Nimide

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

Composition:

Active substance: nimesulide;

1 sachet (2 g granules) contains 100 mg of nimesulide;

Excipients: lactose monohydrate, povidone, sodium saccharin, citric acid monohydrate, orange flavoring, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Granules.

Main physico-chemical properties: light-yellow granules with an orange odor.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. ATC code M01AX17.

Pharmacological properties.

Pharmacodynamics.

Nimesulide is a non-steroidal anti-inflammatory agent 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 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 twice daily for 7 days. Up to 97.5% of nimesulide is bound to plasma proteins.

Metabolism.

Nimesulide is actively metabolized in the liver via multiple pathways, including those involving CYP2C9, a cytochrome P450 isoenzyme. Therefore, there is a potential for drug interactions when nimesulide 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 also possesses pharmacological activity. 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 rate constant of nimesulide. Hydroxynimesulide is the only metabolite detected in plasma and is almost entirely present in conjugated form.

Elimination.

The elimination half-life ranges from 3.2 to 6 hours. Approximately 50% of the administered dose is excreted in urine. Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is excreted exclusively as glucuronide conjugate. About 29% of the administered dose is excreted in feces in metabolized form.

Pharmacokinetics in special patient populations.

The pharmacokinetic profile in elderly subjects is not altered after single or repeated doses.

According to data from 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 increased by 50% 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 studies on pharmacological safety, repeated-dose toxicity, genotoxicity, and carcinogenic potential 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 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 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 substances with potential hepatotoxicity.

Alcoholism and drug dependence.

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

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

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 abnormalities.

Fever and/or flu-like symptoms.

Children under 12 years of age.

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

Interaction with other medicinal products and other forms of interactions.

Pharmacodynamic interactions.

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

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"). 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") and is contraindicated in patients with severe coagulation disorders (see also section "Contraindications"). If such 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 effect 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. This potential interaction should be considered in patients receiving nimesulide-containing medicinal products together with ACE inhibitors or AII antagonists. 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 "Special precautions") with other NSAIDs, including acetylsalicylic acid at 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%) 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").

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 potential 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 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 Nimesulide (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 its effect on renal prostaglandins, prostaglandin synthase inhibitors such as nimesulide may increase the nephrotoxicity of cyclosporine.

Special precautions for use.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control disease symptoms (see section "Dosage and administration" and the risks related to the gastrointestinal tract and cardiovascular system below).

If treatment is ineffective, therapy should be discontinued.

Concomitant use of nimesulide with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided. Patients receiving Nimide® 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 avoided. Use of NSAIDs may mask fever associated with underlying bacterial infection.

Effect on the liver.

Serious liver-related 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 nimesulide treatment, 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 after short-term exposure to the drug.

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

Effect on the gastrointestinal tract.

Gastrointestinal bleeding or ulceration/perforation (with or without warning symptoms or history of serious gastrointestinal events) have been reported with all NSAIDs, which may be fatal and 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, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Therapy in these patients should be initiated at the lowest possible effective dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal complications risk, consideration should be given to using combination therapy with protective agents such as misoprostol or proton pump inhibitors (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.

Bleeding or ulceration/perforation in the gastrointestinal tract may occur at any time during treatment, with or without warning 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 peptic ulcer, gastrointestinal bleeding, Crohn’s disease, or ulcerative colitis in history (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 about 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, antiplatelet agents, may trigger exacerbation of Crohn’s disease and other gastrointestinal disorders.

Effect on cardiovascular and cerebrovascular systems.

Patients with a history of mild or 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 use of some 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. Data to exclude such risk with nimesulide use are insufficient.

Patients with uncontrolled arterial 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 risk factors for cardiovascular disease, such as arterial hypertension, hyperlipidemia, diabetes, or smoking.

Effect on platelets.

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

Effect on kidneys.

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.

In elderly patients, the frequency of adverse reactions to NSAIDs may be increased, particularly gastrointestinal bleeding and perforation, sometimes fatal (see section "Adverse reactions"), as well as impairment of renal, cardiac, and liver 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, with most reactions occurring 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 use. Nimesulide should not be re-administered to patients with a history of nimesulide-associated FDE (see section "Adverse reactions").

Effect on fertility.

Nimesulide use may impair female fertility and is not recommended for women attempting to conceive. Women experiencing difficulty conceiving or undergoing infertility evaluation should consider discontinuation of Nimide® (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".

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

Use during pregnancy or breastfeeding.

Pregnancy.

Nimesulide use 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 defects and gastroschisis. The absolute risk of cardiovascular malformation increased 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 caused increased pre- and post-implantation loss and embryonic/fetal mortality. In addition, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, was observed.

From the 20th week of pregnancy, use of Nimide® may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after treatment initiation and is usually reversible upon discontinuation. Additionally, there have been reports of fetal arterial duct constriction after nimesulide treatment in the second trimester, most of which resolved after treatment cessation. Therefore, Nimide® should not be prescribed during the first and second trimesters of pregnancy except in cases of extreme necessity. If Nimide® is used in women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and fetal arterial duct constriction should be considered after several days of nimesulide exposure, starting from the 20th week of pregnancy. Use of Nimide® should be discontinued if oligohydramnios or fetal arterial duct constriction is detected.

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

• 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, 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 use.

If pregnancy occurs during nimesulide use, 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

Dosage.

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

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

Elderly patients. Elderly patients do not require a reduction in the 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, dosage 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 the medicinal product Nimid® is contraindicated in patients with hepatic dysfunction (see section "Pharmacokinetics"). Adverse reactions can be minimized by using the drug for the shortest duration necessary to control symptoms (see section "Special Precautions").

Method of Administration.

The contents of the sachet should be poured into a glass of warm, non-carbonated water, stirred until dissolved, and taken immediately.

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 apathy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive therapy. 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, patients should receive symptomatic and supportive treatment. There are no specific antidotes. There is no information regarding the removal of nimesulide by hemodialysis; however, considering its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. If symptoms occur or after a 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, urine alkalinization, hemodialysis, or hemoperfusion may be ineffective due to high protein binding. Renal and hepatic functions should be monitored.

Adverse Reactions

The frequency categories of adverse reactions are defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000), including isolated cases, frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:

Rare: anemia, eosinophilia.

Very rare: thrombocytopenia, pancytopenia, purpura.

Immune system disorders:

Rare: hypersensitivity.

Very rare: anaphylaxis.

Metabolic and nutritional disorders:

Rare: hyperkalemia.

Psychiatric disorders:

Rare: fear, nervousness, nightmares.

Nervous system disorders:

Uncommon: dizziness.

Very rare: headache, drowsiness, encephalopathy (Reye's syndrome).

Eye disorders:

Rare: blurred vision.

Very rare: visual disturbances.

Ear and labyrinth disorders:

Very rare: vertigo (dizziness).

Cardiac disorders:

Uncommon: arterial hypertension.

Rare: tachycardia, hemorrhage, blood pressure lability, flushing.

Respiratory, thoracic and mediastinal disorders:

Uncommon: dyspnea.

Very rare: asthma, bronchospasm.

Gastrointestinal disorders:

Common: diarrhea, nausea, vomiting.

Uncommon: constipation, flatulence, gastrointestinal bleeding, peptic ulcer and perforation of the stomach/duodenum.

Very rare: gastritis, abdominal pain, dyspepsia, stomatitis, black stools (melena).

Hepatobiliary disorders (see section "Special precautions for use"):

Common: increased liver enzymes.

Very rare: hepatitis; fulminant hepatitis (including fatal cases), jaundice, cholestasis.

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, skin rash, increased sweating.

Rare: erythema, dermatitis.

Very rare: urticaria, angioneurotic edema, facial swelling, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Frequency not known: fixed drug eruption (see section "Special precautions for use").

Renal and urinary disorders:

Rare: dysuria, hematuria.

Very rare: urinary retention, renal failure, oliguria, interstitial nephritis.

General disorders and administration site conditions:

Uncommon: edema.

Rare: malaise, asthenia.

Very rare: hypothermia.

The most frequently observed adverse reactions are gastrointestinal. Peptic ulcers, gastrointestinal perforation or bleeding, which may sometimes be life-threatening, may occur, particularly in elderly patients (see section "Special precautions for use"). Following administration of medicinal products containing nimesulide, cases of 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 precautions for use"). Gastritis has been observed less frequently. Cases of edema, arterial hypertension, and heart failure associated with NSAID therapy have been reported. 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 during prolonged treatment, may be associated with a small increase in the risk of arterial thrombotic events, such as myocardial infarction or stroke (see section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

2 g per sachet. 30 sachets in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Kusum Healthcare Pvt Ltd.

Manufacturer's address and location of business operations.

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 sachet (2 g of granules) contains 100 mg of nimesulide;

Excipients: lactose monohydrate, povidone, sodium saccharin, citric acid monohydrate, orange flavor, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Granules.

Main physicochemical properties: light yellow granules with an orange odor.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. ATC code M01AX17.

Pharmacological Properties.

Pharmacodynamics.

Nimesulide is a non-steroidal anti-inflammatory agent 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. After a single 100 mg dose of nimesulide 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 twice daily for 7 days. Up to 97.5% of nimesulide is bound to plasma proteins.

Metabolism.

Nimesulide is actively metabolized in the liver via multiple pathways, including those involving CYP2C9, an isoenzyme of cytochrome P450. Therefore, there is a potential for drug interactions when used concomitantly with medicinal products metabolized via CYP2C9 (see section "Interaction with other medicinal products and other forms of interaction"). The main metabolite is the para-hydroxy derivative, which also possesses pharmacological activity. The time to appearance of 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 coefficient of nimesulide. Hydroxynimesulide is the only metabolite detected in plasma and is almost entirely present in a bound form.

Elimination.

The elimination half-life ranges from 3.2 to 6 hours. Nimesulide is excreted from the body via 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.

Pharmacokinetics in special patient populations.

The pharmacokinetic profile in elderly subjects is not altered after single or repeated doses.

According to data from 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 lead to accumulation.

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

Preclinical safety data.

Preclinical data obtained from standard studies on pharmacological safety, repeated-dose toxicity, genotoxicity, and carcinogenic potential 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 but not in rats when the drug was administered to females at non-toxic doses. In rats, increased offspring mortality in the early postnatal period 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 dependence.

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

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

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 section "Use during pregnancy or breastfeeding" and non-clinical safety data).

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

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

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 effect 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 such 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-IIA). NSAIDs may attenuate the effect 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. Such interactions should be considered in patients who are prescribed medicinal products containing nimesulide together with ACE inhibitors or A-IIA. 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 non-steroidal anti-inflammatory drugs (NSAIDs). Concomitant use of medicinal products containing nimesulide (see section "Special precautions for use") 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%) 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 in patients with impaired renal or cardiac function requires caution (see section "Special precautions for use").

Lithium. There have been reports that NSAIDs reduce lithium clearance, leading to increased plasma levels and 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 are not clinically significant.

Other interactions.

Possible pharmacokinetic interactions with glyburide (glibenclamide), theophylline, warfarin, digoxin, cimetidine, and antacids (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 used concomitantly with Nimesulide (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 its effect on renal prostaglandins, prostaglandin synthetase inhibitors such as nimesulide may increase the nephrotoxicity of cyclosporine.

Special precautions for use.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control disease symptoms (see section "Dosage and administration" and the risks related to the gastrointestinal tract and cardiovascular system below).

If treatment is ineffective, therapy 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 therapy, 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 outcomes, have been reported in association with nimesulide use (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury during nimesulide treatment, such as anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine, or who have abnormal liver function test results, should discontinue therapy. Nimesulide should not be re-administered to such patients. Liver injury, mostly reversible, has been reported after short-term exposure to the drug.

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

Gastrointestinal effects.

Gastrointestinal bleeding or ulceration/perforation (with or without preceding symptoms or history of serious gastrointestinal events) have been reported during treatment with all NSAIDs, which may 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. In such patients, treatment should be initiated at the lowest possible effective dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal complications risk, consideration should be given to using combination therapy with protective agents, such as misoprostol or proton pump inhibitors (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 peptic ulcer, gastrointestinal bleeding, Crohn's disease, or ulcerative colitis in history (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 like acetylsalicylic acid, should be informed about 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, antiplatelet agents may lead to 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 medical consultation, as fluid retention and edema have been reported during 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 increase in the risk of arterial thrombotic events, such as myocardial infarction or stroke. Data to exclude such risk with nimesulide use are insufficient.

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.

Effects on platelets.

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

Renal effects.

Patients with impaired renal function or heart failure require caution, 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.

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

Skin reactions.

Very rarely, serious skin reactions, some of which are life-threatening, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAID use (see section "Adverse reactions"). It appears that patients are at greatest risk of such reactions early in treatment, with most reactions occurring 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 use. Nimesulide should not be re-administered to patients with a history of nimesulide-associated FDE (see section "Adverse reactions").

Effects on fertility.

Nimesulide use may impair female fertility and is not recommended for women planning pregnancy. Women experiencing difficulty conceiving or undergoing infertility evaluation 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".

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

Use during pregnancy or breastfeeding.

Pregnancy.

Nimesulide use 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 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 animals, prostaglandin synthesis inhibitors have led to increased pre- and post-implantation loss and embryonic/fetal mortality. Furthermore, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

From the 20th week of pregnancy, use of Nimid® may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation. Additionally, there have been reports of fetal arterial duct constriction after nimesulide treatment in the second trimester, most of which resolved after treatment cessation. Therefore, Nimid® should not be prescribed during the first and second trimesters of pregnancy except in cases of extreme necessity. If Nimid® is used in women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and fetal arterial duct constriction should be considered after exposure to nimesulide for several days starting from the 20th week of pregnancy. Nimid® should be discontinued if oligohydramnios or fetal arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may cause the following effects 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 use, the physician should be informed.

Ability to influence the ability to drive and use machines.

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

Method of Administration and Dosage

Dosage.

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 sachet (100 mg of nimesulide) twice daily after meals.

Elderly patients. Elderly patients do not require dose reduction (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 required in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), whereas the medicinal product 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"). Adverse reactions can be minimized by using the drug for the shortest duration necessary to control symptoms (see section "Special Precautions").

Method of Administration.

The contents of the sachet should be poured into a glass of warm, non-carbonated water, stirred until dissolved, and taken immediately.

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 therapy. 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, considering its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. If symptoms occur or after a 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, urine alkalinization, hemodialysis, or hemoperfusion may be ineffective due to high protein binding. Renal and hepatic functions should be monitored.

Adverse Reactions

The frequency category of adverse reactions is defined as follows: 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 from available data).

Blood and lymphatic system disorders:

Rare: anaemia, eosinophilia.

Very rare: thrombocytopenia, pancytopenia, purpura.

Immune system disorders:

Rare: hypersensitivity.

Very rare: anaphylaxis.

Metabolic and nutritional disorders:

Rare: hyperkalemia.

Psychiatric disorders:

Rare: fear, nervousness, nightmares.

Nervous system disorders:

Uncommon: dizziness.

Very rare: headache, somnolence, encephalopathy (Reye's syndrome).

Eye disorders:

Rare: blurred vision.

Very rare: visual disturbances.

Ear and labyrinth disorders:

Very rare: vertigo (dizziness).

Cardiac disorders:

Uncommon: arterial hypertension.

Rare: tachycardia, haemorrhage, blood pressure lability, flushing.

Respiratory, thoracic and mediastinal disorders:

Uncommon: dyspnea.

Very rare: asthma, bronchospasm.

Gastrointestinal disorders:

Common: diarrhea, nausea, vomiting.

Uncommon: constipation, flatulence, gastrointestinal bleeding, ulceration and perforation of the stomach/duodenum.

Very rare: gastritis, abdominal pain, dyspepsia, stomatitis, black stools (melena).

Hepatobiliary disorders (see section "Special precautions for use"):

Common: increased liver enzymes.

Very rare: hepatitis; fulminant hepatitis (including fatal cases), jaundice, cholestasis.

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, skin rash, increased sweating.

Rare: erythema, dermatitis.

Very rare: urticaria, angioneurotic edema, facial swelling, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Frequency not known: fixed drug eruption (see section "Special precautions for use").

Renal and urinary disorders:

Rare: dysuria, hematuria.

Very rare: urinary retention, renal failure, oliguria, interstitial nephritis.

General disorders and administration site conditions:

Uncommon: edema.

Rare: malaise, asthenia.

Very rare: hypothermia.

The most commonly observed adverse reactions are gastrointestinal. Peptic ulcers, gastrointestinal perforation or bleeding, sometimes life-threatening, may occur, especially in elderly patients (see section "Special precautions for use"). Following 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 precautions for use"). Gastritis has been observed less frequently. Cases of edema, arterial hypertension, and heart failure associated with NSAID therapy have been reported. Very rare cases of bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. Clinical and epidemiological studies suggest that 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 for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any 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 temperatures not exceeding 25 °C.

Keep out of reach of children.

Packaging.

2 g per sachet. 30 sachets in a cardboard package.

Prescription status.

Prescription only.

Manufacturer.

Kusum HealthCare Pvt Ltd.

Manufacturer's address and place of business.

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

INSTRUCTIONS

for medical use of the medicinal product

NIMID®

(NIMID®)

Composition:

Active ingredient: nimesulide;

1 sachet (2 g of granules) contains 100 mg of nimesulide;

Excipients: lactose monohydrate, povidone, sodium saccharin, citric acid monohydrate, orange flavor, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Granules.

Main physicochemical properties: light yellow granules with an orange odor.

Pharmacotherapeutic group.
Non-steroidal anti-inflammatory and antirheumatic agents. ATC code M01AX17.

Pharmacological properties.

Pharmacodynamics.

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

Pharmacokinetics.

Absorption.

Nimesulide is well absorbed after oral administration. Following a single 100 mg dose of nimesulide 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) is 20–35 mg×h/L. There was no statistically significant difference between these parameters and those observed after administration of 100 mg twice daily for 7 days. Up to 97.5% of nimesulide is bound to plasma proteins.

Metabolism.

Nimesulide is actively metabolized in the liver via various pathways, including those involving CYP2C9, a cytochrome P450 isoenzyme. Therefore, there is a risk of drug interactions when it is used concomitantly with medicinal products metabolized via CYP2C9 (see section "Interaction with other medicinal products and other forms of interaction"). The main metabolite is the para-hydroxy derivative, which also possesses pharmacological activity. 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 entirely present in the bound form.

Elimination.

The elimination half-life ranges from 3.2 to 6 hours. Nimesulide is 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.

Pharmacokinetics in special patient groups.

The pharmacokinetic profile in elderly individuals is not altered following single or repeated doses.

According to data from 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 always 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, when administered to females at non-toxic doses, embryotoxic and teratogenic effects (skeletal developmental defects, brain ventricle dilation) were observed in rabbits 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 dependence.

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

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

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 section "Use during pregnancy or lactation" and non-clinical safety data).

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

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

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 potentiate the effect 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 such combination therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (AIIA). 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. Such interactions should be considered in patients receiving nimesulide-containing medicinal products together with ACE inhibitors or AIIA. Therefore, this 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 "Special precautions for use") 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 the natriuretic effect of furosemide and to a lesser extent its kaliuretic effect, and also reduces 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 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 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 potential effect on its plasma concentration, such interactions are not clinically significant.

Other interactions.

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

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

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

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

Special precautions for use.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control disease symptoms (see section "Dosage and administration" and the risks related to gastrointestinal and cardiovascular systems below).

If treatment is ineffective, therapy should be discontinued.

Concomitant use of nimesulide with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided. During treatment with the medicinal product Nimid®, patients should be advised to refrain from using other analgesics.

During nimesulide therapy, concomitant use of hepatotoxic drugs should be avoided, and alcohol consumption should be avoided. Use of NSAIDs may mask fever associated with underlying bacterial infection.

Hepatic effects.

Serious liver reactions, very rarely including fatal cases, have been reported with nimesulide use (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury during nimesulide treatment, such as anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine, or who show 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 receiving nimesulide who develop fever and/or flu-like symptoms should discontinue treatment.

Gastrointestinal effects.

Gastrointestinal bleeding or ulceration/perforation (with or without warning symptoms or history of serious gastrointestinal events) have been reported with all NSAIDs, which could be fatal and 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, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Therapy in such patients should be initiated at the lowest possible effective dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal complications risk, consideration should be given to using combination therapy with protective agents such as misoprostol or proton pump inhibitors (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 peptic ulcer, gastrointestinal bleeding, Crohn’s disease, or ulcerative colitis in history (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 about 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 they may exacerbate the condition (see section "Ad游戏副本 reactions").

Concomitant use of nimesulide with other medicinal products such as oral contraceptives, anticoagulants, antiplatelets 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 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 use.

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.

Effect on platelets.

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

Renal effects.

Patients with impaired renal function or heart failure require caution, 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.

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

Skin reactions.

Very rarely, serious skin reactions, some of which are life-threatening, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAID use (see section "Adverse reactions"). It appears that patients are at highest risk of such reactions during the initial stages of treatment, with most reactions occurring 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 use. Nimesulide should not be re-administered to patients with a history of nimesulide-associated FDE (see section "Adverse reactions").

Effect on fertility.

Nimesulide use may impair female fertility and is not recommended for women attempting to conceive. Women experiencing difficulty 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.

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

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 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 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 animals, prostaglandin synthesis inhibitors have been shown to increase pre- and post-implantation loss and embryonic/fetal mortality. Furthermore, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

From the 20th week of pregnancy, use of the medicinal product Nimid® may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation. Additionally, there have been reports of fetal arterial duct constriction following nimesulide treatment in the second trimester, most of which resolved after treatment cessation. Therefore, Nimid® should not be prescribed during the first and second trimesters of pregnancy except in cases of extreme necessity. If Nimid® is used in women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and fetal arterial duct constriction should be considered after nimesulide exposure of several days, starting from the 20th week of pregnancy. Use of Nimid® should be discontinued if oligohydramnios or fetal arterial duct constriction is detected.

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

• 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, 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 occurs during nimesulide treatment, the physician should be informed.

Ability to affect driving and use of machines.

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.

Dosage.

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

Adults. 1 sachet (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"). Based on the pharmacokinetic profile in adults and the pharmacodynamic characteristics of nimesulide, dose adjustment is not required in children and adolescents aged 12 to 18 years.

Renal impairment. Considering the pharmacokinetics, dose adjustment is not required 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 impairment (see section "Pharmacokinetics"). 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").

Method of Administration.

The contents of the sachet should be poured into a glass of warm, non-carbonated water, stirred until dissolved, and taken immediately.

Children.

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

Overdose.

Symptoms of acute NSAID overdose are usually limited to: apathy, 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 after 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, alkalinization of urine, hemodialysis, or hemoperfusion may be ineffective due to high protein binding. Renal and hepatic functions should be monitored.

Adverse reactions.

The frequency category of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000), including isolated cases, frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:

Rare: anaemia, eosinophilia.

Very rare: thrombocytopenia, pancytopenia, purpura.

Immune system disorders:

Rare: hypersensitivity.

Very rare: anaphylaxis.

Metabolism and nutrition disorders:

Rare: hyperkalemia.

Psychiatric disorders:

Rare: fear, nervousness, night terrors.

Nervous system disorders:

Uncommon: dizziness.

Very rare: headache, somnolence, encephalopathy (Reye's syndrome).

Eye disorders:

Rare: blurred vision.

Very rare: visual disturbances.

Ear and labyrinth disorders:

Very rare: vertigo (dizziness).

Cardiac disorders:

Uncommon: arterial hypertension.

Rare: tachycardia, haemorrhage, blood pressure lability, flushing.

Respiratory, thoracic and mediastinal disorders:

Uncommon: dyspnoea.

Very rare: asthma, bronchospasm.

Gastrointestinal disorders:

Common: diarrhoea, nausea, vomiting.

Uncommon: constipation, flatulence, gastrointestinal haemorrhage, ulcer and perforation of duodenum/stomach.

Very rare: gastritis, abdominal pain, dyspepsia, stomatitis, black stools (melena).

Hepatobiliary disorders (see section "Special precautions"):

Common: increased liver enzymes.

Very rare: hepatitis; fulminant hepatitis (including fatal cases), jaundice, cholestasis.

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, skin rash, increased sweating.

Rare: erythema, dermatitis.

Very rare: urticaria, angioneurotic oedema, facial swelling, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Frequency not known: fixed drug eruption (see section "Special precautions").

Renal and urinary disorders:

Rare: dysuria, haematuria.

Very rare: urinary retention, renal failure, oliguria, interstitial nephritis.

General disorders:

Uncommon: oedema.

Rare: malaise, asthenia.

Very rare: hypothermia.

The most frequently observed adverse reactions are gastrointestinal. Peptic ulcers, gastrointestinal perforation or gastrointestinal bleeding, sometimes life-threatening, may occur, particularly in elderly patients (see section "Special precautions"). After administration of medicinal products containing nimesulide, nausea, vomiting, diarrhoea, bloating, constipation, dyspepsia, abdominal pain, melena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported (see section "Special precautions"). Gastritis has been observed less frequently. Cases of oedema, arterial hypertension and heart failure associated with NSAID therapy have been reported. 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 during prolonged treatment, may be associated with a small increased 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 medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicine via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

2 g per sachet. 30 sachets in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and location of business activity.

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

INSTRUCTION

for medical use of the medicinal product

NIMID®

(NIMID®)

Composition:

Active ingredient: nimesulide;

1 sachet (2 g of granules) contains 100 mg of nimesulide;

Excipients: lactose monohydrate, povidone, sodium saccharin, citric acid monohydrate, orange flavor, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Granules.

Main physicochemical characteristics: light yellow granules with an orange odor.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. ATC code M01AX17.

Pharmacological Properties

Pharmacodynamics

Nimesulide is a non-steroidal anti-inflammatory agent 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 concentration-time curve (AUC) is 20–35 mg×h/L. There was no statistically significant difference between these parameters and those observed after administration of 100 mg twice daily for 7 days. Up to 97.5% of nimesulide is bound to plasma proteins.

Metabolism.

Nimesulide is actively metabolized in the liver via various pathways, including those involving CYP2C9, an isoenzyme of cytochrome P450. Therefore, there is a risk of drug interactions when nimesulide is used concomitantly with medicinal products metabolized by CYP2C9 (see section "Interaction with other medicinal products and other forms of interactions"). The main metabolite is para-hydroxy derivative, which also possesses pharmacological activity. The time to detection 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 entirely present in a bound form.

Elimination.

The elimination half-life ranges from 3.2 to 6 hours. Nimesulide is excreted from the body via urine—approximately 50% of the administered dose. Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is found exclusively as a glucuronide. Approximately 29% of the administered dose is excreted in feces in metabolized form.

Pharmacokinetics in special patient populations.

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

According to data from 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 up to 50% higher but always 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 studies on pharmacological safety, repeated-dose toxicity, genotoxicity, and carcinogenic potential 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 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 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 dependence.

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

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

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 section "Use in pregnancy or lactation" and non-clinical safety data).

Interaction with other medicinal products and other forms of interactions.

Pharmacodynamic interactions.

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

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 effect of anticoagulants such as warfarin (see section "Special precautions for use"). In patients receiving warfarin or similar anticoagulants or acetylsalicylic acid, treatment with nimesulide is associated with 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 such combination therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (AIIA). NSAIDs may attenuate the effect 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. Such interactions should be considered in patients receiving nimesulide-containing medicinal products together with ACE inhibitors or AIIA. Therefore, this 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 nimesulide-containing medicinal products (see section "Special precautions for use") 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 nimesulide-containing medicinal products in patients with impaired renal or cardiac function requires caution (see section "Special precautions for use").

Lithium. There have been reports that NSAIDs reduce lithium clearance, leading to increased plasma levels and 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 are not clinically significant.

Other interactions.

Pharmacokinetic interactions with glyburide (glibenclamide), theophylline, warfarin, digoxin, cimetidine, and antacid agents (specifically, a combination of aluminum and magnesium hydroxide) 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 used concomitantly with 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 its effect on renal prostaglandins, prostaglandin synthase inhibitors such as nimesulide may increase the nephrotoxicity of cyclosporine.

Special precautions for use.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control disease symptoms (see section "Dosage and administration" and the risks related to the gastrointestinal tract and cardiovascular system below).

If treatment is ineffective, therapy 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.

Effect on the liver.

Serious hepatic reactions associated with nimesulide use, very rarely including fatal cases, have been reported (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, dark urine, or who have abnormal liver function test results, should discontinue therapy. Nimesulide should not be re-administered to such patients. Liver injury, mostly reversible, has been reported after short-term exposure to the drug.

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

Effect on the gastrointestinal tract.

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. Therapy in such patients should be initiated at the lowest possible effective dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal complications risk, consideration should be given to using combination therapy with protective agents such as misoprostol or proton pump inhibitors (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 peptic ulcer, gastrointestinal bleeding, Crohn's disease, or ulcerative colitis in history (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 about 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, antiplatelet agents may cause exacerbation of Crohn's disease and other gastrointestinal disorders.

Effect on the cardiovascular and cerebrovascular systems.

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

Clinical studies 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 increase in the risk of arterial thrombotic events, such as myocardial infarction or stroke. There are insufficient data to exclude such a risk with nimesulide.

Patients with uncontrolled arterial 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 arterial hypertension, hyperlipidemia, diabetes, or smoking.

Effect on platelets.

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

Effect on the kidneys.

Patients with impaired renal function or heart failure should be treated with caution, 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.

In elderly patients, the frequency of adverse reactions to NSAIDs may be increased, particularly gastrointestinal bleeding and perforation, sometimes fatal (see section "Adverse reactions"), as well as impairment of 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 NSAID use (see section "Adverse reactions"). It appears that patients are at greatest risk of such reactions during the initial course of treatment, with most reactions occurring 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 use. Nimesulide should not be re-administered to patients with a history of nimesulide-associated FDE (see section "Adverse reactions").

Effect on fertility.

Nimesulide use 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 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.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Nimesulide use 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 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 animals, prostaglandin synthesis inhibitors have led to increased pre- and post-implantation loss and embryonic/fetal mortality. In addition, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

From the 20th week of pregnancy, use of Nimid® may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of fetal arterial duct constriction after nimesulide treatment in the second trimester, most of which resolved after treatment cessation. Therefore, Nimid® should not be prescribed during the first and second trimesters of pregnancy, except in cases of extreme necessity. If Nimid® is used in women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and fetal arterial duct constriction should be considered after exposure to nimesulide for several days starting from the 20th week of pregnancy. Nimid® should be discontinued if oligohydramnios or fetal arterial duct constriction is detected.

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

• 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, 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 non-clinical 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 occurs during nimesulide use, 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.

Method of Administration and Dosage

Dosage.

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

Adults. 1 sachet (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, dosage 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"). 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").

Method of Administration.

The contents of the sachet should be poured into a glass of warm, non-carbonated water, stirred until dissolved, and taken immediately.

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, considering its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. If symptoms occur or after 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, urine alkalinization, hemodialysis, or hemoperfusion may be ineffective due to high protein binding. Renal and hepatic functions should be monitored.

Adverse Reactions

The frequency categories of adverse reactions are defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000), including rare cases, frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:

Rare: anaemia, eosinophilia.
Very rare: thrombocytopenia, pancytopenia, purpura.

Immune system disorders:

Rare: hypersensitivity.
Very rare: anaphylaxis.

Metabolic and nutritional disorders:

Rare: hyperkalaemia.

Psychiatric disorders:

Rare: fear, nervousness, nightmares.

Nervous system disorders:

Uncommon: dizziness.
Very rare: headache, somnolence, encephalopathy (Reye's syndrome).

Eye disorders:

Rare: blurred vision.
Very rare: visual disturbances.

Ear and labyrinth disorders:

Very rare: vertigo (dizziness).

Cardiac and vascular disorders:

Uncommon: arterial hypertension.
Rare: tachycardia, haemorrhage, blood pressure lability, flushing.

Respiratory system disorders:

Uncommon: dyspnoea.
Very rare: asthma, bronchospasm.

Gastrointestinal disorders:

Common: diarrhoea, nausea, vomiting.
Uncommon: constipation, flatulence, gastrointestinal bleeding, peptic ulcer and perforation of the stomach/duodenum.
Very rare: gastritis, abdominal pain, dyspepsia, stomatitis, black stools (melena).

Hepatobiliary disorders (see section "Special precautions for use"):

Common: increased levels of liver enzymes.
Very rare: hepatitis; fulminant hepatitis (including fatal cases), jaundice, cholestasis.

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, skin rash, increased sweating.
Rare: erythema, dermatitis.
Very rare: urticaria, angioneurotic oedema, facial swelling, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Frequency not known: fixed drug eruption (see section "Special precautions for use").

Renal and urinary disorders:

Rare: dysuria, haematuria.
Very rare: urinary retention, renal failure, oliguria, interstitial nephritis.

General disorders:

Uncommon: oedema.
Rare: malaise, asthenia.
Very rare: hypothermia.

The most commonly observed adverse reactions are gastrointestinal. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes life-threatening, may occur, especially in elderly patients (see section "Special precautions for use"). After administration of medicinal products containing nimesulide, nausea, vomiting, diarrhoea, abdominal distension, constipation, dyspepsia, abdominal pain, melena, haematemesis, ulcerative stomatitis, and exacerbation of colitis and Crohn's disease have been reported (see section "Special precautions for use"). Gastritis has been observed less frequently. Cases of oedema, arterial hypertension and heart failure associated with NSAID therapy have been reported. 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 result in 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 marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all 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 temperatures not exceeding 25 °C.
Keep out of reach and sight of children.

Packaging.

2 g per sachet. 30 sachets in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

GLEDFARM LTD LLC.

Manufacturer's address and place of business.

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