Nimedár®

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

Composition:

Active substance: nimesulide;

One tablet contains 100 mg of nimesulide;

Excipients: lactose monohydrate, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, colloidal anhydrous silicon dioxide, hydroxypropylcellulose, sodium croscarmellose, sodium lauryl sulfate, talc, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: light-yellow, round-shaped tablets with a biconvex surface. Marbling on the tablet surface is permissible.

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

Pharmacological Properties.

Pharmacodynamics.

Nimesulide is a non-steroidal anti-inflammatory agent belonging to the methanesulfonanilide group, exhibiting anti-inflammatory, analgesic, and antipyretic effects. The therapeutic effect of nimesulide is due to its interaction with the arachidonic acid cascade and reduction of prostaglandin biosynthesis through inhibition of cyclooxygenase.

Pharmacokinetics.

Nimesulide is well absorbed in the human body after oral administration, reaching maximum plasma concentration within 2–3 hours. Approximately 97.5% of nimesulide is bound to plasma proteins. Nimesulide is actively metabolized in the liver via CYP2C9, a cytochrome P450 isoenzyme. The main metabolite is para-hydroxy derivative, which also possesses pharmacological activity. 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. The pharmacokinetic profile in elderly individuals is not altered.

Clinical characteristics.

Indications.

Treatment of acute pain; primary dysmenorrhea.

Nimesulide should be used only as a second-line medicinal product. The decision to prescribe the drug should be made based on an assessment of all risks for a specific patient.

Contraindications.

Hypersensitivity to nimesulide or to any component of the medicinal product; previous hypersensitivity reactions (bronchospasm, rhinitis, urticaria) associated with the use of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs); previous hepatotoxic reactions to nimesulide; gastric or duodenal ulcer in the phase of exacerbation; recurrent peptic ulcers or gastrointestinal bleeding; history of gastrointestinal bleeding associated with previous use of nonsteroidal anti-inflammatory drugs; cerebrovascular bleeding; bleeding associated with other diseases; severe coagulation disorders; severe heart failure; severe renal failure (creatinine clearance < 30 ml/min); severe hepatic impairment; elevated body temperature and/or flu-like symptoms; suspicion of acute surgical pathology. Alcoholism and drug dependence.

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

Children under 12 years of age.

Third trimester of pregnancy and breastfeeding period.

Interaction with other medicinal products and other types of interactions.

Pharmacodynamic interactions.

Glucocorticoids: increased risk of gastrointestinal ulcers or bleeding.

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

Anticoagulants: NSAIDs may enhance the effect of anticoagulants such as warfarin or acetylsalicylic acid; therefore, such combination is not recommended or 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 effect of diuretics and other antihypertensive agents. In some patients with impaired renal function (including dehydrated patients or elderly individuals), concomitant use of ACE inhibitors, angiotensin II antagonists, or agents 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 patients are taking nimesulide concomitantly with ACE inhibitors or angiotensin II antagonists. Extreme caution should be exercised when using such combinations, especially in elderly patients. Patients should receive adequate fluid intake, and renal function should be closely monitored after initiation of such combination therapy. Nimesulide temporarily reduces the sodium-excreting effect of furosemide, to a lesser extent the potassium excretion, and reduces the diuretic effect. Concomitant use of furosemide and nimesulide in patients with impaired renal or cardiac function requires caution.

In healthy individuals, nimesulide rapidly reduces the sodium-excreting effect of furosemide, to a lesser extent the potassium excretion, and reduces diuretic action. Concomitant use of nimesulide and furosemide results in a reduction (by approximately 20%) of the area under the concentration-time curve (AUC) and decreased cumulative excretion of furosemide, without changes in renal clearance of furosemide.

Pharmacokinetic interactions.

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

Tolbutamide, salicylic acid, and valproic acid displace nimesulide from binding sites. However, despite a potential effect on plasma drug levels, these interactions are not considered clinically significant.

No clinically significant interaction has been observed with glipizide, theophylline, warfarin, digoxin, cimetidine, or antacid preparations (aluminum and magnesium hydroxide combination).

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 is prescribed less than 24 hours before or less than 24 hours after methotrexate administration, as this may lead to increased serum levels of methotrexate and enhanced toxicity.

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

Effect of other drugs on nimesulide.

In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid, and valproic acid. Although these interactions have been identified in plasma, such effects have not been observed during clinical use of the drug.

Special precautions for use.

Nimesulide should only be used as a second-line medicinal agent. The decision to prescribe it should be based on an assessment of all risks for the individual patient.

Undesirable side effects can be minimized by taking the lowest effective dose for the shortest duration necessary to control disease symptoms. If treatment is ineffective (i.e., symptoms of the disease do not subside), therapy with the medicinal product should be discontinued.

Cases of severe hepatic reactions, including fatal outcomes, have been reported during use of the drug. Patients who develop symptoms suggestive of liver injury (e.g., anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine) or who have abnormal liver function test results should discontinue the drug immediately. Re-administration of nimesulide to such patients is contraindicated. In most cases, reversible liver damage was observed after short-term use of the drug.

Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, with or without warning symptoms, both in patients with and without a history of gastrointestinal disorders. The drug should be discontinued if gastrointestinal bleeding or ulceration occurs.

Gastrointestinal ulcers, bleeding, or perforation may be life-threatening, particularly in patients with a history of such events during treatment with any other NSAIDs (regardless of time elapsed). The risk of such events increases with higher NSAID doses, in patients with a history of gastrointestinal ulcers (especially if complicated by bleeding or perforation), and in elderly patients. These patients should be started on the lowest possible effective dose.

The frequency of adverse reactions to NSAIDs is increased in elderly patients, particularly with regard to possible gastrointestinal bleeding and perforation, which may be fatal.

Patients with toxic gastrointestinal injury, especially elderly individuals, should report any unusual gastrointestinal symptoms, particularly bleeding. This is especially important during the initial stages of treatment.

Patients taking concomitant medications that increase the risk of ulceration or bleeding—such as corticosteroids, anticoagulants (warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (acetylsalicylic acid)—should be informed of the need for caution when using nimesulide. For these patients, as well as for those taking low-dose acetylsalicylic acid or other drugs that increase the risk of gastrointestinal complications, consideration should be given to combination therapy with agents such as misoprostol or proton pump inhibitors.

During treatment with this drug, concomitant use of hepatotoxic medicinal agents, analgesics, other nonsteroidal anti-inflammatory drugs (including selective COX-2 inhibitors), and alcohol should be avoided.

NSAIDs should be prescribed with caution in patients with a history of Crohn’s disease or ulcerative colitis, as nimesulide may exacerbate these conditions. Patients with arterial hypertension, heart failure, or fluid retention and edema due to NSAID use require appropriate monitoring and physician consultation. Clinical trials and epidemiological data suggest that some NSAIDs, particularly at high doses and with prolonged use, may increase the risk of arterial thrombotic events such as myocardial infarction and stroke. There is insufficient data to exclude such risks with nimesulide.

Nimesulide should be prescribed to patients with uncontrolled hypertension, acute heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful evaluation of their condition. Patients with risk factors for cardiovascular disease (e.g., hypertension, hyperlipidemia, diabetes, smoking) should also be carefully assessed before initiating treatment.

The drug should be used with caution in patients with renal or cardiac insufficiency due to the potential for worsening renal function. If the patient's condition deteriorates, treatment should be discontinued.

Elderly patients require careful clinical monitoring due to the risk of gastrointestinal bleeding and perforation, as well as impaired kidney, liver, or heart function.

Since nimesulide may affect platelet function, it should be used cautiously and under continuous medical supervision in patients with hemorrhagic diathesis.

Nimesulide does not replace acetylsalicylic acid for the prevention of cardiovascular diseases.

Rare cases of severe skin reactions have been reported with NSAIDs, some of which may be life-threatening, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Patients are at particularly high risk of such reactions if they occurred during the first month of previous treatment. Nimesulide should be discontinued at the first signs of skin rash, mucosal lesions, or other signs of allergic reaction.

Cases of fixed drug eruption (FDE) have been reported with nimesulide. Nimesulide should not be re-administered to patients with a history of nimesulide-associated FDE.

The use of nonsteroidal anti-inflammatory drugs may mask fever associated with underlying bacterial infection. If fever or flu-like symptoms develop in patients taking nimesulide, the drug should be discontinued.

Nimesulide may impair female fertility and is not recommended for women attempting to conceive. Nimesulide is not recommended for women who are infertile or undergoing fertility investigations.

The medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

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

Use during pregnancy or breastfeeding.

Fertility. Nimesulide may impair female fertility and is not recommended for women who are trying to become pregnant. Nimesulide is not recommended for women who have difficulty conceiving or who are undergoing fertility evaluation. If pregnancy occurs during nimesulide treatment, the physician should be informed immediately.

Pregnancy. The drug is not recommended for use during the first and second trimesters of pregnancy.

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

From the 20th week of pregnancy, the use of Nemedar may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction following second-trimester treatment, most of which resolved after stopping the drug.

Nimesulide should not be taken during the first and second trimesters of pregnancy unless absolutely necessary. If use is required 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 selected. Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after several days of nimesulide exposure, starting from the 20th gestational week. Nemedar should be discontinued if oligohydramnios or arterial duct constriction is detected.

Animal studies have shown that administration of prostaglandin synthesis inhibitors leads to increased pre- and post-implantation loss and embryonic/fetal mortality.

Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

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

• cardiopulmonary toxicity (premature closure of the arterial duct and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure and oligohydramnios.

In the mother and fetus near the end of pregnancy, the following may occur:

• prolonged bleeding time and anti-aggregatory effect, which may occur even with very low doses of the drug;
• inhibition of uterine contractility, potentially leading to delayed or prolonged labor.

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

Like other NSAIDs that 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. There have been isolated reports of renal failure in newborns born to women who used nimesulide late in pregnancy.

Breastfeeding. Since it is unknown whether nimesulide is excreted in breast milk, its use is contraindicated during breastfeeding.

Ability to influence the speed of reactions when driving vehicles 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 drowsiness after taking nimesulide should refrain from driving or operating machinery.

Dosage and Administration

The medicinal product should be prescribed only after careful assessment of the benefit/risk ratio. Use the lowest effective dose for the shortest possible duration. The maximum duration of treatment with nimesulide is 15 days.

Adults and children aged 12 years and older: administer 1 tablet (100 mg) twice daily (daily dose – 200 mg).

Elderly patients: dose adjustment is not required.

Patients with renal impairment: dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). The medicinal product should be taken orally after food and with sufficient fluid. The use of the medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Patients with hepatic impairment: the use of nimesulide in patients with impaired liver function is contraindicated (see section "Contraindications").

Children:
The medicinal product is contraindicated in children under 12 years of age. The dosage for children aged 12 years and older is the same as for adults.

Overdose

Symptoms: acute overdose of nonsteroidal anti-inflammatory drugs (NSAIDs) usually presents with symptoms such as 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 during therapeutic use of NSAIDs as well as in cases of overdose.

Treatment: symptomatic and supportive therapy. There are no data on the elimination of nimesulide by hemodialysis; 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 medicinal product, within 4 hours of intake, patients may be given induced vomiting and/or activated charcoal (60–100 g for adults) and/or an osmotic laxative. Forced diuresis, urine alkalinization, hemodialysis, and hemoperfusion may be ineffective due to the high degree of plasma protein binding of nimesulide. Renal and hepatic functions should be monitored.

There is no specific antidote.

Side effects.

The following classification is used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), including isolated cases.

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, gastritis, gastrointestinal bleeding, ulcer and perforation of the duodenum or stomach; very rare – gastritis, abdominal pain, dyspepsia, stomatitis, black stools.

Hepatobiliary disorders: common – increased liver enzyme levels; very rare – hepatitis, fulminant hepatitis with fatal outcome, 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, night terrors.

Cardiac disorders: uncommon – arterial hypertension; rare – tachycardia, hemorrhage, blood pressure fluctuations, 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: common – pruritus, skin rash, increased sweating; rare – erythema, dermatitis; very rare – urticaria, angioneurotic edema, facial swelling, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis; frequency not known – fixed drug eruption.

General disorders: uncommon – edema; rare – malaise, asthenia; very rare – hypothermia, hyperthermia.

Investigations: common – increased liver enzyme levels.

Adverse effects from the gastrointestinal tract are most commonly observed during the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Peptic ulcers, perforations, or gastrointestinal bleeding, sometimes life-threatening, may occur, particularly in elderly patients. Reports of the following adverse effects have been received after administration of this class of drugs: nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, black stools, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease. Gastritis has been observed less frequently. There have been reports of edema, arterial hypertension, and heart failure as reactions to NSAID use. Very rarely, skin reactions such as blistering, Stevens-Johnson syndrome, and toxic epidermal necrolysis may occur during NSAID therapy. Data indicate that some NSAIDs, particularly at high doses and with prolonged use, may slightly increase the risk of arterial thrombotic events, such as myocardial infarction or stroke.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging, out of the reach of children, at a temperature not exceeding 25 °C.

Packaging. 10 tablets in a blister pack; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13, Boryspilska Street, Kyiv, 02093, Ukraine.