Sigan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIGAN

Composition:

Active substances: 1 tablet contains: 100 mg of nimesulide, 20 mg of dicycloverine hydrochloride;

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

Film coating: hypromellose, talc, titanium dioxide (E 171), macrogol 6000, quinoline yellow supraline colorant (E 104).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, yellow in color, round, biconvex, smooth on both sides.

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

ATC code M01AX.

Pharmacological Properties

Pharmacodynamics

Sigan is a combination drug whose effect is determined by the action of its constituent components. Sigan has anti-inflammatory, analgesic, antipyretic, and spasmolytic properties.

Nimesulide is an active substance with anti-inflammatory, analgesic, and antipyretic effects. Nimesulide selectively inhibits cyclooxygenase-2 (COX-2) and suppresses prostaglandin synthesis at the site of inflammation.

Nimesulide inhibits the release of the enzyme myeloperoxidase and also suppresses the formation of reactive oxygen species, without affecting phagocytosis and chemotaxis processes. It reduces the production of tumor necrosis factor and other inflammatory mediators.

Dicycloverine hydrochloride reduces spasms of smooth muscles in the gastrointestinal tract. It acts as an antagonist of cholinergic (muscarinic) receptors and also exerts a direct effect on smooth muscles by antagonizing bradykinin and histamine.

Pharmacokinetics

After oral administration, nimesulide is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 2–3 hours. Plasma protein binding of nimesulide is approximately 97.5%.

The drug is metabolized in the liver, with the main metabolite being hydroxynimesulide, a pharmacologically active compound. Approximately 65% of the administered dose of nimesulide is excreted in urine, and the remaining 35% is excreted in feces.

After oral administration, dicycloverine is rapidly absorbed, with peak plasma concentration achieved within approximately 1.5 hours. The elimination half-life is 4–6 hours. Dicycloverine is excreted in urine (79.5%) and feces (8.4%).

Clinical characteristics.

Indications.

Symptomatic treatment of pain and spasm.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients of the medicinal product.

History of hypersensitivity reactions (e.g., bronchospasm, rhinitis, urticaria) associated with the use of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs).

History of hepatotoxic reactions to nimesulide.

Concomitant use of other substances with potential hepatotoxicity.

Alcoholism and drug dependence.

History of gastrointestinal bleeding or perforation related to previous use of NSAIDs.

Active peptic ulcer, or history of gastrointestinal bleeding, ulcer, or perforation; paralytic ileus; pyloric stenosis of the gastrointestinal tract with obstruction; severe ulcerative colitis or toxic megacolon; reflux esophagitis.

Cerebrovascular hemorrhage or other bleeding disorders, as well as diseases associated with bleeding tendencies.

Severe coagulation disorders.

Severe heart failure, unstable cardiovascular status in acute bleeding.

Severe renal impairment.

Hepatic dysfunction.

Obstructive gastrointestinal, biliary, or urinary tract disorders; prostatic adenoma with difficult urination; prostatic hypertrophy.

Glaucoma.

Myasthenia gravis.

Thyrotoxicosis.

Fever and/or flu-like symptoms.

Suspicion of acute surgical pathology.

Pediatric age.

Pregnancy and breastfeeding (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Nimesulide

Pharmacodynamic interactions.

Glucocorticoids. Glucocorticoids increase the risk of gastrointestinal ulceration or bleeding (see section "Special precautions for use").

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs) increase the risk of gastrointestinal ulceration or bleeding (see section "Special precautions for use").

Anticoagulants. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special precautions for use"). The combination of nimesulide with warfarin or similar anticoagulants or acetylsalicylic acid increases the risk of hemorrhagic complications and is therefore not recommended (see also section "Special precautions for use") and is contraindicated in patients with severe coagulation disorders (see also section "Contraindications"). If concomitant use cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (A-IIA). NSAIDs may reduce the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of ACE inhibitors and cyclooxygenase inhibitors may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. This potential interaction should be considered in patients receiving nimesulide-containing medicinal products together with ACE inhibitors or A-IIA. Therefore, such combination should be used with caution, especially in elderly patients. Patients should receive adequate fluid intake. Renal function should be monitored after initiation of concomitant therapy and periodically after its discontinuation.

Other nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant use of medicinal products containing nimesulide (see section "Clinical characteristics") with other NSAIDs, including acetylsalicylic acid at anti-inflammatory doses (≥ 1 g as a single dose or ≥ 3 g daily), is not recommended.

Pharmacokinetic interactions

Effect of nimesulide on the pharmacokinetics of other medicinal products.

Furosemide. In healthy volunteers, nimesulide transiently reduces sodium excretion and to a lesser extent potassium excretion, and decreases the diuretic effect. Concomitant use of nimesulide and furosemide results in a reduction (by approximately 20%) of the area under the concentration-time curve (AUC) and cumulative excretion of furosemide without changes in its renal clearance. Concomitant use of furosemide and nimesulide-containing medicinal products in patients with impaired renal or cardiac function requires caution (see section "Special precautions for use").

Lithium. There have been reports that NSAIDs reduce lithium clearance, leading to increased plasma levels and toxicity of lithium. When nimesulide is prescribed to patients receiving lithium therapy, plasma lithium levels should be closely monitored.

Effect of other medicinal products on the pharmacokinetics of nimesulide.

In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid, and valproic acid. However, despite a possible effect on its plasma concentration, such interactions are not clinically significant.

Other interactions.

Potential pharmacokinetic interactions with glyburide, theophylline, warfarin, digoxin, cimetidine, and antacid agents (specifically aluminum and magnesium hydroxide combination) have also been investigated in vivo. No clinically significant interactions were observed.

Nimesulide inhibits the activity of the CYP2C9 enzyme. Plasma concentrations of drugs that are substrates of this enzyme may increase when used concomitantly with nimesulide.

Caution is required when nimesulide is administered less than 24 hours before or less than 24 hours after methotrexate, as this may lead to increased serum levels of methotrexate and enhanced toxicity.

Due to its effect on renal prostaglandins, nimesulide may increase the nephrotoxicity of cyclosporine.

Dicycloverine.

Amantadine, class I antiarrhythmic drugs (e.g., quinidine), antihistamines, antipsychotics (e.g., phenothiazines), benzodiazepines, monoamine oxidase inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetics, tricyclic antidepressants, corticosteroids, and other agents with anticholinergic activity may potentiate the effects or adverse effects of dicycloverine.

Anticholinergic agents may counteract the effects of antiglaucoma medications; therefore, the medicinal product should be used with caution in patients with elevated intraocular pressure and when corticosteroids are used concomitantly.

Anticholinergic agents may enhance the effects of digoxin, salicylic acid, pyrazolone, codeine, caffeine, and other cholinolytic agents (e.g., atropine sulfate); therefore, their concomitant use with the medicinal product is not recommended.

Dicycloverine may counteract the effects of agents affecting gastrointestinal motility, such as metoclopramide. It potentiates the effects of spasmolytics.

Since antacid agents may reduce the absorption of anticholinergic drugs, concomitant use of the medicinal product with antacids should be avoided.

The inhibitory effect of anticholinergic agents on gastric hydrochloric acid secretion may counteract the effects of drugs used to treat achlorhydria and to study gastric secretion.

Special precautions for use.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration").

If treatment is ineffective, therapy should be discontinued.

The medicinal product should be prescribed only after careful assessment of the risk/benefit ratio. If the patient's condition does not improve, treatment must be discontinued. During prolonged use of the drug, liver function parameters should be monitored every 2 weeks.

If liver enzyme levels rise or signs of liver damage occur (e.g., anorexia, nausea, vomiting, abdominal pain, increased fatigue, dark-colored urine), the drug should be discontinued. Patients with such conditions must not be prescribed Sigan in the future.

During treatment with the drug, concomitant use of hepatotoxic agents, analgesics, other nonsteroidal anti-inflammatory drugs (NSAIDs), and alcohol consumption should be avoided.

Gastrointestinal bleeding or ulceration/perforation may develop at any time during treatment, with or without preceding symptoms, both in patients with and without a history of gastrointestinal complications. If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued.

Gastrointestinal ulcers, bleeding, or perforation may be life-threatening, especially in patients with a history of such events during treatment with any other NSAIDs (regardless of time elapsed). The risk of such events increases with higher NSAID doses in patients with a history of gastrointestinal ulcers, particularly those complicated by bleeding or perforation, and in elderly patients. In such patients, treatment should be initiated at the lowest possible effective dose. For these patients, as well as for those concurrently taking low-dose acetylsalicylic acid or other drugs increasing gastrointestinal complications risk, consideration should be given to using combination therapy with protective agents, such as misoprostol or proton pump inhibitors.

Patients with gastrointestinal toxicity, especially elderly patients, should be informed about any unusual gastrointestinal symptoms, particularly bleeding. This is especially important during the initial stages of treatment. Patients taking concomitant medications that may increase the risk of ulcers or bleeding, such as corticosteroids, anticoagulants, selective serotonin reuptake inhibitors, antiplatelet agents (acetylsalicylic acid), should be informed about the need for caution when using nimesulide.

If gastrointestinal bleeding or ulcers develop in a patient receiving nimesulide, treatment with the drug must be discontinued.

Patients with a history of arterial hypertension, as well as those with fluid retention and edema due to NSAID use, require appropriate monitoring and physician consultation.

Clinical studies and epidemiological data suggest that some NSAIDs, particularly at high doses and with long-term use, slightly increase the risk of arterial thrombotic events, such as myocardial infarction and stroke. Data on the risk of such events with nimesulide use are insufficient.

Nimesulide should be prescribed only after careful evaluation in patients with uncontrolled arterial hypertension, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Patients with cardiovascular risk factors, such as arterial hypertension, hyperlipidemia, diabetes mellitus, or smoking, should also be carefully evaluated before prescribing the drug.

The drug should be used with caution in patients with gastrointestinal disorders, including a history of ulcerative colitis or Crohn’s disease.

The drug should be used cautiously in patients with renal impairment, as its use may lead to deterioration of kidney function. If the patient's condition worsens, treatment should be discontinued.

Rare cases of severe skin reactions have been reported with NSAID use, some of which may be life-threatening, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Patients are at very high risk of such reactions if severe skin reactions occurred during previous NSAID treatment within the first month of therapy. Nimesulide should be discontinued at the first signs of skin rash, mucosal lesions, or other allergic manifestations.

Cases of fixed drug eruption have been reported during nimesulide use.

Nimesulide should not be re-administered to patients with a history of fixed drug eruption associated with nimesulide use (see section "Adverse reactions").

Nimesulide may impair female fertility and is not recommended for women planning pregnancy. Nimesulide is not recommended for women experiencing infertility or undergoing infertility evaluation.

Adverse effects are most commonly observed in elderly patients receiving the drug, including gastrointestinal bleeding, perforations, and impaired cardiac, renal, and liver function. Therefore, regular clinical monitoring of the patient is recommended.

Since nimesulide may affect platelet function in patients with hemorrhagic diathesis, it should be used with caution under constant monitoring.

The use of nonsteroidal anti-inflammatory drugs may mask fever associated with underlying bacterial infection. If fever or flu-like symptoms occur, the drug should be discontinued. During nimesulide treatment, patients should avoid using other analgesics. Concomitant use of other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

If treatment is ineffective (lack of symptom improvement), therapy with the drug should be discontinued. Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforations, which may be life-threatening.

Serious hepatic reactions, including fatal outcomes, have been reported with nimesulide use. Regarding liver damage: re-administration of nimesulide to such patients is contraindicated.

Use with caution in high ambient temperatures during treatment, as hyperthermia (elevated body temperature and heat stroke due to reduced sweating) may occur. If such symptoms appear, the drug should be discontinued and medical advice sought.

In individuals with individual hypersensitivity to anticholinergic agents, the drug may cause central nervous system effects such as confusion, disorientation, ataxia, increased fatigue, or conversely, euphoria, excitement, insomnia, and affective disturbances. These symptoms usually resolve within 12–24 hours after discontinuation of the drug.

The medicinal product should be used with caution in patients with autonomic neuropathy, liver or kidney disease, ulcerative colitis (high doses may cause paralytic ileus and development or exacerbation of serious complications such as toxic megacolon), arterial hypertension, ischemic heart disease, tachyarrhythmias, tachycardia, or hiatal hernia.

Excipients.

The medicinal product contains lactose. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

The medicinal product contains the colorant quinoline yellow (E 104), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Nimesulide may impair female fertility and is not recommended for women planning pregnancy. Like other nonsteroidal anti-inflammatory drugs that inhibit prostaglandin synthesis, nimesulide may cause premature closure of the ductus arteriosus, pulmonary hypertension, oliguria, and oligohydramnios. The risk of bleeding, uterine atony, and peripheral edema increases. Considering also the lack of data on nimesulide use in pregnant women, Sigan is contraindicated during pregnancy. Since it is unknown whether nimesulide passes into breast milk, the drug is contraindicated during breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

During treatment, caution should be exercised when driving or engaging in other potentially hazardous activities requiring high concentration and rapid psychomotor reactions.

Method of Administration and Dosage

The drug is prescribed to adults after careful assessment of the benefit/risk ratio.

It is taken orally after meals, with sufficient amount of liquid.

For adults: 1 tablet (100 mg of nimesulide) 1–2 times daily – in the morning and evening. Daily dose: 200 mg of nimesulide.

Maximum duration of treatment – 5 days.

For elderly patients, no dose adjustment is required.

Renal impairment. Considering the pharmacokinetics of the drug, dose modification is not necessary in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). The use of the drug is contraindicated in severe renal impairment (creatinine clearance less than 30 mL/min).

Hepatic impairment. The use of tablets containing 100 mg of nimesulide for the treatment of patients with hepatic insufficiency is contraindicated.

Children.

The use of the medicinal product is contraindicated in children.

Overdose.

Symptoms of acute NSAID overdose are usually limited to the following: apathy, drowsiness, nausea, vomiting, and epigastric pain. These symptoms are generally reversible with supportive therapy. Gastrointestinal bleeding may occur. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma may develop. There have been reports of anaphylactoid reactions with therapeutic doses of NSAIDs, which may also occur in overdose. In case of NSAID overdose, patients should receive symptomatic and supportive treatment. There are no specific antidotes. There is no information regarding the elimination of nimesulide by hemodialysis; however, considering its high degree of plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose.

Overdose of cyclobenzaprine is characterized by a biphasic pattern: initially, central nervous system stimulation occurs, manifested by restlessness, illusions, hallucinations, persistent mydriasis, tachycardia, and arterial hypertension. This is followed by central nervous system depression progressing to coma.

Symptoms: headache, nausea, vomiting, abdominal pain, loss of appetite, pallor, increased intraocular pressure, dizziness, blurred vision, dilated pupils, hot and dry skin, dry mouth, difficulty swallowing, central nervous system stimulation, tachycardia, and changes in respiratory rate.

Curare-like effects (neuromuscular blockade, sensation of muscle weakness, and paralysis) may also occur.

Treatment: symptomatic therapy. In the first hours after acute poisoning, gastric lavage via a tube should be performed, followed by administration of activated charcoal and/or an osmotic laxative. Renal and hepatic functions should be monitored. To control psychomotor agitation, diazepam (0.5% solution, 2 mL) may be administered.

Adverse reactions.

When using the medicinal product, the following adverse effects may occur, mainly during the first week of treatment.

Adverse effects of di cyclomine hydrochloride.

Cardiovascular system: tachycardia, palpitations, fainting, flushing sensations.

Nervous system: dizziness, headache, paresthesia, sensory disturbances, somnolence, nervousness, dyskinesia, gait instability, lethargy, insomnia, general weakness, increased fatigue, syncope (loss of consciousness), numbness of upper and lower limbs, cold extremities.

Psychiatric disorders: hallucinations, confusion and/or agitation, speech disorders, mood changes, tinnitus, psychosis, coma, disorientation, transient memory loss, hallucinations, dysarthria, ataxia, euphoria, inappropriate emotional responses (symptoms subside within 12–24 hours after dose reduction).

Skin and subcutaneous tissue: skin rashes, rarely maculopapular erythematous eruptions, urticaria, pruritus, dry skin, and other dermatological manifestations.

Gastrointestinal system: dry mouth, thirst, nausea, vomiting, constipation, meteorism (bloating), abdominal pain, taste disturbances, digestive disorders, anorexia.

Musculoskeletal and connective tissue: muscle weakness.

Renal and genital system: micturition disorders, urinary retention, difficult urination, in men – erectile dysfunction.

Eye disorders: blurred vision, darkening of vision, diplopia, mydriasis, cycloplegia (accommodation paralysis), increased intraocular pressure.

Respiratory system and thoracic organs: dyspnea, apnea, asphyxia, nasal congestion, sneezing, hyperemia of the throat.

Immune system: severe allergic reactions or drug idiosyncrasy, including anaphylaxis.

Endocrine system: suppression of lactation.

Adverse effects of nimesulide.

Skin and subcutaneous tissue: most commonly hyperemia, rashes, pruritus, increased sweating, decreased sweating, erythema, dermatitis; in isolated cases – angioneurotic edema, facial swelling, hyperemia and swelling of oral mucosa, tongue swelling, lip swelling, eyelid swelling, facial puffiness, erythema multiforme; rarely – vesicular eruptions; in isolated cases – petechial rashes, skin redness, urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis; frequency unknown – fixed drug eruption (see section "Special precautions for use").

Gastrointestinal system: nausea, heartburn, gastritis, abdominal pain, diarrhea, constipation, meteorism; in isolated cases – stomatitis, melena, peptic ulcer of the stomach or duodenum, ulcer perforation or gastrointestinal bleeding.

Hepatic effects: jaundice, cholestasis, elevated liver transaminase levels; cases of acute hepatitis, sometimes with fatal outcome, are possible.

Central nervous system: somnolence, headache, dizziness, encephalopathy (Reye's syndrome).

Psychiatric disorders: anxiety, nervousness, nightmares.

Renal effects: edema, dysuria, hematuria, urinary retention, isolated cases of oliguria, interstitial nephritis, and renal failure.

Blood and lymphatic system: anemia, eosinophilia, isolated cases of pancytopenia, purpura, and thrombocytopenia.

Immune system: hypersensitivity reactions, anaphylaxis, Quincke's edema.

Respiratory system: dyspnea; in isolated cases – asthma, bronchospasm, particularly in patients with hypersensitivity to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs).

Cardiovascular system: tachycardia, arterial hypertension, rarely bleeding, flushing, hot sensations, palpitations, blood pressure fluctuations, rarely collapse.

Other possible adverse effects during treatment include visual blurring, asthenia, hypothermia, hyperkalemia.

The most frequently observed adverse reactions are gastrointestinal. Peptic ulcers, perforation, or gastrointestinal bleeding, sometimes life-threatening, may occur, especially in elderly patients. Reports include nausea, vomiting, diarrhea, bloating, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn's disease following administration of nimesulide-containing medicinal products. Gastritis has been reported less frequently. Cases of edema, arterial hypertension, and heart failure associated with NSAID therapy have been reported. Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely. Clinical and epidemiological studies indicate that the use of certain NSAIDs, particularly at high doses and during prolonged treatment, slightly increases the risk of arterial thrombotic complications such as myocardial infarction or stroke (see section "Special precautions for use").

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions.

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

Packaging.

4 tablets per strip, 1 strip per cardboard pouch.

Prescription status.

Prescription only.

Manufacturer.

Genome Biotech Pvt. Ltd.

Manufacturer's address and location of operations.

Plot No. D-121, 122, 123, MIDC Malegaon, Tal. Sinnar, Nashik 422103, Maharashtra State, India.