Nimelgan

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

Composition:

Active substance: nimesulide;

One 2 g sachet of granules contains 100 mg of nimesulide;

Excipients: macrogol cetostearyl ether, sucrose, maltodextrin, anhydrous citric acid, orange flavor.

Pharmaceutical form. Granules for oral suspension.

Main physicochemical properties: light yellow granular powder with an orange odor; after partial dissolution, the suspension is white or light yellow in color.

Pharmacotherapeutic group. Non-selective non-steroidal anti-inflammatory drugs. 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, which is 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) 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 various pathways, including those involving the cytochrome P450 isoenzyme CYP2C9. Therefore, there is a potential 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 interaction"). The main metabolite is the para-hydroxy derivative, which is also pharmacologically active. The time to detection of this metabolite in systemic circulation is short (approximately 0.8 hours), but the rate constant of its formation is low and significantly less than the absorption coefficient of nimesulide. Hydroxynimesulide is the only metabolite detected in blood plasma and is almost entirely present in a conjugated form. The elimination half-life ranges from 3.2 to 6 hours.

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

In a short-term clinical study conducted in patients with mild to moderate renal impairment (creatinine clearance

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

Preclinical safety data.

Preclinical data obtained from standard pharmacological safety, repeated-dose toxicity, genotoxicity, and carcinogenicity studies revealed no special hazard for humans. In repeated-dose toxicity studies, nimesulide showed gastrointestinal, renal, and hepatic toxicity. In reproductive toxicity studies, embryotoxic and teratogenic effects (skeletal malformations, brain ventricle dilation) were observed in rabbits 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 be used only 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 nonsteroidal anti-inflammatory drugs.

Hepatotoxic reactions to nimesulide in the past.

Concomitant use of other substances with potential hepatotoxicity.

Alcoholism and drug addiction.

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

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

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

Severe coagulation disorders.

Severe heart failure.

Severe renal impairment.

Hepatic dysfunction.

Fever and/or flu-like symptoms.

Children under 12 years of age.

Third trimester of pregnancy and breastfeeding period (see section "Use in pregnancy or lactation" and non-clinical safety data).

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

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

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

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

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (AIIAs). NSAIDs may attenuate the effects of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of ACE inhibitors and cyclooxygenase inhibitors may lead to further deterioration of renal function, including the development of acute renal failure, which is usually reversible. Such interactions should be considered in patients who require treatment with nimesulide-containing medicinal products together with ACE inhibitors or AIIAs. 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 "Clinical characteristics") 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%) of the area under the concentration-time curve (AUC) and cumulative excretion of furosemide, without changes in its renal clearance. Concomitant use of furosemide and nimesulide-containing medicinal products in patients with impaired renal or cardiac function requires caution (see section "Special precautions").

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

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

In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid, and valproic acid. However, despite a possible effect on its plasma concentration, such interactions have no clinical significance.

Other interactions.

Pharmacokinetic interactions with glyburide (glibenclamide), theophylline, warfarin, digoxin, cimetidine, and 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 NIMELGAN.

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 enhanced toxicity.

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

Special precautions for use.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration" and the risks related to 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. Patients receiving NIMELGAN® should be advised to refrain from using other analgesics.

NIMELGAN contains sucrose. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medication.

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

Hepatic effects.

Serious hepatic reactions associated with nimesulide use have been rarely reported, including very rare cases with fatal outcomes (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury during nimesulide therapy, such as anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine, or who have abnormal liver function test results, should discontinue therapy. Re-administration of nimesulide to such patients is not recommended. Liver injury, mostly reversible, has been reported after short-term exposure to the drug.

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

Gastrointestinal effects.

Gastrointestinal bleeding or ulceration/perforation has been reported during treatment with all NSAIDs, with or without warning symptoms or history of serious gastrointestinal events, and may be fatal. 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 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 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 be informed about 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, ulcerative colitis, or Crohn’s disease 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 prescribed with caution to patients with a history of gastrointestinal disorders (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.

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 during NSAID therapy.

Clinical trials and epidemiological data suggest that the use of certain NSAIDs, particularly at high doses and during long-term treatment, may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction or stroke. 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. Such assessment should also be performed before initiating long-term treatment in patients with cardiovascular risk factors, such as arterial hypertension, hyperlipidemia, diabetes, or smoking.

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

Renal effects.

Caution is required in patients with impaired renal function or heart failure, as 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.

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

Skin reactions.

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

Cases of drug rash have been reported with nimesulide use (see section "Adverse reactions").

Effects on fertility.

Use of the medicinal product NIMELGAN may impair female fertility and is not recommended for women attempting to conceive. Women who have difficulty 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 congenital malformations, including 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 treatment.

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

Starting from the 20th week of pregnancy, nimesulide use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Furthermore, there have been reports of arterial duct constriction following second-trimester treatment, most of which resolved after stopping therapy. Therefore, nimesulide should not be used during the first and second trimesters of pregnancy unless absolutely necessary. If nimesulide is used in women attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose and shortest possible duration of treatment should be prescribed.

Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after nimesulide exposure for several days starting from the 20th gestational week. Treatment with NIMELGAN should be discontinued if oligohydramnios or 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 arterial duct and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oliguria (see above).

In the mother and newborn at the end of pregnancy, the following effects are possible:

• 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 who have difficulty conceiving or undergoing infertility evaluation should discontinue nimesulide.

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

Ability to influence reaction rate 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 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"). 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 pharmacokinetic data, dose adjustment is not necessary in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). However, the medicinal product NIMELGAN is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Contraindications" and "Pharmacokinetics").

Hepatic impairment. The use of NIMELGAN 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 non-carbonated water. Stir with a spoon until a suspension with an orange odor is obtained. The suspension should be taken immediately after mixing.

Children.

Nimesulide 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, considering its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. If symptoms are present 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 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: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10000 – < 1/1000); very rare (< 1/10000), including isolated cases.

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

Suspected adverse reaction reporting

Reporting of suspected adverse reactions after medicinal product registration is important. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to 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 the reach and sight of children.

Packaging.

In sachets made of laminated foil.

10, 20, or 30 sachets in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

ASTRAFARM LLC.

Manufacturer's address and location of business activity.

6, Kyivska Street, Vyshneve, Kyiv-Sviatoshyn District, Kyiv Region, 08132, Ukraine.