Nimedár

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

Composition:

Active ingredient: nimesulide;

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

Excipients: polyethylene glycol cetylstearyl ether, maltodextrin, citric acid anhydrous, orange flavor, sucrose.

Pharmaceutical form. Granules for oral suspension.

Main physicochemical characteristics: granules from light yellow to yellow in color.

Pharmacotherapeutic group.

Non-selective non-steroidal anti-inflammatory drugs. ATC code M01AX17.

Pharmacological properties.

Pharmacodynamics.

Nimedal is a non-steroidal anti-inflammatory drug (NSAID) of the methanesulfonanilide group, exhibiting anti-inflammatory, analgesic, and antipyretic effects. The therapeutic effect of Nimedal is due to its interaction with the arachidonic acid cascade and reduction of prostaglandin biosynthesis through cyclooxygenase inhibition.

Pharmacokinetics.

Nimedal is well absorbed in the human body 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. Approximately 97.5% of nimesulide is protein-bound in plasma. Nimesulide is actively metabolized in the liver via CYP2C9, an isoenzyme of cytochrome P450. Therefore, there is a risk of drug interactions when used concomitantly with medicinal products metabolized by CYP2C9 (see section "Interaction with other medicinal products and other forms of interactions"). The main metabolite is para-hydroxy derivative, which also possesses pharmacological activity. The time to detection 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 present in bound form. 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. About 29% of the administered dose is excreted in feces in metabolized form. Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is detected solely as a glucuronide conjugate. Approximately 29% of the administered dose is excreted in feces in metabolized form. The pharmacokinetic profile in elderly patients does not change after single or repeated doses.

A short-term experimental study was conducted involving patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min) and healthy volunteers. The maximum plasma concentration of nimesulide and its main metabolite in patients was not higher than that 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").

Safety data.

Preclinical data obtained from standard pharmacological safety, repeated-dose toxicity, genotoxicity, and carcinogenicity studies revealed no particular hazard to humans. In repeated-dose toxicity studies, nimesulide showed gastrointestinal, renal, and hepatic toxicity. In reproductive toxicity studies, when administered to pregnant animals at non-toxic doses, embryotoxic and teratogenic effects (skeletal malformations, 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 only be used as a second-line medicinal product. The decision to prescribe nimesulide must be based on an assessment of all risks for the individual patient.

Contraindications.

Hypersensitivity to nimesulide or to any other NSAID or to any component of the medicinal product. History of hypersensitivity reactions (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 substances with potential hepatotoxicity.

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

Active gastric or duodenal ulcer, history of ulcer, perforation, or gastrointestinal bleeding.

History of cerebrovascular hemorrhage or other bleeding conditions, as well as diseases associated with bleeding tendency.

Severe coagulation disorders.

Severe heart failure.

Severe renal impairment.

Hepatic dysfunction.

Elevated body temperature in the patient and/or flu-like symptoms.

Alcoholism and drug dependence.

Children under 12 years of age.

Third trimester of pregnancy and breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding. Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal ulceration or bleeding.

Anticoagulants: NSAIDs may enhance the effect of anticoagulants such as warfarin or acetylsalicylic acid. In patients treated with nimesulide who are taking warfarin or similar anticoagulants or acetylsalicylic acid, there is an increased risk of hemorrhagic complications; therefore, such combination is not recommended and is contraindicated in patients with severe coagulation disorders. 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 efficacy of diuretics and other antihypertensive medicinal products. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients), concomitant use of ACE inhibitors, angiotensin II antagonists, or substances that inhibit the cyclooxygenase system may lead to further deterioration of renal function and development of acute renal failure, which is usually reversible. These interactions should be considered when the patient is using the medicinal product Nimedaru in combination with ACE inhibitors or angiotensin II antagonists. Extreme caution should be exercised when using such combination, especially in elderly patients. Patients should receive adequate hydration, and renal function should be carefully monitored after initiation of such combination therapy and periodically after its discontinuation.

Nimesulide temporarily reduces the effect of furosemide on sodium excretion and to a lesser extent on potassium excretion, and also 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 Nimedaru in patients with impaired renal or cardiac function requires caution.

Pharmacokinetic interactions with other medicinal products.

Concomitant use of medicinal products containing nimesulide with other NSAIDs, including acetylsalicylic acid at anti-inflammatory doses (≥ 1 g as a single dose or ≥ 3 g per day), is not recommended.

There have been reports that NSAIDs reduce lithium clearance, leading to increased plasma lithium levels and lithium toxicity. When prescribing the medicinal product Nimedaru to patients receiving lithium therapy, plasma lithium levels should be monitored frequently.

There is no clinically significant interaction with glyburide, theophylline, warfarin, digoxin, cimetidine, and antacid agents (aluminum and magnesium hydroxide combination) in vivo. Nimesulide inhibits the activity of the CYP2C9 enzyme. When administered concomitantly with drugs that are substrates of this enzyme, their plasma concentrations may increase. Caution is required when nimesulide must be administered less than 24 hours before or less than 24 hours after methotrexate administration, as this may lead to increased serum levels of methotrexate and increased toxicity.

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

Effect of other medicinal products on nimesulide.

In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid, and valproic acid. Despite the fact that these interactions were identified in blood plasma, the stated effects have not been observed during clinical use of the medicinal product and are not clinically significant.

Special precautions for use.

Undesirable side effects can be minimized by using the lowest effective dose for the shortest duration necessary to control disease symptoms.

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

The use of nonsteroidal anti-inflammatory drugs may mask fever associated with underlying bacterial infection. In case of elevated body temperature or development of influenza-like symptoms in patients taking nimesulide, the medicinal product should be discontinued.

During treatment with Nimedар, patients should refrain from using other analgesics. Concomitant use of other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Hepatic effects.

During treatment with nimesulide, concomitant use of hepatotoxic medicinal products should be avoided, and alcohol consumption should be refrained from. Serious hepatic reactions, including fatal outcomes, have been reported during treatment with nimesulide-containing products. Patients who develop symptoms suggestive of liver injury, such as anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine, or who have abnormal liver function test results, must discontinue the medicinal product. Re-administration of nimesulide to such patients is contraindicated. Liver injury, which in most cases is reversible, occurs after short-term exposure to the drug.

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. Such events can 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. These patients should be initiated on the lowest possible effective dose. For these patients, as well as for those concurrently taking low-dose acetylsalicylic acid or other medicinal products increasing gastrointestinal complications risk, consideration should be given to using combination therapy with protective agents, such as misoprostol or proton pump inhibitors.

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 medical history, as nimesulide may exacerbate these conditions.

Patients with toxic gastrointestinal injury, particularly elderly patients, should report any unusual gastrointestinal symptoms, especially bleeding. This is particularly important during the initial stages of treatment. Patients taking concomitant medicinal products that 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 a patient receiving Nimedар, treatment with the medicinal product should be discontinued.

Concomitant use of nimesulide with other medicinal products, such as oral contraceptives, anticoagulants, or antiplatelet agents, may exacerbate 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, as well as those with fluid retention and edema due to NSAID use, require appropriate monitoring and physician consultation.

Clinical trials and epidemiological data suggest that certain NSAIDs, especially at high doses and with prolonged use, may increase the risk of arterial thrombotic events, such as myocardial infarction and stroke. There are insufficient data to exclude such risk with nimesulide use.

Nimesulide should be prescribed with caution after careful assessment in patients with uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. This also applies to patients with risk factors for cardiovascular disease, such as arterial hypertension, hyperlipidemia, diabetes mellitus, or smoking.

Since nimesulide may affect platelet function, it should be used cautiously in patients with hemorrhagic diathesis. However, nimesulide does not replace acetylsalicylic acid for cardiovascular disease prevention.

Renal effects.

The medicinal product should be used with caution in patients with impaired renal function or heart failure due to the possibility of worsening renal function. If the patient's condition deteriorates, treatment should be discontinued.

Elderly patients.

Elderly patients require close monitoring due to increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be life-threatening, as well as worsening renal, hepatic, or cardiac function.

Skin reactions.

Rare cases of severe skin reactions have been reported with NSAID use, some of which may be fatal, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The risk of such reactions is significantly increased if they occur within the first month of treatment. Nimedар should be discontinued at the first signs of skin rash, mucosal lesions, or other allergic manifestations. 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.

Effects on fertility.

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

Important information about excipients.

Nimedар contains sucrose. If a patient has known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

This medicinal product should not be taken by patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Pregnancy.

Nimesulide is contraindicated during the third trimester of pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological data suggest that use of prostaglandin synthesis inhibitors during early pregnancy increases the risk of spontaneous abortion and congenital malformations, including 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 treatment.

In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and 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. Fetal monitoring for oligohydramnios and constriction of the arterial duct should be considered after several days of nimesulide exposure starting from the 20th week of gestation. Treatment with Nimedар should be discontinued if abnormalities in pregnancy or fetal development are detected.

Nimesulide should not be used during the first and second trimesters of pregnancy unless absolutely necessary. If prescribed to women attempting to conceive or during the first or second trimester of pregnancy, the lowest possible dose and shortest possible duration of treatment should be selected.

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

• Cardiotoxic effects (with premature closure of the arterial ducts and pulmonary hypertension);
• Renal dysfunction, which may progress to renal failure with oligohydramnios.

In the mother and fetus near term, the following may occur:

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

Therefore, nimesulide is contraindicated during the third trimester of pregnancy.

Since NSAIDs inhibit prostaglandin synthesis, nimesulide may cause premature closure of the ductus arteriosus, pulmonary hypertension, oliguria, and oligohydramnios. The risk of bleeding, weak labor, and peripheral edema increases. Cases of renal failure in newborns whose mothers used nimesulide late in pregnancy have been reported.

Breastfeeding.

Since it is unknown whether nimesulide passes into breast milk, its use is contraindicated during breastfeeding.

Fertility.

Nimesulide may impair female fertility and is not recommended for women attempting to conceive. Women experiencing difficulty conceiving or undergoing infertility evaluation should discontinue nimesulide. If pregnancy occurs during nimesulide treatment, the physician should be informed.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of nimesulide on the ability to drive or operate machinery have not been conducted. However, if patients experience headache, dizziness, vertigo, or somnolence during nimesulide treatment, they should refrain from driving or operating machinery.

Method of Administration and Dosage

To minimize the possibility of adverse side effects, the lowest effective dose for the shortest duration necessary should be used. It is recommended to take the medication after food.

The maximum duration of treatment with Nimedar is 15 days.

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

Elderly patients. Dose adjustment is not required.

Children aged 12 years and older. Dose adjustment is not required.

Patients with impaired renal function. For patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), dose adjustment is not necessary. However, severe renal impairment (creatinine clearance < 30 mL/min) is a contraindication for the use of Nimedar.

Patients with impaired hepatic function. The use of Nimedar is contraindicated in patients with hepatic impairment. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

The contents of the sachet should be poured into a glass, dissolved with water, and taken orally.

Children.

Nimedar 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. These symptoms are generally reversible with supportive therapy. Gastrointestinal bleeding, arterial hypertension, acute renal failure, respiratory depression, and coma are possible but occur rarely. Anaphylactoid reactions have been reported following therapeutic doses of NSAIDs as well as in cases of overdose. There is no specific antidote. Treatment of overdose is symptomatic and supportive. There are no data on the effectiveness of hemodialysis in removing nimesulide; however, considering the high degree of plasma protein binding of nimesulide (up to 97.5%), dialysis is unlikely to be effective. If symptoms of overdose occur or after ingestion of a large dose of the drug, within 4 hours of intake, patients may be given induced vomiting and/or activated charcoal (60–100 g for adults) and an osmotic laxative. Forced diuresis, alkalinization of urine, hemodialysis, and hemoperfusion may be ineffective due to the high degree of plasma protein binding of nimesulide. Renal and hepatic functions should be monitored.

Adverse reactions.

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data).

Eye disorders: rare – blurred vision; very rare – visual disturbances.

Ear and labyrinth disorders: very rare – vertigo (dizziness).

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnea; very rare – asthma, bronchospasm.

Gastrointestinal disorders: common – diarrhea, nausea, vomiting; uncommon – constipation, flatulence, gastrointestinal hemorrhage, peptic ulcer and perforation of the stomach or duodenum; very rare – gastritis, abdominal pain, dyspepsia, stomatitis, black stools, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease.

Hepatobiliary disorders: very rare – hepatitis, fulminant hepatitis (including fatal cases), jaundice, cholestasis.

Renal and urinary disorders: rare – dysuria, hematuria; very rare – urinary retention, renal failure, oliguria, interstitial nephritis.

Metabolism and nutrition disorders: rare – hyperkalemia.

Nervous system disorders: uncommon – dizziness; very rare – headache, somnolence, encephalopathy (Reye's syndrome).

Psychiatric disorders: rare – fear, nervousness, nightmares.

Cardiac disorders: uncommon – arterial hypertension; rare – tachycardia, hemorrhage, fluctuations in blood pressure, flushing.

Vascular disorders: rare – flushing.

Blood and lymphatic system disorders: rare – anemia, eosinophilia; very rare – thrombocytopenia, pancytopenia, purpura.

Immune system disorders: rare – hypersensitivity reactions; very rare – anaphylaxis.

Skin and subcutaneous tissue disorders: uncommon – pruritus, skin rashes, 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.

General disorders and administration site conditions: uncommon – edema; rare – malaise, asthenia; very rare – hypothermia.

Investigations: common – increased levels of liver enzymes.

Gastrointestinal adverse reactions are the most commonly observed during NSAID use. Peptic ulcers, gastrointestinal perforation or bleeding, sometimes life-threatening, may occur, particularly in elderly patients (see section "Special instructions"). After 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 instructions"). 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 indicate that some NSAIDs, especially when used at high doses and for prolonged periods, may increase the risk of arterial thrombotic events such as myocardial infarction or stroke.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is an important procedure. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

2 g of granules in a sachet; 30 sachets in a box.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical company "Darnytsia".

Manufacturer's address and location of operations.

13, Boryspilska Street, Kyiv, 02093, Ukraine.