Nimide

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIMID® (NIMID®)

Composition:

Active substance: nimesulide;

1 tablet contains 100 mg of nimesulide;

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

Pharmaceutical form. Tablets.

Main physico-chemical properties: round, light-yellow tablets, smooth on both sides.

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

ATC code M01AX17.

Pharmacological properties.

Pharmacodynamics.

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties, acting as an inhibitor of the cyclooxygenase enzyme responsible for prostaglandin synthesis.

Pharmacokinetics.

Absorption.

Nimesulide is well absorbed after oral administration. After a single 100 mg dose in adults, maximum plasma concentration is reached within 2–3 hours and amounts to 3–4 mg/L.

The area under the plasma concentration–time curve (AUC) ranges from 20 to 35 mg×h/L. No statistically significant differences were observed between these parameters and those after administration of 100 mg of nimesulide twice daily for 7 days. Nimesulide is bound to plasma proteins by up to 97.5%.

Biotransformation and elimination.

Nimesulide is actively metabolized in the liver via various pathways, including those involving the cytochrome P450 isoenzyme CYP2C9. Therefore, there is a risk of drug interactions when it is used concomitantly with medicinal products metabolized by CYP2C9 (see section "Interaction with other medicinal products and other forms of interaction"). The main metabolite is the para-hydroxy derivative, which is also pharmacologically active. The time to detection of this metabolite in systemic circulation is short (approximately 0.8 hours), but the rate constant of its formation is low and significantly less than the absorption coefficient of nimesulide. Hydroxynimesulide is the only metabolite detected in plasma and is almost entirely present in the bound form. The elimination half-life ranges from 3.2 to 6 hours.

Nimesulide is primarily excreted in urine (approximately 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is excreted exclusively as a glucuronide conjugate. Approximately 29% of the administered dose is excreted in feces in metabolized form.

The pharmacokinetic profile of nimesulide in elderly individuals is not altered following single or repeated administration.

In a short-term experimental study conducted in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min) and healthy volunteers, the maximum plasma concentrations of nimesulide and its main metabolite in patients were not higher than those in healthy volunteers. AUC and elimination half-life in patients with renal impairment were 50% higher but remained within the range of pharmacokinetic parameters observed in healthy volunteers receiving nimesulide. Repeated administration did not lead to accumulation.

Nimesulide is contraindicated in patients with hepatic impairment (see section "Contraindications").

Preclinical safety data.

Preclinical data obtained from standard safety pharmacology, repeated-dose toxicity, genotoxicity, and carcinogenicity studies revealed no special hazard for humans. In repeated-dose toxicity studies, nimesulide showed gastrointestinal, renal, and hepatic toxicity. In reproductive toxicity studies, embryotoxic and teratogenic effects (skeletal malformations, dilatation of brain ventricles) were observed in rabbits but not in rats when administered to females at non-toxic doses. In rats, increased postnatal mortality in offspring and adverse effects on fertility were observed.

Clinical characteristics.

Indications.

Treatment of acute pain, primary dysmenorrhea.

Nimesulide should only be used as a second-line agent.

The decision to prescribe nimesulide should be based on an assessment of all risks for the individual patient.

Contraindications.

Known hypersensitivity to nimesulide, to any other NSAID, 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 NSAIDs.

History of hepatotoxic reactions to nimesulide.

Concomitant use of other substances with potential hepatotoxicity.

Alcoholism and drug addiction.

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

Peptic ulcer in the active phase or history of gastrointestinal bleeding, ulcer, or perforation.

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

Severe coagulation disorders.

Severe heart failure.

Severe renal impairment.

Hepatic dysfunction.

Fever and/or flu-like symptoms.

Children under 12 years of age.

Third trimester of pregnancy and breastfeeding period (see sections "Use during pregnancy or breastfeeding" and "Preclinical safety data").

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Corticosteroids. Corticosteroids may 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"). In patients treated with nimesulide who are also taking warfarin or similar anticoagulants or acetylsalicylic acid, there is an increased risk of hemorrhagic complications. Therefore, such combination is not recommended (see also section "Special precautions for use") and is contraindicated in patients with severe coagulation disorders (see also section "Contraindications"). If combination therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (AII antagonists). NSAIDs may attenuate the effects of diuretics and other antihypertensive drugs. 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 development of acute renal failure, which is usually reversible. Such interactions should be considered in patients receiving nimesulide-containing medicinal products together with ACE inhibitors or AII antagonists. Therefore, this combination should be prescribed with caution, especially in elderly patients. Patients should receive adequate hydration. The need for monitoring renal function after initiation of concomitant therapy and periodically after its discontinuation should be evaluated.

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

Pharmacokinetic interactions: effect of nimesulide on the pharmacokinetics of other medicinal products.

Furosemide. In healthy volunteers, nimesulide transiently reduces furosemide-induced sodium excretion and to a lesser extent potassium excretion, and decreases the diuretic effect. Concomitant administration 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 lithium levels and lithium toxicity. When prescribing nimesulide to a patient receiving lithium therapy, plasma lithium levels should be closely monitored.

Pharmacokinetic interactions: 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.

Pharmacokinetic interactions with glipizide, theophylline, warfarin, digoxin, cimetidine, and antacid preparations (specifically aluminum and magnesium hydroxide combination) have also been studied in vivo. No clinically significant interactions were observed.

Nimesulide inhibits the activity of the CYP2C9 enzyme. Plasma concentrations of medicinal products that are substrates of this enzyme may increase when administered concomitantly with the medicinal product Nimid®. 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 methotrexate serum levels and increased toxicity.

Due to its effect on renal prostaglandins, prostaglandin synthase inhibitors such as nimesulide may increase the nephrotoxicity of cyclosporine.

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" and the risks related to the gastrointestinal tract and cardiovascular system below).

If treatment is ineffective, therapy with the drug should be discontinued.

Concomitant use of nimesulide with NSAIDs, including selective COX-2 inhibitors, should be avoided. Patients receiving Nymid® should be advised to refrain from using other analgesics.

During nimesulide treatment, concomitant use of hepatotoxic drugs should be avoided, and alcohol consumption should be refrained from.

The use of NSAIDs may mask fever associated with underlying bacterial infection.

Hepatic effects.

Serious liver-related reactions, including very rare cases with fatal outcomes, have been reported with nimesulide (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury during treatment with nimesulide, such as anorexia, nausea, vomiting, abdominal pain, fatigue, or dark urine, or who have abnormal liver function test results, should discontinue therapy. Nimesulide should not be re-administered to such patients.

Hepatic injury, mostly reversible, has been reported following short-term exposure to the drug.

Patients who develop fever and/or flu-like symptoms while taking nimesulide should discontinue treatment.

Gastrointestinal effects.

Gastrointestinal bleeding or ulceration/perforation (with or without warning symptoms or history of serious gastrointestinal events) has been reported during treatment with all NSAIDs, which may be fatal and can occur at any time during therapy. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should be initiated on the lowest possible dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other agents increasing gastrointestinal complications risk, consideration should be given to combination therapy with protective agents, such as misoprostol or proton pump inhibitors (see below and section "Interaction with other medicinal products and other forms of interaction").

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

Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, with or without preceding symptoms or history of gastrointestinal events. If gastrointestinal bleeding or ulceration occurs, nimesulide should be discontinued.

Nimesulide should be used with caution in patients with gastrointestinal disorders, including a history of peptic ulcer, gastrointestinal bleeding, ulcerative colitis, or Crohn’s disease (see section "Adverse reactions").

Patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid, should be informed of the need for caution.

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

NSAIDs should be prescribed with caution to patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as exacerbation may occur (see section "Adverse reactions"). Concomitant use of nimesulide with other medicinal products, such as oral contraceptives, anticoagulants, or antiplatelet agents, may trigger exacerbation of Crohn’s disease and other gastrointestinal disorders.

Cardiovascular and cerebrovascular effects.

Patients with a history of mild to moderate arterial hypertension and/or congestive heart failure require appropriate monitoring and physician consultation, as fluid retention and edema have been reported with NSAID therapy.

Clinical trials and epidemiological data suggest that the use of certain NSAIDs, particularly at high doses and during long-term treatment, may be associated with a small increase in the risk of arterial thrombotic events, such as myocardial infarction or stroke. There are insufficient data to exclude such risk with nimesulide use.

Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with nimesulide after careful benefit-risk assessment. A similar assessment should be performed before initiating long-term treatment in patients with cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, or smoking.

Since nimesulide may affect platelet function, it should be used with caution in patients with hemorrhagic diathesis (see also section "Contraindications"). However, the medicinal product Nymid® cannot replace acetylsalicylic acid for the prevention of cardiovascular diseases.

Renal effects.

Caution is required in patients with impaired renal function or heart failure, as nimesulide use may lead to worsening of renal function. If deterioration occurs, treatment should be discontinued (see also section "Interaction with other medicinal products and other forms of interaction").

Elderly patients.

The incidence of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation (in some cases fatal), as well as impaired renal, cardiac, and hepatic function, may be increased in elderly patients (see section "Adverse reactions"); therefore, appropriate clinical monitoring is recommended.

Skin reactions.

Very rare serious skin reactions, some of which are life-threatening, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAIDs (see section "Adverse reactions"). It appears that the highest risk of such reactions occurs early in the treatment course: most cases occur within the first month of therapy. Nimesulide should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

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

Effects on fertility.

The use of the medicinal product Nymid® may impair female fertility and is not recommended for women attempting to conceive. Women who have difficulty conceiving or undergoing infertility evaluation should consider discontinuing Nymid® (see section "Use during pregnancy or breastfeeding").

Excipients.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

The use of nimesulide is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest that the use of prostaglandin synthesis inhibitors during early pregnancy may increase the risk of miscarriage and fetal congenital heart defects and gastroschisis. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy.

In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and elevated embryonic or fetal mortality. Furthermore, increased incidence of various fetal malformations, including cardiovascular defects, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

Use of nimesulide from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal arterial duct constriction have been reported after second-trimester exposure, most of which resolved after treatment cessation. Therefore, nimesulide should not be used during the first and second trimesters unless absolutely necessary. If nimesulide is used in women attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose and shortest possible duration of treatment should be prescribed. Prenatal monitoring for oligohydramnios and fetal arterial duct constriction should be considered if nimesulide is used for several days starting from the 20th gestational week. Pregnant women should discontinue nimesulide if oligohydramnios or fetal arterial duct constriction is detected.

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

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligohydramnios (see above).

In the mother at the end of pregnancy and in the newborn, the following may occur:

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

Breastfeeding.

It is unknown whether nimesulide passes into human breast milk. Nimesulide is contraindicated during breastfeeding (see section "Contraindications" and non-clinical safety data).

Fertility.

Like other NSAIDs, medicinal products containing nimesulide are not recommended for women attempting to conceive (see section "Special precautions for use"). Women experiencing difficulty conceiving or undergoing infertility evaluation should discontinue nimesulide.

If pregnancy occurs during nimesulide treatment, the physician should be informed.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of nimesulide-containing medicinal products on the ability to drive or operate machinery have not been conducted. However, patients experiencing dizziness, vertigo, or somnolence after taking nimesulide should refrain from driving or operating machinery.

Method of Administration and Dosage

To reduce the frequency of adverse reactions, the lowest effective dose should be used for the shortest possible duration (see section "Special Warnings and Precautions for Use"). The maximum duration of treatment with nimesulide is 15 days.

Adults. 1 tablet (100 mg of nimesulide) twice daily after meals.

Elderly patients. Elderly patients do not require a reduction in daily dose (see section "Pharmacokinetics").

Children. Medicinal products containing nimesulide are contraindicated in children under 12 years of age (see also section "Contraindications"). Considering the pharmacokinetic profile in adults and the pharmacodynamic characteristics of nimesulide, dose adjustment is not required in children aged 12 to 18 years.

Renal impairment. Based on pharmacokinetics, dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). However, Nimid® is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Contraindications" and "Pharmacokinetics").

Hepatic impairment. The use of Nimid® is contraindicated in patients with hepatic impairment (see section "Pharmacokinetics"). The risk of adverse reactions can be minimized by using the medicinal product for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

Children.

Nimid® is contraindicated in children under 12 years of age.

Overdose.

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive treatment. Gastrointestinal bleeding may occur. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma may develop. Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs and may also occur in overdose. In case of NSAID overdose, symptomatic and supportive treatment should be provided. There are no specific antidotes. There is no information regarding the elimination of nimesulide by hemodialysis; however, due to its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. If symptoms occur or in cases of significant overdose, within 4 hours of drug intake, patients may be given induced emesis and/or activated charcoal (60–100 g for adults), and/or an osmotic laxative. Forced diuresis, urinary alkalinization, hemodialysis, or hemoperfusion may be ineffective due to high protein binding. Renal and hepatic function should be monitored.

Adverse reactions.

The adverse reactions listed below are based on data from controlled clinical trials* and post-marketing surveillance, classified according to the following frequency categories: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10000 – < 1/1000); very rare (< 1/10000), including rare cases, frequency unknown (cannot be estimated from available data).

The most commonly observed adverse reactions are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes life-threatening, may occur, particularly in elderly patients (see section "Special warnings and precautions for use"). After administration of medicinal products containing nimesulide, nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbation of colitis and Crohn's disease have been reported (see section "Special warnings and precautions for use"). Gastritis has been observed less frequently. There have been reports of edema, arterial hypertension, and heart failure associated with NSAID therapy. Very rarely, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Clinical and epidemiological studies suggest that the use of certain NSAIDs, especially at high doses and for prolonged treatment periods, may result in a small increased risk of arterial thrombotic events, such as myocardial infarction or stroke (see section "Special warnings and precautions for use").

Reporting suspected adverse reactions

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

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

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

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

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and place of business.

54 Skryabina Street, Sumy, Sumy Region, 40020, Ukraine.

INSTRUCTION

for medical use of the medicinal product

NIMID®

(NIMID®)

Composition:

Active substance: nimesulide;

1 tablet contains 100 mg of nimesulide;

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

Pharmaceutical form. Tablets.

Main physicochemical characteristics: round, light-yellow tablets, smooth on both sides.

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

ATC code M01AX17.

Pharmacological Properties.

Pharmacodynamics.

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties, acting as an inhibitor of the enzyme cyclooxygenase responsible for prostaglandin synthesis.

Pharmacokinetics.

Absorption.

Nimesulide is well absorbed after oral administration. Following a single 100 mg dose in adults, maximum plasma concentration is reached within 2–3 hours and amounts to 3–4 mg/L.

The area under the plasma concentration-time curve (AUC) ranges from 20 to 35 mg×h/L. No statistically significant differences were observed between these parameters and those after administration of 100 mg of nimesulide twice daily for 7 days. Approximately 97.5% of nimesulide is bound to plasma proteins.

Biotransformation and elimination

Nimesulide is actively metabolized in the liver via multiple pathways, including the cytochrome P450 isoenzyme CYP2C9. Therefore, there is a risk of drug interactions when used concomitantly with medicinal products metabolized by CYP2C9 (see section "Interaction with other medicinal products and other forms of interactions"). The main metabolite is the para-hydroxy derivative, which is also pharmacologically active. The time to appearance of this metabolite in systemic circulation is short (about 0.8 hours), but the rate constant of its formation is low and significantly less than the absorption coefficient of nimesulide. Hydroxynimesulide is the only metabolite detected in plasma and is almost entirely present in its conjugated form. The elimination half-life ranges from 3.2 to 6 hours.

Nimesulide is primarily excreted in urine (approximately 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is found exclusively as a glucuronide conjugate. About 29% of the administered dose is excreted in feces in metabolized form.

The pharmacokinetic profile of nimesulide in elderly subjects is not altered after single or repeated administration.

In a short-term clinical study conducted in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min) and healthy volunteers, the maximum plasma concentrations of nimesulide and its main metabolite in patients were not higher than those in healthy volunteers. AUC and elimination half-life in patients with renal impairment were 50% higher but remained within the range of pharmacokinetic parameters observed in healthy volunteers receiving nimesulide. Repeated administration did not result in accumulation.

Nimesulide is contraindicated in patients with hepatic function impairment (see section "Contraindications").

Preclinical safety data.

Preclinical data obtained from standard pharmacological safety, repeated-dose toxicity, genotoxicity, and carcinogenicity studies revealed no special hazard for humans. In repeated-dose toxicity studies, nimesulide showed gastrointestinal, renal, and hepatic toxicity. In reproductive toxicity studies, embryotoxic and teratogenic effects (skeletal malformations, dilatation of brain ventricles) were observed in rabbits but not in rats when administered to females at doses not producing toxic effects. In rats, increased postnatal mortality in offspring and adverse effects on fertility were observed.

Clinical characteristics.

Indications.

Treatment of acute pain, primary dysmenorrhea.

Nimesulide should only be used as a second-line agent.

The decision to prescribe nimesulide must be based on an assessment of all risks for the individual patient.

Contraindications.

Known hypersensitivity to nimesulide, to any other NSAID, 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 NSAIDs.

History of hepatotoxic reactions to nimesulide.

Concomitant use of other agents with potential hepatotoxicity.

Alcoholism and drug dependence.

History of gastrointestinal bleeding or perforation related to previous NSAID therapy.

Peptic ulcer in the active phase or history of gastrointestinal bleeding, ulcer, or perforation.

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

Severe coagulation disorders.

Severe heart failure.

Severe renal impairment.

Hepatic dysfunction.

Fever and/or flu-like symptoms.

Children under 12 years of age.

Third trimester of pregnancy and breastfeeding period (see sections "Use in pregnancy or lactation" and "Preclinical safety data").

Interaction with other medicinal products and other forms of interactions.

Pharmacodynamic interactions.

Corticosteroids. Corticosteroids may increase the risk of gastrointestinal ulceration or bleeding (see section "Special precautions").

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").

Anticoagulants. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special precautions"). When treating patients receiving warfarin or similar anticoagulants or acetylsalicylic acid with nimesulide, there is an increased risk of hemorrhagic complications. Therefore, such combination is not recommended (see also section "Special precautions") and is contraindicated in patients with severe coagulation disorders (see also section "Contraindications"). If combined therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (AIIAs). NSAIDs may attenuate the effect of diuretics and other antihypertensive drugs. 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 development of acute renal failure, which is usually reversible. Such interactions should be considered in patients receiving medicinal products containing nimesulide together with ACE inhibitors or AIIAs. Therefore, this combination should be prescribed with caution, especially in elderly patients. Patients should receive adequate hydration. The need for monitoring renal function after initiation of concomitant therapy and periodically after its discontinuation should be evaluated.

Other nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant use of medicinal products containing nimesulide (see section "Clinical characteristics") with other NSAIDs, including acetylsalicylic acid in 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 furosemide-induced sodium excretion and to a lesser extent potassium excretion, and decreases diuretic effect. Concomitant administration 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 medicinal products containing nimesulide requires caution in patients with impaired renal or cardiac function (see section "Special precautions").

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

Pharmacokinetic interactions: 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, these interactions have no clinical significance.

Other interactions.

Pharmacokinetic interactions with glipizide, theophylline, warfarin, digoxin, cimetidine, and antacid preparations (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 medicinal products that are substrates of this enzyme may increase when administered concomitantly with the medicinal product Nimid®. 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 the effect on renal prostaglandins, prostaglandin synthetase inhibitors such as nimesulide may increase the nephrotoxicity of cyclosporine.

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" and the risks related to the gastrointestinal tract and cardiovascular system below).

If treatment is ineffective, therapy with the drug should be discontinued.

Concomitant use of nimesulide with NSAIDs, including selective COX-2 inhibitors, should be avoided. Patients receiving Nimid® should be advised to refrain from using other analgesics.

During treatment with nimesulide, simultaneous use of hepatotoxic drugs should be avoided, and alcohol consumption should be avoided.

NSAIDs may mask fever associated with underlying bacterial infection.

Hepatic effects.

Serious hepatic reactions, including very rare cases with fatal outcomes, have been reported with nimesulide (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury during treatment with nimesulide, such as anorexia, nausea, vomiting, abdominal pain, fatigue, or dark urine, or those with laboratory test results indicating abnormal liver function, should discontinue therapy. Nimesulide should not be re-administered to such patients.

Hepatic injury, mostly reversible, has been reported after short-term exposure to the drug.

Patients who develop fever and/or flu-like symptoms while taking nimesulide should discontinue treatment.

Gastrointestinal effects.

Gastrointestinal bleeding or ulceration/perforation has been reported during NSAID therapy, with or without warning symptoms or prior history of serious gastrointestinal events, and may be fatal. Such events may occur at any time during treatment. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. These patients should be initiated on the lowest possible dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risk, consideration should be given to combination therapy with protective agents, such as misoprostol or proton pump inhibitors (see below and section "Interaction with other medicinal products and other forms of interaction").

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

Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, with or without preceding symptoms or history of gastrointestinal events. If gastrointestinal bleeding or ulceration occurs, nimesulide should be discontinued.

Nimesulide should be used with caution in patients with gastrointestinal disorders, including a history of peptic ulcer, gastrointestinal bleeding, ulcerative colitis, or Crohn’s disease (see section "Adverse reactions").

Patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid, should be informed of the need for caution.

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

NSAIDs should be prescribed with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease), as exacerbation is possible (see section "Adverse reactions"). Concomitant use of nimesulide with other medicinal products, such as oral contraceptives, anticoagulants, or antiplatelet agents, may trigger exacerbation of Crohn’s disease and other gastrointestinal disorders.

Cardiovascular and cerebrovascular effects.

Patients with a history of mild to moderate arterial hypertension and/or congestive heart failure require appropriate monitoring and physician consultation, as fluid retention and edema have been reported with NSAID therapy.

Clinical trials and epidemiological data suggest that the use of certain NSAIDs, particularly at high doses and during long-term treatment, may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction or stroke. There are insufficient data to exclude such risk with nimesulide.

Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with nimesulide only after careful benefit-risk assessment. A similar assessment should be performed before initiating long-term treatment in patients with cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, or smoking.

Since nimesulide may affect platelet function, it should be used with caution in patients with hemorrhagic diathesis (see also section "Contraindications"). However, the medicinal product Nimid® cannot replace acetylsalicylic acid for the prevention of cardiovascular diseases.

Renal effects.

Patients with impaired renal function or heart failure should be treated with caution, as nimesulide may lead to deterioration of renal function. If worsening occurs, treatment should be discontinued (see also section "Interaction with other medicinal products and other forms of interaction").

Elderly patients.

The elderly may have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, sometimes fatal (see section "Adverse reactions"), as well as impaired renal, cardiac, and hepatic function. Therefore, appropriate clinical monitoring is recommended.

Skin reactions.

Very rare serious skin reactions, some of which are life-threatening, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAIDs (see section "Adverse reactions"). These reactions appear to occur most frequently early in treatment, typically within the first month. Nimesulide should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

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

Effects on fertility.

Use of the medicinal product Nimid® may impair female fertility and is not recommended for women attempting to conceive. Women experiencing difficulty conceiving or undergoing fertility investigations should consider discontinuation of Nimid® (see section "Use during pregnancy or breastfeeding").

Excipients.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

Nimesulide is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest that use of prostaglandin synthesis inhibitors during early pregnancy may increase the risk of miscarriage and fetal cardiac malformations and gastroschisis. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of treatment.

In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and embryonic/fetal mortality. Furthermore, increased incidence of various fetal abnormalities, including cardiovascular defects, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

Use of nimesulide from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal arterial duct constriction have been reported after second-trimester exposure, most of which resolved after treatment cessation. Therefore, nimesulide should not be used during the first and second trimesters unless strictly necessary. If nimesulide is used in women attempting to conceive or during the first or second trimester, the lowest possible dose and shortest possible duration of treatment should be prescribed. Prenatal monitoring for oligohydramnios and fetal arterial duct constriction should be considered if nimesulide is used for several days starting from the 20th gestational week. Pregnant women should discontinue nimesulide if oligohydramnios or fetal arterial duct constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors may cause the following in the fetus:

• Cardiorenal toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• Renal dysfunction, which may progress to renal failure with oliguria (see above).

In the mother at the end of pregnancy and in the newborn, the following may occur:

• Prolonged bleeding time and antiplatelet effect, which may occur even with very low doses;
• Inhibition of uterine contractility, leading to delayed or prolonged labor.

Breastfeeding.

It is unknown whether nimesulide passes into human breast milk. Nimesulide is contraindicated during breastfeeding (see section "Contraindications" and preclinical safety data).

Fertility.

As with other NSAIDs, medicinal products containing nimesulide are not recommended for women attempting to conceive (see section "Special precautions for use"). Women experiencing difficulty conceiving or undergoing fertility investigations should discontinue nimesulide.

If pregnancy occurs during nimesulide treatment, the physician should be informed.

Ability to influence reaction speed while driving or operating machinery.

Studies on the effect of nimesulide-containing medicinal products on the ability to drive or operate machinery have not been conducted. However, patients experiencing dizziness, vertigo, or somnolence after taking nimesulide should refrain from driving or operating machinery.

Method of Administration and Dosage

To reduce the frequency of adverse reactions, the lowest effective dose should be used for the shortest duration necessary (see section "Special Warnings and Precautions for Use"). The maximum duration of treatment with nimesulide is 15 days.

Adults. 1 tablet (100 mg of nimesulide) twice daily after meals.

Elderly patients. Elderly patients do not require a reduction in daily dose (see section "Pharmacokinetics").

Children. Medicinal products containing nimesulide are contraindicated in children under 12 years of age (see also section "Contraindications"). Considering the pharmacokinetic profile in adults and the pharmacodynamic characteristics of nimesulide, dose adjustment is not required for adolescents aged 12 to 18 years.

Renal impairment. Based on pharmacokinetics, dose adjustment is not necessary in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). However, in patients with severe renal impairment (creatinine clearance < 30 mL/min), the medicinal product Nimid® is contraindicated (see sections "Contraindications" and "Pharmacokinetics").

Hepatic impairment. The use of Nimid® is contraindicated in patients with hepatic dysfunction (see section "Pharmacokinetics"). The risk of adverse reactions can be minimized by using the medicinal product for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

Children.

Nimid® is contraindicated in children under 12 years of age.

Overdose.

Symptoms of acute nonsteroidal anti-inflammatory drug (NSAID) overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive treatment. Gastrointestinal bleeding may occur. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma may develop. Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs and may also occur in cases of overdose. In the event of NSAID overdose, symptomatic and supportive treatment should be provided. There are no specific antidotes. There is no information available regarding the elimination of nimesulide by hemodialysis; however, due to its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose management. If symptoms are present or in cases of significant overdose, within 4 hours of drug ingestion, induction of emesis and/or administration of activated charcoal (60–100 g for adults), and/or an osmotic laxative may be considered. Forced diuresis, urine alkalinization, hemodialysis, or hemoperfusion may be ineffective due to the high degree of protein binding. Renal and hepatic function should be monitored.

Adverse reactions

The adverse reactions listed below are based on data from controlled clinical trials* and post-marketing surveillance, classified according to the following frequency categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000), including rare cases, and frequency not known (cannot be estimated from the available data).

The most commonly observed adverse reactions are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation or bleeding may occur, sometimes life-threatening, particularly in elderly patients (see section "Special precautions for use"). After using medicinal products containing nimesulide, nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported (see section "Special precautions for use"). Gastritis has been observed less frequently. There have been reports of edema, arterial hypertension, and heart failure associated with NSAID therapy. Very rare cases of bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. Clinical and epidemiological studies suggest that the use of certain NSAIDs, especially at high doses and for prolonged periods, may lead to a small increase in the risk of arterial thrombotic events, such as myocardial infarction or stroke (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister, 1 blister in a cardboard pack No. 10 (10×1).

10 tablets in a blister, 1 blister in a cardboard pack, 10 packs in a box No. 100 (10×1×10).

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and site of operations.

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

INSTRUCTIONS

for medical use of the medicinal product

NIMID®

(NIMID®)

Composition:

Active substance: nimesulide;

1 tablet contains nimesulide 100 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: round, light-yellow tablets, smooth on both sides.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and anti-rheumatic drugs.

ATC code M01A X17.

Pharmacological properties.

Pharmacodynamics.

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties, acting as an inhibitor of the enzyme cyclooxygenase, which is responsible for the synthesis of prostaglandins.

Pharmacokinetics.

Absorption.

Nimesulide is well absorbed after oral administration. After a single 100 mg dose in adults, maximum plasma concentration is reached within 2–3 hours and amounts to 3–4 mg/L.

The area under the concentration-time curve (AUC) ranges from 20 to 35 mg×h/L. No statistically significant differences were observed between these parameters and those after administration of 100 mg of nimesulide twice daily for 7 days. Up to 97.5% of nimesulide is bound to plasma proteins.

Biotransformation and elimination

Nimesulide is actively metabolized in the liver via multiple pathways, including through the cytochrome P450 isoenzyme CYP2C9. Therefore, there is a potential risk of drug interactions when used concomitantly with medicinal products metabolized by CYP2C9 (see section "Interaction with other medicinal products and other forms of interaction"). The main metabolite is the para-hydroxy derivative, which is also pharmacologically active. The time to appearance of this metabolite in circulating blood is short (approximately 0.8 hours), but the rate constant of its formation is low and significantly less than the absorption coefficient of nimesulide. Hydroxynimesulide is the only metabolite detected in plasma and is almost completely present in a bound form. The elimination half-life ranges from 3.2 to 6 hours.

Nimesulide is primarily excreted in urine (approximately 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is excreted exclusively as a glucuronide. Approximately 29% of the administered dose is excreted in feces in metabolized form.

The pharmacokinetic profile of nimesulide in elderly individuals is not altered after single or repeated administration.

In a short-term clinical study conducted in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min) and healthy volunteers, maximum plasma concentrations of nimesulide and its main metabolite in patients were not higher than those in healthy volunteers. AUC and elimination half-life in patients with renal impairment were 50% higher but remained within the range of pharmacokinetic parameters observed in healthy volunteers receiving nimesulide. Repeated administration did not lead to accumulation.

Nimesulide is contraindicated in patients with hepatic impairment (see section "Contraindications").

Preclinical safety data.

Preclinical data obtained from standard pharmacological safety, repeated-dose toxicity, genotoxicity, and carcinogenicity studies revealed no special hazard for humans. In repeated-dose toxicity studies, nimesulide showed gastrointestinal, renal, and hepatic toxicity. In reproductive toxicity studies, embryotoxic and teratogenic effects (skeletal malformations, brain ventricle dilation) were observed in rabbits at doses that were not maternally toxic, but not in rats. In rats, increased postnatal mortality in offspring and adverse effects on fertility were observed.

Clinical characteristics.

Indications.

Treatment of acute pain, primary dysmenorrhea.

Nimesulide should be used only as a second-line agent.

The decision to prescribe nimesulide should be based on an assessment of all risks for the individual patient.

Contraindications.

Known hypersensitivity to nimesulide, to any other NSAID, 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 NSAIDs.

History of hepatotoxic reactions to nimesulide.

Concomitant use of other substances with potential hepatotoxicity.

Alcoholism and drug addiction.

History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.

Active peptic ulcer or history of gastrointestinal bleeding, ulceration, or perforation.

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

Severe coagulation disorders.

Severe heart failure.

Severe renal impairment.

Hepatic dysfunction.

Fever and/or flu-like symptoms.

Children under 12 years of age.

Third trimester of pregnancy and breastfeeding period (see sections "Use in pregnancy or lactation" and "Preclinical safety data").

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Corticosteroids. Corticosteroids may 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"). In patients treated with nimesulide who are also taking warfarin or similar anticoagulants or acetylsalicylic acid, there is an increased risk of bleeding complications. Therefore, such combination is not recommended (see also section "Special precautions for use") and is contraindicated in patients with severe coagulation disorders (see also section "Contraindications"). If combination therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (ARBs). NSAIDs may attenuate the effects 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 development of acute renal failure, which is usually reversible. These interactions should be considered in patients receiving nimesulide-containing medicinal products together with ACE inhibitors or ARBs. Therefore, such combination should be prescribed with caution, especially in elderly patients. Patients should receive adequate hydration. 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 furosemide-induced sodium excretion and to a lesser extent potassium excretion, and decreases diuretic effect. Concomitant administration of nimesulide and furosemide results in a reduction (by approximately 20%) in 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 lithium levels and lithium toxicity. When prescribing nimesulide to a patient receiving lithium therapy, plasma lithium levels should be closely monitored.

Pharmacokinetic interactions: 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, these interactions have no clinical significance.

Other interactions.

Pharmacokinetic interactions with glipizide, theophylline, warfarin, digoxin, cimetidine, and antacid preparations (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 medicinal products that are substrates of this enzyme may increase when administered concomitantly with the medicinal product Nimesil®. 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 methotrexate serum levels and increased toxicity.

Due to its effect on renal prostaglandins, prostaglandin synthase inhibitors such as nimesulide may increase the nephrotoxicity of cyclosporine.

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" and the risks related to the gastrointestinal tract and cardiovascular system below).

If no therapeutic effect is observed, treatment with the drug should be discontinued.

Concomitant use of nimesulide with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided. Patients receiving NIMID® should be advised to refrain from using other analgesics.

During nimesulide treatment, simultaneous use of hepatotoxic drugs and consumption of alcohol should be avoided.

NSAIDs may mask fever associated with underlying bacterial infection.

Hepatic effects.

Serious hepatic reactions, including very rare cases with fatal outcomes, have been reported with nimesulide (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury during nimesulide treatment, such as anorexia, nausea, vomiting, abdominal pain, fatigue, or dark urine, or those with abnormal liver function test results, should discontinue therapy. Re-administration of nimesulide to such patients is not recommended.

Hepatic injury, mostly reversible, has been reported following short-term exposure to the drug.

Patients who develop fever and/or flu-like symptoms while taking nimesulide should discontinue treatment.

Gastrointestinal effects.

Gastrointestinal bleeding or ulceration/perforation (with or without warning symptoms or history of serious gastrointestinal events) has been reported during treatment with all NSAIDs, which could be fatal and may occur at any time during therapy. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially when complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Treatment in these patients should be initiated at the lowest possible dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risk, consideration should be given to combination therapy with protective agents such as misoprostol or proton pump inhibitors (see below and section "Interaction with other medicinal products and other forms of interaction").

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

Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, with or without preceding symptoms or history of gastrointestinal events. If gastrointestinal bleeding or ulceration occurs, nimesulide should be discontinued.

Nimesulide should be used with caution in patients with gastrointestinal disorders, including history of peptic ulcer, gastrointestinal bleeding, ulcerative colitis, or Crohn’s disease (see section "Adverse reactions").

Patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants like warfarin, selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid, should be informed of the need for caution.

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

NSAIDs should be prescribed with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as exacerbation may occur (see section "Adverse reactions"). Concomitant use of nimesulide with other medicinal products such as oral contraceptives, anticoagulants, or antiplatelet agents may trigger exacerbation of Crohn’s disease and other gastrointestinal disorders.

Cardiovascular and cerebrovascular effects.

Patients with a history of mild to moderate arterial hypertension and/or congestive heart failure require appropriate monitoring and physician consultation, as fluid retention and edema have been reported with NSAID therapy.

Clinical studies and epidemiological data suggest that use of certain NSAIDs, particularly at high doses and during long-term treatment, may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction or stroke. There are insufficient data to exclude such risk with nimesulide.

Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with nimesulide after careful assessment. A similar assessment should be performed before initiating long-term treatment in patients with cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, or smoking.

Since nimesulide may affect platelet function, it should be used with caution in patients with hemorrhagic diathesis (see also section "Contraindications"). However, the medicinal product NIMID® cannot replace acetylsalicylic acid for prevention of cardiovascular diseases.

Renal effects.

Caution is required in patients with impaired renal function or heart failure, as nimesulide use may lead to deterioration of kidney function. If worsening occurs, treatment should be discontinued (see also section "Interaction with other medicinal products and other forms of interaction").

Elderly patients.

In elderly patients, the incidence of adverse reactions to NSAIDs may be increased, particularly gastrointestinal bleeding and perforation, sometimes fatal (see section "Adverse reactions"), as well as impaired renal, cardiac, and hepatic function. Therefore, appropriate clinical monitoring is recommended.

Skin reactions.

Very rare serious skin reactions, some of which are life-threatening, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAIDs (see section "Adverse reactions"). These reactions appear to occur most frequently early in the course of therapy—most cases are reported within the first month of treatment. Nimesulide should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

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

Effects on fertility.

Use of the medicinal product NIMID® may impair female fertility and is not recommended for women attempting to conceive. NIMID® should be considered for discontinuation in women experiencing difficulty conceiving or undergoing infertility evaluation (see section "Use during pregnancy or breastfeeding").

Excipients.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

Use of nimesulide is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Inhibition of prostaglandin synthesis may have adverse effects on pregnancy and/or embryonic/fetal development. Epidemiological data suggest that use of prostaglandin synthesis inhibitors during early pregnancy may increase the risk of miscarriage and congenital heart defects and gastroschisis in the fetus. The absolute risk of cardiovascular malformation increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy.

In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and embryofetal mortality. Furthermore, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various fetal abnormalities, including cardiovascular malformations, has been reported.

Use of nimesulide from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal ductus arteriosus constriction have been reported after second-trimester exposure, most of which resolved after discontinuation of treatment. Therefore, nimesulide should not be used during the first and second trimesters unless absolutely necessary. If nimesulide is used in women attempting to conceive or during the first or second trimester of pregnancy, the lowest possible dose and shortest possible duration of treatment should be prescribed. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered if nimesulide is used for several days starting from the 20th gestational week. Pregnant women should discontinue nimesulide if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may cause fetal effects:

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oliguria (see above).

In the mother at the end of pregnancy and in the newborn, possible effects include:

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

Breastfeeding.

It is unknown whether nimesulide passes into human breast milk. Nimesulide is contraindicated during breastfeeding (see section "Contraindications" and preclinical safety data).

Fertility.

Like other NSAIDs, medicinal products containing nimesulide are not recommended for women attempting to conceive (see section "Special precautions for use"). Women experiencing difficulty conceiving or undergoing infertility evaluation should discontinue nimesulide.

If pregnancy is diagnosed during nimesulide treatment, the physician should be informed.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of nimesulide-containing medicinal products on the ability to drive or operate machinery have not been conducted. However, patients experiencing dizziness, vertigo, or somnolence after taking nimesulide should refrain from driving or operating machinery.

Dosage and Administration

To reduce the frequency of adverse reactions, the lowest effective dose should be used for the shortest duration possible (see section "Special Precautions"). The maximum duration of treatment with nimesulide is 15 days.

Adults. 1 tablet (100 mg of nimesulide) twice daily after meals.

Elderly patients. Elderly patients do not require a reduction in daily dose (see section "Pharmacokinetics").

Children. Medicinal products containing nimesulide are contraindicated in children under 12 years of age (see also section "Contraindications"). Considering the pharmacokinetic profile in adults and the pharmacodynamic characteristics of nimesulide, dose adjustment is not required for children aged 12 to 18 years.

Renal impairment. Based on pharmacokinetics, dose adjustment is not necessary in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). However, in patients with severe renal impairment (creatinine clearance < 30 mL/min), the medicinal product Nimid® is contraindicated (see sections "Contraindications" and "Pharmacokinetics").

Hepatic impairment. The use of Nimid® is contraindicated in patients with hepatic dysfunction (see section "Pharmacokinetics"). The risk of adverse reactions can be minimized by using the drug for the shortest duration necessary to control symptoms (see section "Special Precautions").

Children.

The medicinal product Nimid® is contraindicated in children under 12 years of age.

Overdose.

Symptoms of acute nonsteroidal anti-inflammatory drug (NSAID) overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive treatment. Gastrointestinal bleeding may occur. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma are possible. Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs and may also occur in cases of overdose. In the event of NSAID overdose, symptomatic and supportive treatment should be provided. There are no specific antidotes. There is no information regarding the elimination of nimesulide by hemodialysis; however, due to its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. If symptoms occur or in cases of significant overdose within 4 hours of drug ingestion, induction of emesis and/or administration of activated charcoal (60–100 g for adults) and/or an osmotic laxative may be considered. Forced diuresis, urine alkalinization, hemodialysis, or hemoperfusion may be ineffective due to high protein binding. Renal and hepatic functions should be monitored.

Side effects.

The adverse reactions listed below are based on data from controlled clinical studies* and post-marketing surveillance, classified according to the following frequency categories: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1,000 – < 1/100); rare (≥ 1/10,000 – < 1/1,000); very rare (< 1/10,000), including rare cases, and frequency not known (cannot be estimated from available data).

The most commonly observed adverse reactions are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation or bleeding, sometimes life-threatening, may occur, especially in elderly patients (see section "Special precautions"). Nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration of medicinal products containing nimesulide (see section "Special precautions"). Gastritis has been observed less frequently. Cases of edema, arterial hypertension and heart failure have been reported in connection with NSAID treatment. Very rare cases of bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Clinical and epidemiological studies suggest that the use of certain NSAIDs, particularly at high doses and over prolonged treatment periods, may lead to a small increase in the risk of arterial thrombotic events such as myocardial infarction or stroke (see section "Special precautions").

Reporting of suspected adverse reactions

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

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister, 1 blister in a cardboard pack No. 10 (10×1).

10 tablets in a blister, 1 blister in a cardboard pack, 10 packs in a box No. 100 (10×1×10).

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and place of business.

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

INSTRUCTIONS

for medical use of the medicinal product

NIMID®

(NIMID®)

Composition:

Active ingredient: nimesulide;

1 tablet contains nimesulide 100 mg;

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

Pharmaceutical form. Tablets.

Main physico-chemical properties: round, light-yellow, smooth tablets on both sides.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents.

ATC code M01AX17.

Pharmacological properties.

Pharmacodynamics.

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties, acting as an inhibitor of the cyclooxygenase enzyme responsible for prostaglandin synthesis.

Pharmacokinetics.

Absorption.

Nimesulide is well absorbed after oral administration. Following a single 100 mg dose of nimesulide in adults, peak plasma concentration is reached within 2–3 hours and amounts to 3–4 mg/L.

The area under the plasma concentration–time curve (AUC) ranges from 20 to 35 mg×h/L. No statistically significant differences were observed between these parameters and those after administration of 100 mg of nimesulide twice daily for 7 days. Approximately 97.5% of nimesulide is bound to plasma proteins.

Biotransformation and elimination

Nimesulide is actively metabolized in the liver via multiple pathways, including through the cytochrome P450 isoenzyme CYP2C9. Therefore, there is a potential for drug interactions when used concomitantly with medicinal products metabolized by CYP2C9 (see section "Interaction with other medicinal products and other forms of interaction"). The main metabolite is para-hydroxy derivative, which is also pharmacologically active. The time to detect this metabolite in systemic circulation is short (approximately 0.8 hours), but the rate constant of its formation is low and significantly lower than the absorption rate coefficient of nimesulide. Hydroxynimesulide is the only metabolite detected in plasma and is almost entirely present in conjugated form. The elimination half-life ranges from 3.2 to 6 hours.

Nimesulide is primarily excreted in urine (approximately 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is excreted exclusively as glucuronide. Approximately 29% of the administered dose is excreted in feces in metabolized form.

The pharmacokinetic profile of nimesulide in elderly individuals is not altered following single or repeated administration.

In a short-term experimental study conducted in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min) and healthy volunteers, the maximum plasma concentrations of nimesulide and its main metabolite in patients were not higher than those in healthy volunteers. AUC and elimination half-life in patients with renal impairment were approximately 50% higher but remained within the range of pharmacokinetic parameters observed in healthy volunteers receiving nimesulide. Repeated administration did not result in accumulation.

Nimesulide is contraindicated in patients with hepatic function impairment (see section "Contraindications").

Preclinical safety data.

Preclinical data obtained from standard safety pharmacology, repeat-dose toxicity, genotoxicity, and carcinogenicity studies revealed no special hazard for humans. In repeat-dose toxicity studies, nimesulide showed gastrointestinal, renal, and hepatic toxicity. In reproductive toxicity studies, embryotoxic and teratogenic effects (skeletal malformations, brain ventricle dilation) were observed in rabbits but not in rats when the drug was administered to females at non-toxic doses. In rats, increased postnatal mortality in offspring and adverse effects on fertility were observed.

Clinical characteristics.

Indications.

Treatment of acute pain, primary dysmenorrhea.

Nimesulide should only be used as a second-line agent.

The decision to prescribe nimesulide should be made based on an assessment of all risks for the individual patient.

Contraindications.

Known hypersensitivity to nimesulide, to any other NSAID, 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 NSAIDs.

History of hepatotoxic reactions to nimesulide.

Concomitant use of other substances with potential hepatotoxicity.

Alcoholism and drug addiction.

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

Peptic ulcer in the active phase or history of gastrointestinal bleeding, ulceration, or perforation.

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

Severe coagulation disorders.

Severe heart failure.

Severe renal impairment.

Hepatic dysfunction.

Liver function impairment.

Fever and/or flu-like symptoms.

Children under 12 years of age.

Third trimester of pregnancy and breastfeeding period (see sections "Use in pregnancy or lactation" and "Preclinical safety data").

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Corticosteroids. Corticosteroids may 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"). In patients treated with nimesulide who are also taking warfarin or similar anticoagulants or acetylsalicylic acid, there is an increased risk of bleeding complications. Therefore, such combination is not recommended (see also section "Special precautions for use") and is contraindicated in patients with severe coagulation disorders (see also section "Contraindications"). If combination therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (A-IIAs). NSAIDs may attenuate the effect of diuretics and other antihypertensive drugs. 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 the development of acute renal failure, which is usually reversible. This potential interaction should be considered in patients receiving medicinal products containing nimesulide together with ACE inhibitors or A-IIAs. Therefore, such combination should be prescribed 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 furosemide-induced sodium excretion and to a lesser extent potassium excretion, and decreases the diuretic effect. Concomitant administration of nimesulide and furosemide results in a reduction (by approximately 20%) in the area under the concentration-time curve (AUC) and cumulative excretion of furosemide without changes in its renal clearance. Concomitant use of furosemide and medicinal products containing nimesulide 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 lithium levels and lithium toxicity. When prescribing nimesulide to a patient receiving lithium therapy, plasma lithium levels should be closely monitored.

Pharmacokinetic interactions: 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 have no clinical significance.

Other interactions.

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

Nimesulide inhibits the activity of the CYP2C9 enzyme. Plasma concentrations of medicinal products that are substrates of this enzyme may increase when administered concomitantly with the medicinal product Nimid®. 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 methotrexate serum levels and increased toxicity.

Due to its effect on renal prostaglandins, prostaglandin synthase inhibitors such as nimesulide may increase the nephrotoxicity of cyclosporine.

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" and the risks related to the gastrointestinal and cardiovascular systems below).

If there is no therapeutic effect, treatment with the drug should be discontinued.

Concomitant use of nimesulide with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided. Patients receiving Nimid® should be advised to refrain from using other analgesics.

During treatment with nimesulide, concomitant use of hepatotoxic drugs should be avoided, and alcohol consumption should be avoided.

The use of NSAIDs may mask fever associated with underlying bacterial infection.

Hepatic effects.

Serious liver reactions, including very rare cases with fatal outcome, have been reported with nimesulide (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury during treatment with nimesulide, such as anorexia, nausea, vomiting, abdominal pain, fatigue, or dark urine, or patients with abnormal liver function test results, should discontinue therapy. Nimesulide should not be re-administered to such patients.

Liver injury, mostly reversible, has been reported following short-term exposure to the drug.

Patients who develop fever and/or flu-like symptoms while taking nimesulide should discontinue treatment.

Gastrointestinal effects.

Gastrointestinal bleeding or ulceration/perforation (with or without warning symptoms or history of serious gastrointestinal events) has been reported during treatment with all NSAIDs, which could be fatal and may occur at any time during therapy. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Treatment in these patients should be initiated at the lowest possible dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing the risk of gastrointestinal complications, consideration should be given to combination therapy with protective agents, such as misoprostol or proton pump inhibitors (see below and section "Interaction with other medicinal products and other forms of interaction").

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

Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, with or without preceding symptoms or history of gastrointestinal events. If gastrointestinal bleeding or ulceration occurs, nimesulide should be discontinued.

Nimesulide should be used with caution in patients with gastrointestinal disorders, including a history of peptic ulcer, gastrointestinal bleeding, ulcerative colitis, or Crohn’s disease (see section "Adverse reactions").

Patients taking concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants like warfarin, selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid, should be informed of the need for caution.

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

NSAIDs should be used with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease), as exacerbation is possible (see section "Adverse reactions"). Concomitant use of nimesulide with other medicinal products, such as oral contraceptives, anticoagulants, or antiplatelet agents, may cause exacerbation of Crohn’s disease and other gastrointestinal disorders.

Cardiovascular and cerebrovascular effects.

Patients with a history of hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and physician consultation, as fluid retention and edema have been reported with NSAID therapy.

Clinical trials and epidemiological data suggest that the use of some NSAIDs, particularly at high doses and during long-term treatment, may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction or stroke. There is insufficient data to exclude such risk with the use of nimesulide.

Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with nimesulide only after careful assessment. A similar assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular disease, such as hypertension, hyperlipidemia, diabetes, or smoking.

Since nimesulide may affect platelet function, it should be used with caution in patients with hemorrhagic diathesis (see also section "Contraindications"). However, the medicinal product Nimid® cannot replace acetylsalicylic acid in the prevention of cardiovascular diseases.

Renal effects.

Caution is required in patients with impaired renal function or heart failure, as the use of nimesulide may lead to worsening of renal function. If deterioration occurs, treatment should be discontinued (see also section "Interaction with other medicinal products and other forms of interaction").

Elderly patients.

Elderly patients may have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, in some cases with fatal outcome (see section "Adverse reactions"), as well as impaired renal, cardiac, and hepatic function; therefore, appropriate clinical monitoring is recommended.

Skin reactions.

Very rare serious skin reactions, some of which are life-threatening, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAIDs (see section "Adverse reactions"). It appears that patients are at greatest risk of such reactions early in treatment: most cases occur within the first month of therapy. Nimesulide should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

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

Effects on fertility.

The use of the medicinal product Nimid® may impair female fertility and is not recommended for women attempting to conceive. Women experiencing difficulty in conceiving or undergoing infertility evaluation should consider discontinuation of the medicinal product Nimid® (see section "Use during pregnancy or breastfeeding").

Excipients.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy.

The use of nimesulide is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest that the use of prostaglandin synthesis inhibitors during early pregnancy may increase the risk of miscarriage and congenital heart defects and gastroschisis. The absolute risk of cardiovascular malformation increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy.

In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation losses and embryonic or fetal mortality. In addition, increased incidence of various fetal abnormalities, including cardiovascular defects, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

The use of nimesulide from week 20 of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal ductus arteriosus constriction have been reported after second-trimester use, most of which resolved after discontinuation of treatment. Therefore, nimesulide should not be used during the first and second trimesters unless absolutely necessary. If nimesulide is used in women attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose and shortest possible duration of treatment should be prescribed. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered if nimesulide is used for several days starting from the 20th gestational week. Pregnant women should discontinue nimesulide if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors may cause the following in the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligohydramnios (see above);

In the mother at the end of pregnancy and in the newborn, the following may occur:

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

Breastfeeding.

It is unknown whether nimesulide passes into human breast milk. Nimesulide is contraindicated during breastfeeding (see section "Contraindications" and preclinical safety data).

Fertility.

As with other NSAIDs, medicinal products containing nimesulide are not recommended for women attempting to conceive (see section "Special precautions for use"). Women experiencing difficulty conceiving or undergoing infertility evaluation should discontinue nimesulide.

If pregnancy is diagnosed during nimesulide treatment, the physician should be informed.

Ability to drive and use machines.

Studies on the effects of nimesulide-containing medicinal products on the ability to drive or operate machinery have not been conducted; however, patients experiencing dizziness, vertigo, or somnolence after taking nimesulide should refrain from driving or operating machinery.

Dosage and Administration

To reduce the frequency of adverse reactions, the lowest effective dose should be used for the shortest duration necessary (see section "Special Warnings and Precautions for Use"). The maximum duration of treatment with nimesulide is 15 days.

Adults. 1 tablet (100 mg of nimesulide) twice daily after meals.

Elderly patients. Elderly patients do not require a reduction in daily dose (see section "Pharmacokinetics").

Children. Medicinal products containing nimesulide are contraindicated in children under 12 years of age (see also section "Contraindications"). Considering the pharmacokinetic profile in adults and the pharmacodynamic characteristics of nimesulide, dose adjustment is not required for children aged 12 to 18 years.

Renal impairment. Based on pharmacokinetic data, dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). However, Nimid® is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Contraindications" and "Pharmacokinetics").

Hepatic impairment. The use of Nimid® is contraindicated in patients with hepatic dysfunction (see section "Pharmacokinetics"). The risk of adverse reactions can be minimized by using the drug for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

Children.

Nimid® is contraindicated in children under 12 years of age.

Overdose.

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding may occur. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma may develop. Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs and may also occur in overdose. In case of NSAID overdose, symptomatic and supportive treatment should be provided. There are no specific antidotes. There is no information regarding the elimination of nimesulide by hemodialysis; however, due to its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. In symptomatic patients or in cases of significant overdose within 4 hours of drug ingestion, induction of emesis and/or administration of activated charcoal (60–100 g for adults), and/or an osmotic laxative may be considered. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may be ineffective due to high protein binding. Renal and hepatic function should be monitored.

Adverse reactions.

The adverse reactions listed below are based on data from controlled clinical trials* and post-marketing observations, classified according to the following frequency categories: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10000 – < 1/1000); very rare (< 1/10000), including rare cases, frequency not known (cannot be estimated based on available data).

The most commonly observed adverse reactions are those affecting the gastrointestinal tract. Peptic ulcers, gastrointestinal perforation or bleeding, which may sometimes be life-threatening, may occur, especially in elderly patients (see section "Special precautions"). Nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbation of colitis and Crohn's disease have been reported after using medicinal products containing nimesulide (see section "Special precautions"). Gastritis has been observed less frequently. There have been reports of edema, arterial hypertension, and heart failure associated with NSAID treatment. Very rare cases of bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Clinical and epidemiological studies indicate that the use of certain NSAIDs, particularly at high doses and over prolonged treatment periods, may result in a small increase in the risk of arterial thrombotic events, such as myocardial infarction or stroke (see section "Special precautions").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 1 blister per cardboard pack No. 10 (10×1).

10 tablets per blister, 10 blisters per cardboard pack No. 100 (10×10).

Prescription status.

Prescription only.

Manufacturer.

GLEDFARM LTD LLC.

Manufacturer's address and location of its business activity.

54 Davydovskoho Hryhorii Street, Sumy, Sumy region, 40020, Ukraine.