Nimesulide

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

Composition:

Active substance: nimesulide;

1 sachet of granules contains 100 mg of nimesulide;

Excipients: cetomacrogol 1000, sucrose, maltodextrin, citric acid, orange flavoring.

Pharmaceutical form. Granules for oral suspension.

Main physicochemical properties: free-flowing granules of yellowish color with an orange odor and sweet taste, free from foreign inclusions.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents.

ATC code M01A X17.

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 the synthesis of prostaglandins.

Pharmacokinetics

Absorption. Nimesulide is well absorbed after oral administration. After a single 100 mg dose in adults, maximum plasma concentration is reached within 2–3 hours and amounts to 3–4 mg/L. The area under the plasma concentration-time curve (AUC) is 20–35 mg·h/L. No statistically significant differences were observed between these parameters and those after administration of 100 mg twice daily for 7 days. Approximately 97.5% of nimesulide is bound to plasma proteins.

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

Nimesulide is primarily excreted in the urine (approximately 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide is the main metabolite found exclusively in the form of 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 involving patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min) and healthy volunteers, maximum plasma concentrations of nimesulide and its main metabolite in patients were not higher than those in healthy volunteers. AUC and elimination half-life in patients with renal impairment were 50% higher but remained within the range of pharmacokinetic parameters observed in healthy volunteers receiving nimesulide. Repeated administration did not lead to accumulation. Nimesulide is contraindicated in patients with hepatic impairment (see section "Contraindications").

Preclinical safety data

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

Clinical characteristics

Indications. For the 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

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.

History of hepatotoxic reactions to nimesulide.

Concomitant use of other agents with potential hepatotoxicity.

Alcoholism and drug dependence.

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

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

Cerebrovascular bleeding or other hemorrhages, 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 lactation (see section "Use in pregnancy or lactation" and "Preclinical safety data").

Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

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

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

Anticoagulants. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special precautions for use"). In patients treated with nimesulide who are also taking warfarin or similar anticoagulants or acetylsalicylic acid, there is an increased risk of bleeding complications; therefore, this 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 combined therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

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

Other nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant use of 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 lithium levels and lithium toxicity. When nimesulide is prescribed to a patient receiving lithium therapy, plasma lithium levels should be closely monitored.

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

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

Other interactions

Pharmacokinetic interactions with glyburide, 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 nimesulide is administered concomitantly.

Caution is required when nimesulide is administered less than 24 hours before or less than 24 hours after methotrexate, as this may increase methotrexate serum levels and enhance its toxicity.

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

Special precautions for use

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

During nimesulide therapy, simultaneous 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 hepatic reactions, including very rare cases with fatal outcome, 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 patients with 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 taking nimesulide who develop fever and/or flu-like symptoms should discontinue treatment.

Gastrointestinal effects. Gastrointestinal bleeding or ulceration/perforation have been reported with all NSAIDs, which may be fatal and can occur at any time during treatment, with or without warning symptoms or history of serious gastrointestinal events. 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 dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risk, consideration should be given to combination therapy with protective agents such as misoprostol or proton pump inhibitors (see below and section "Interaction with other medicinal products and other forms of interaction").

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

Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, with or without preceding symptoms, regardless of the presence or absence of gastrointestinal events in history. 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 receiving concomitant medications that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid, should be informed of the need for caution.

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

NSAIDs should be prescribed with caution in patients with gastrointestinal disorders (ulcerative colitis, Crohn's disease) in history, 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 hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and physician consultation, as fluid retention and edema have been reported with NSAID therapy.

Clinical studies and epidemiological data suggest that use of certain NSAIDs, particularly at high doses and during long-term treatment, is 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 hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with nimesulide only after careful benefit-risk assessment. A similar assessment should be performed before initiating long-term treatment in patients with cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, or smoking.

Since nimesulide may affect platelet function, it should be used with caution in patients with hemorrhagic diathesis (see also section "Contraindications"). However, the medicinal product Nimesulide 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, especially gastrointestinal bleeding and perforation, sometimes fatal (see section "Adverse reactions"), as well as impaired renal, cardiac, and hepatic function; therefore, appropriate clinical monitoring is recommended.

Skin reactions. Very rare serious skin reactions, some of which are life-threatening, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAIDs (see section "Adverse reactions"). The highest risk of such reactions occurs early in treatment: most cases appear within the first month of therapy. Nimesulide should be discontinued at the first sign 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. The medicinal product Nimesulide may impair female fertility and is not recommended for women attempting to conceive. For women experiencing difficulty in conceiving or undergoing infertility investigations, discontinuation of Nimesulide should be considered (see section "Use during pregnancy or breastfeeding").

The medicinal product Nimesulide contains sucrose. If a patient has been diagnosed with intolerance to certain sugars, consultation with a physician is necessary 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 increases the risk of miscarriage and congenital heart defects and gastroschisis in the fetus. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy.

In animal studies, prostaglandin synthesis inhibitors caused increased pre- and post-implantation loss and embryonic and fetal mortality. Additionally, in animals treated with prostaglandin synthesis inhibitors during organogenesis, increased incidence of various fetal malformations, including cardiovascular defects, was observed.

Use of nimesulide from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after initiation of treatment and is usually reversible upon discontinuation of the drug. Furthermore, cases of fetal arterial duct constriction have been reported after drug use during the second trimester, which usually resolves after discontinuation of treatment. Therefore, nimesulide should not be used during the first and second trimesters unless absolutely necessary. If nimesulide is used in women attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose and shortest possible duration of treatment should be prescribed.

Prenatal monitoring for oligohydramnios and fetal arterial duct constriction may be appropriate if nimesulide is used for several days starting from the 20th gestational week. Pregnant women should discontinue nimesulide if oligohydramnios or fetal arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may cause 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 at the end of pregnancy and in the newborn, the following may occur:

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

Breastfeeding. It is unknown whether nimesulide passes into human breast milk. Nimesulide is contraindicated in women 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 in conceiving or undergoing infertility investigations 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 medicinal products containing nimesulide 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"). Due to 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. Due to the pharmacokinetic profile, dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). However, nimesulide is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Contraindications" and "Pharmacokinetics").

Hepatic impairment. The use of nimesulide 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

Empty the contents of the sachet into a glass of still water. Stir with a spoon until an orange-scented suspension is formed. 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. These 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, due to 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, vomiting may be induced and activated charcoal (60–100 g for adults) and/or an osmotic laxative may be administered. Forced diuresis, urine alkalinization, hemodialysis, or hemoperfusion may be ineffective due to the high degree of 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 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 isolated cases; frequency not known (cannot be estimated from the available data).

The most commonly observed adverse reactions are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation or bleeding, which may sometimes be 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. Clinical and epidemiological studies suggest that the use of certain NSAIDs, especially at high doses and during prolonged treatment, may slightly increase the risk of arterial thrombotic events, such as myocardial infarction or stroke (see section "Special precautions").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 30 sachets in a cardboard box.

Prescription status. Prescription only.

Manufacturer. FINE FOODS & PHARMACEUTICALS N.T.M. S.P.A. / FINE FOODS & PHARMACEUTICALS N.T.M. S.Р.A.

Address of manufacturer and location of its business operations / applicant and/or applicant's representative.

Via Grignano, 43 – 24041 Brembate (BG), Italy / Via Grignano, 43 – 24041 Brembate (BG), Italy.

Contact details of the applicant's representative in Ukraine – LLC "CALLIPHARM" / CALLIPHARM LLC. Ukraine, 08205, Kyiv region, Irpin, 2 Poesii street, office 35 / Ukraine, 08205, Kyiv region, Irpin, 2 Poesii street, 35 office.