDs, including diclofenac, reduce prostaglandin levels, which are important for maintaining renal blood flow.

Since fluid retention, edema, and hypertension have been frequently reported (1–10%) during treatment with NSAIDs, including diclofenac, 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 extracellular fluid volume depletion from any cause (e.g., before or after major surgery). In such cases, monitoring of renal function is recommended. Discontinuation of therapy usually results in return to the pre-treatment state.

Skin effects.

Serious skin reactions (some of which were fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported in association with NSAIDs, including diclofenac. The highest risk of these reactions occurs early in the course of therapy, with most cases appearing within the first month of treatment. Fanigan 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 when treated with diclofenac.

Cardiovascular and cerebrovascular effects.

Treatment with diclofenac is generally not recommended in patients with diagnosed cardiovascular disease (heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled arterial hypertension.

Diclofenac may be prescribed to patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation and only at doses up to 100 mg daily for treatment courses exceeding 4 weeks. Since cardiovascular risks increase with higher doses and longer duration of treatment, diclofenac should be used for the shortest possible duration and at the lowest effective dose. The need for continued diclofenac use for symptom relief and response to therapy should be periodically reviewed.

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

Diclofenac should be used with caution in patients who are concurrently taking diuretics or ACE inhibitors or who have an increased risk of hypovolemia.

Clinical and epidemiological data indicate that the use of diclofenac, especially at high doses (150 mg/day) and during prolonged treatment, is associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

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

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

Hematological effects.

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

Diclofenac may temporarily inhibit platelet aggregation. Patients with coagulation disorders, hemorrhagic diathesis, or hematological disorders should be carefully monitored.

History of asthma.

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

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

Fertility.

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

Based on animal studies, impairment of male reproductive function cannot be excluded. The relevance of these findings to humans has not been established.

Effects on pregnancy and/or embryonic/fetal development.

Inhibition of prostaglandin synthesis by diclofenac may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and/or congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. Animal studies have shown that prostaglandin synthesis inhibitors increase pre- and post-implantation loss and embryonic/fetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, was observed.

From the 20th week of pregnancy, the use of diclofenac may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may lead to fetal:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired renal function (see above).

In the mother and newborn near the end of pregnancy:

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

For paracetamol.

The medicinal product contains paracetamol; therefore, it should not be used together with other products containing paracetamol used, for example, to reduce fever, relieve pain, treat flu and cold symptoms, or for insomnia. Concomitant use with other paracetamol-containing products may lead to overdose. Paracetamol overdose may 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 product.

It should be noted that patients with liver disease have an increased risk of hepatotoxic effects of 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, chronic alcoholism, or sepsis.

Caution is recommended when paracetamol is used concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis, particularly in patients with severe renal impairment, sepsis, malnutrition, and other sources of glutathione deficiency (e.g., chronic alcoholism), as well as those taking maximum daily doses of paracetamol. Close monitoring, including measurement of 5-oxoproline in urine, is recommended.

Patients with reduced glutathione levels are at increased risk of metabolic acidosis when taking paracetamol. 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. Do not exceed the recommended doses. Very prolonged use without medical supervision may be dangerous.

The medicinal product should be used only when clearly necessary.

If symptoms persist, a physician should be consulted.

Keep the product out of sight and reach of children.

The product contains the colorant sunset yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

The medicinal product Fanigan is contraindicated during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness (vertigo), somnolence, lethargy, fatigue, or other central nervous system disorders during treatment should refrain from driving or operating machinery.

Method of Administration and Dosage.

Do not exceed the recommended dose. The lowest effective dose should be used for the shortest duration necessary to achieve the treatment goal.

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

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

The interval between doses should be at least 4 hours.

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.

The maximum duration of use without medical consultation is 3 days.

Do not take together with other medicinal products containing paracetamol.

Elderly patients (aged 65 years and older).

Although the pharmacokinetics of diclofenac do not deteriorate to any clinically significant extent in elderly patients, NSAIDs should be used with particular caution in such patients, who are generally more susceptible to adverse reactions. In particular, for frail elderly patients or patients with low body weight, the lowest effective doses are recommended; patients should also be monitored for gastrointestinal bleeding during NSAID therapy.

Presence of cardiovascular diseases or significant risk factors.

The medicinal product may be prescribed to patients with significant cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation. Since cardiovascular risks increase with higher doses and longer duration of treatment, diclofenac should be used for the shortest possible duration and at the lowest effective dose. The patient's need for diclofenac to relieve symptoms and response to therapy should be reviewed periodically.

Patients with impaired renal function.

The medicinal product is contraindicated in patients with renal insufficiency (glomerular filtration rate < 15 mL/min/1.73 m²; see section "Contraindications").

Specific studies in patients with impaired renal function have not been conducted; therefore, no recommendations for dose adjustment can be provided. Diclofenac should be used with caution in patients with impaired renal function (see section "Special Warnings and Precautions for Use").

Patients with impaired hepatic function.

The medicinal product is contraindicated in patients with hepatic insufficiency (see section "Contraindications").

Specific studies in patients with impaired hepatic function have not been conducted; therefore, no recommendations for dose adjustment can be provided. Diclofenac should be used with caution in patients with mild to moderate hepatic impairment (see section "Special Warnings and Precautions for Use").

Children.

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

Overdose.

Diclofenac.

Symptoms.

There is no typical clinical picture characteristic of diclofenac overdose. Overdose may cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhea, dizziness, disorientation, excitement, coma, drowsiness, tinnitus, or convulsions. Acute renal failure and hepatic injury are possible in cases of severe intoxication.

Treatment.

Management of acute poisoning with NSAIDs, including diclofenac, involves supportive and symptomatic therapy. This includes treatment of manifestations such as arterial hypotension, renal failure, convulsions, gastrointestinal disturbances, and respiratory depression. Specific interventions such as forced diuresis, dialysis, or hemoperfusion are unlikely to be effective in eliminating NSAIDs, including diclofenac, because the active substances are highly protein-bound and undergo extensive metabolism. After potentially toxic doses, activated charcoal is recommended; after potentially life-threatening doses, gastric decontamination (e.g., induction of emesis, gastric lavage) should be performed.

Paracetamol.

Paracetamol overdose may cause hepatic failure, which may necessitate liver transplantation or result in death. Clinical signs of liver damage after paracetamol overdose usually appear 24–48 hours after ingestion and peak at 4–6 days.

There is an increased risk of paracetamol poisoning, particularly in elderly patients, children, patients with liver disease, chronic alcoholism, and chronic malnutrition.

Symptoms within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Overdose may also be asymptomatic. Acute overdose of paracetamol in adults and children may cause reversible or irreversible necrosis of liver cells, leading to impaired glucose metabolism, metabolic acidosis, hepatocellular failure, encephalopathy, hemorrhage, hypoglycemia, coma, and death. Elevated levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, bilirubin, and prolonged prothrombin time may occur 12–48 hours after ingestion. Liver damage is likely in adults who have ingested more than the recommended amount of paracetamol. It is believed that an increased amount of a paracetamol metabolite (normally neutralized by glutathione at therapeutic doses) irreversibly binds to liver tissue. 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 injury. Cardiac arrhythmias and acute pancreatitis, usually accompanied by liver function abnormalities and hepatotoxicity, have also been reported.

With prolonged use of the drug in high doses, blood disorders may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Neurological side effects may include dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis). Gastrointestinal effects may include hepatic necrosis.

Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage.

Risk factors for paracetamol overdose include:

• prolonged treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, and other drugs that induce liver enzyme synthesis;
• chronic alcohol abuse;
• reduced glutathione levels, for example, due to malnutrition, fasting, cachexia, cystic fibrosis, or HIV.

Treatment: urgent supportive and symptomatic therapy.

In case of overdose, immediate medical assistance is required. Treatment for overdose or even suspected overdose should be initiated immediately. The patient should be taken to hospital, even if early symptoms are absent, because liver damage may not develop immediately. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier measurements are unreliable).

If an excessive dose of paracetamol (>150 mg/kg) was ingested within the past hour, administration of activated charcoal should be considered. Treatment with N-acetylcysteine or methionine may be beneficial. Symptomatic treatment should also be provided.

Adverse Reactions

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, agranulocytosis, anemia, including aplastic and hemolytic anemia (particularly in patients with glucose-6-phosphate dehydrogenase deficiency).

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

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

Psychiatric disorders: confusion, depression, insomnia, nightmares, irritability, psychotic disorders; hallucinations.

Nervous system disorders: headache, dizziness; drowsiness, fatigue; paresthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disturbances, cerebral circulation disorders, stroke; confusion, sensory disturbances, general malaise.

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

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

Cardiac and vascular system disorders: palpitations, chest pain, heart failure, myocardial infarction, arterial hypertension, arterial hypotension, vasculitis; Kounis syndrome.

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

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

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

Renal and urinary system disorders: fluid retention, edema; acute kidney injury (acute renal failure), hematuria, proteinuria, interstitial nephritis, nephrotic syndrome, renal papillary necrosis.

Reproductive system and breast disorders: impotence.

General disorders: edema.

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

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

Additionally, the following adverse reactions may occur after paracetamol intake: epigastric pain, hypoglycemia up to hypoglycemic coma, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia, bruises or bleeding, increased liver enzyme activity, usually without development of jaundice.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows ongoing 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 of the medicinal product through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

4 tablets in a blister, 25 blisters in a cardboard pack.

10 tablets in a blister, 10 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Kusum Healthcare Pvt Ltd.

Manufacturer's address and place of business.

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.