Nimelgan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIMELGAN (NIMELGAN)

Composition:

Active substance: nimesulide;

1 tablet contains nimesulide (calculated as 100% substance) 100 mg;

Excipients: hydroxypropylcellulose; sodium docusate; microcrystalline cellulose; lactose monohydrate; sodium starch glycolate (type A); magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: tablets of round shape with a biconvex surface, with a score line on one side, pale yellow in color.

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.

Biotransformation and elimination.

Nimesulide is actively metabolized in the liver via multiple pathways, including the cytochrome P450 isoenzyme CYP2C9. Therefore, there is a potential for drug interactions when co-administered with medicinal products metabolized by CYP2C9 (see section "Interaction with other medicinal products and other forms of interaction"). The main metabolite is the para-hydroxy derivative, which is also pharmacologically active. The time to detection of this metabolite in circulating blood 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 its conjugated form. The elimination half-life ranges from 3.2 to 6 hours.

Nimesulide is primarily excreted in urine (approximately 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is excreted exclusively as a glucuronide conjugate. Approximately 29% of the administered dose is excreted in feces in metabolized form. The pharmacokinetic profile of nimesulide in elderly patients is not altered after single or repeated administration.

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

Preclinical safety data.

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

Clinical characteristics.

Indications.

Treatment of acute pain. Primary dysmenorrhea.

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

The decision to prescribe the drug 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 (bronchospasm, rhinitis, urticaria) associated with the use of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs).

History of hepatotoxic reactions to nimesulide.

Do not use simultaneously with other drugs that may potentially cause hepatotoxic reactions.

Alcoholism and drug dependence.

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

Active peptic ulcer of the stomach or duodenum, or history of gastrointestinal bleeding, ulcer, or perforation.

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

Severe coagulation disorders.

Severe heart failure.

Severe renal impairment.

Hepatic dysfunction.

Elevated body temperature and flu-like symptoms.

Children under 12 years of age.

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

Interaction with other medicinal products and other forms of interactions.

Pharmacodynamic interactions.

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

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding (see section "Special precautions for use").2

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 (ACE) inhibitors, and angiotensin II antagonists. NSAIDs may reduce 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. These interactions should be considered when a patient is using nimesulide concomitantly with ACE inhibitors or angiotensin II antagonists. Extreme caution is advised when using such combinations, especially in elderly patients. Adequate hydration should be ensured. Renal function should be monitored after initiation of concomitant therapy and periodically after discontinuation.

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

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

Furosemide. Nimesulide transiently reduces the effect of furosemide on sodium excretion, to a lesser extent on potassium excretion, and reduces the diuretic effect. Concomitant administration of nimesulide and furosemide leads to a reduction (by approximately 20%) in the area under the concentration–time curve (AUC) and decreased cumulative excretion of furosemide without changes in renal clearance of furosemide. Concomitant use of furosemide and medicinal products containing nimesulide requires caution in patients with impaired renal or cardiac function (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. In patients receiving lithium therapy, plasma lithium levels should be monitored frequently when nimesulide is prescribed.

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. Despite these interactions being identified in plasma, such effects have not been observed during clinical use of the drug.

Other interactions.

No clinically significant interaction has been observed with glipizide, theophylline, warfarin, digoxin, cimetidine, or antacid agents (aluminum and magnesium hydroxide combination). Nimesulide inhibits the activity of the CYP2C9 enzyme. When administered concomitantly with medicinal products that are substrates of this enzyme, their plasma concentrations may increase. Caution is required if 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 increased toxicity.

Due to effects on renal prostaglandins, inhibitors of synthetases, including nimesulide, may increase the nephrotoxicity of cyclosporine.

Special precautions for use.

Adverse side 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 (no reduction in disease symptoms), therapy with the drug should be discontinued.

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

The product contains lactose; therefore, it should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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

Hepatic effects.

Serious liver reactions associated with nimesulide use have been reported rarely, including very rare cases with fatal outcomes (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury, such as anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine, or those with abnormal liver function test results, should discontinue the drug. Re-administration of nimesulide to such patients is contraindicated. Liver injury, mostly reversible, has been reported after short-term exposure to the drug.

If fever or flu-like symptoms occur in patients taking nimesulide, the drug should be discontinued.

Gastrointestinal effects.

Gastrointestinal bleeding or ulceration/perforation has been reported during NSAID therapy, with or without warning symptoms or history of serious gastrointestinal events, and may be fatal and 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 those taking concomitant low-dose acetylsalicylic acid or other drugs increasing gastrointestinal complications risk, consideration should be given to concomitant use of protective agents such as misoprostol or proton pump inhibitors. Patients with gastrointestinal toxicity, especially elderly patients, should report any unusual gastrointestinal symptoms, particularly bleeding. This is especially important during the initial stages of treatment. 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 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, ulcerative colitis, or Crohn’s disease in medical history (see section "Adverse reactions").

Patients taking concomitant medications that may increase the risk of ulceration or bleeding, such as corticosteroids, anticoagulants (warfarin), selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents (acetylsalicylic acid), should be informed about the need for caution when using nimesulide. If gastrointestinal bleeding or ulceration occurs in patients receiving nimesulide, treatment should be discontinued.

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

Cardiovascular and cerebrovascular effects.

Patients with mild to moderate history of hypertension and/or 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 some NSAIDs, particularly at high doses and with prolonged use, may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction and stroke. Data on the risk of such events with nimesulide use are insufficient.

Nimesulide should be prescribed only after careful benefit-risk assessment in patients with uncontrolled hypertension, acute heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. The same approach should be applied before prescribing the drug to patients with cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes, or smoking.

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

Renal effects.

The drug should be administered with caution to patients with renal or cardiac insufficiency due to the potential for worsening renal function. If deterioration occurs, treatment should be discontinued.

Elderly patients.

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

Skin reactions.

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-related FDE (see section "Adverse reactions").

Rare cases of severe skin reactions have been reported with NSAID use, some of which may be life-threatening, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see section "Adverse reactions"). In most cases, the risk of such reactions significantly increases if they occurred during the first month of prior treatment. The drug should be discontinued at the first signs of skin rash, mucosal lesions, or other allergic manifestations of hypersensitivity.

Effects on fertility.

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

Use during pregnancy or breastfeeding.

Pregnancy.

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

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

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

Use of nimesulide from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal ductus arteriosus constriction have been reported after second-trimester use, most of which resolved after treatment cessation. Therefore, nimesulide should not be used during the first and second trimesters unless absolutely necessary.

If nimesulide is used in women attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose and shortest possible duration of treatment should be prescribed.

Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered if nimesulide is used for several days starting from the 20th gestational week. Pregnant women should discontinue nimesulide if oligohydramnios or ductus arteriosus constriction is detected.

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

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure and 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, nimesulide-containing medicinal products are not recommended for women attempting to conceive (see section "Special precautions for use"). Women experiencing difficulty conceiving or undergoing infertility evaluation should discontinue nimesulide.

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

Ability to influence reaction speed when driving or operating machinery.

The effect of nimesulide on the ability to drive or operate machinery has not been studied. However, patients who experience dizziness or somnolence after taking nimesulide should refrain from driving or performing tasks requiring high attention.

Dosage and Administration

To prevent the occurrence and reduce the severity of adverse reactions, the drug should be taken for the shortest possible duration and at the lowest effective dose. The drug should be prescribed only after careful assessment of the risk-benefit ratio.

The drug should be taken orally after meals with sufficient amount of liquid.

For adults and children aged 12 years and older – 1 tablet (100 mg) twice daily, in the morning and evening. Maximum duration of treatment is 15 days.

For elderly patients, the specified dosage regimen does not require dose adjustment (see section "Pharmacokinetics").

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

Renal impairment. Based on pharmacokinetic data, dose adjustment is not 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 Nimegan is contraindicated (see sections "Contraindications" and "Pharmacokinetics").

Hepatic impairment. The use of the medicinal product Nimegan 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").

Children.

The drug is contraindicated in children under 12 years of age.

Overdose.

Symptoms. 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.

Treatment. There is no specific antidote. In case of overdose, symptomatic and supportive therapy should be administered. 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 management. Within the first 4 hours after ingestion, gastric lavage, activated charcoal (60–100 g for adults), and an osmotic laxative should be administered. Forced diuresis, alkalinization of urine, hemodialysis, and hemoperfusion may be ineffective due to the high degree of nimesulide plasma protein binding. Careful monitoring of renal and hepatic function is required.

Adverse reactions.

The adverse reactions listed below are based on data from controlled clinical trials* (approximately 7800 patients) and post-marketing surveillance, classified according to the following frequency categories: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10000 – < 1/1000); very rare (< 1/10000), including rare cases, frequency not known (cannot be estimated from available data).

The most commonly observed adverse reactions are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation or bleeding, sometimes life-threatening, may occur, particularly in elderly patients (see section "Special precautions"). Nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn's disease have been reported following administration of medicinal products containing nimesulide (see section "Special precautions"). Gastritis has been observed less frequently. Cases of edema, arterial hypertension, and heart failure have been reported in association with NSAID therapy. Very rare cases of bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported.

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 should report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets per blister; 1, 3, or 10 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

LLC "ASTRAFARM".

Manufacturer's address and place of business.

6 Kyivska Street, city of Vyshneve, Kyiv-Sviatoshyn district, Kyiv region, 08132, Ukraine.