Nimesulide

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

Composition:

Active substance: nimesulide;

One tablet contains 100 mg of nimesulide, calculated as 100% dry substance;

Excipients: lactose monohydrate; potato starch; microcrystalline cellulose; colloidal anhydrous silicon dioxide; calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: intact, regular, round cylindrical tablets with flat upper and lower surfaces and beveled edges, without a break line, light yellow in color; marbling on the 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 drug (NSAID) of 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.

In humans, nimesulide is well absorbed 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 the parahydroxy 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 does not change.

Clinical characteristics.

Indications.

Treatment of acute pain, primary dysmenorrhea.

Nimesulide should be used only 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 or to any component of the drug.

History of hypersensitivity reactions (bronchospasm, rhinitis, urticaria) to acetylsalicylic acid or other NSAIDs. History of hepatotoxic reactions to nimesulide.

Concomitant use of other agents with potential hepatotoxicity.

Alcoholism and drug addiction.

History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.

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

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

Severe coagulation disorders.

Severe heart failure.

Severe renal impairment.

Hepatic dysfunction.

Patients with elevated body temperature and/or flu-like symptoms.

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.

Glucocorticoids: increased risk of gastrointestinal ulceration or bleeding.

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

Anticoagulants: NSAIDs may potentiate the effects of anticoagulants such as warfarin or acetylsalicylic acid, making this combination 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 attenuate the effects of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients), 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 a patient is 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 hydration, and renal function should be closely monitored after initiation of such combination therapy. Nimesulide temporarily reduces the sodium-excreting effect of furosemide and to a lesser extent the potassium excretion, and also diminishes the diuretic effect. Concomitant use of furosemide and nimesulide in patients with impaired renal or cardiac function requires caution.

In healthy volunteers, nimesulide rapidly reduces the sodium-excreting effect of furosemide and to a lesser extent the potassium excretion, and also reduces diuretic action. Concomitant administration 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 with other medicinal products.

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.

No clinically significant interactions with glyburide, theophylline, warfarin, digoxin, cimetidine, and antacid agents (aluminum and magnesium hydroxide combination) have been observed in vivo. Nimesulide inhibits the activity of the CYP2C9 enzyme. When used concomitantly with medicinal products that are substrates of this enzyme, their plasma concentrations may increase. Caution is required if nimesulide is administered less than 24 hours before or less than 24 hours after methotrexate, as this may lead to increased methotrexate serum levels and enhanced toxicity.

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

Effects of other drugs on nimesulide.

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

Special precautions for use.

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

If treatment is ineffective (no reduction in disease symptoms), therapy with the drug should be discontinued.

During treatment with nimesulide, concomitant use of hepatotoxic drugs should be avoided, and alcohol consumption should be refrained from. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) may mask fever associated with underlying bacterial infection. If body temperature increases or flu-like symptoms occur in patients taking nimesulide, the drug should be discontinued.

Serious liver-related reactions, including fatal outcomes, have been reported during nimesulide treatment. Patients who develop symptoms suggestive of liver injury, such as anorexia, nausea, vomiting, abdominal pain, increased fatigue, dark urine, or who have abnormal liver function test results, should discontinue the drug. Re-administration of nimesulide to such patients is contraindicated. During treatment with nimesulide, patients should refrain from using other analgesics. Concomitant use of other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Patients taking nimesulide who develop flu-like symptoms should discontinue its use.

Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be life-threatening.

Gastrointestinal ulceration, bleeding, or perforation may be life-threatening, especially in patients with a history of such events during treatment with any other NSAID (regardless of time elapsed). The risk of such events increases with higher NSAID doses in patients with a history of gastrointestinal ulcers, particularly those complicated by bleeding or perforation, and in elderly patients. In such patients, treatment should be initiated with the lowest possible effective dose. For these patients, as well as for those concurrently taking 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.

Patients with gastrointestinal toxicity, especially elderly patients, should report any unusual gastrointestinal symptoms, particularly bleeding. This is especially important during the initial stages of treatment. Patients taking concomitant medications that may increase the risk of ulcers or bleeding, such as corticosteroids, anticoagulants, selective serotonin reuptake inhibitors, or antiplatelet agents (acetylsalicylic acid), should be informed about the need for caution when using nimesulide.

If gastrointestinal bleeding or ulcers occur in a patient receiving nimesulide, treatment with the drug should be discontinued.

NSAIDs should be prescribed with caution in patients with a history of Crohn’s disease or ulcerative colitis, as nimesulide may exacerbate these conditions.

Concomitant use of nimesulide with other medicinal products, such as oral contraceptives, anticoagulants, and antiplatelet agents, may trigger exacerbations of Crohn’s disease and other gastrointestinal disorders.

Patients with a history of arterial hypertension and/or heart failure, as well as those experiencing fluid retention and edema due to NSAID use, require appropriate monitoring and physician consultation.

Clinical studies and epidemiological data suggest that some NSAIDs, particularly at high doses and with prolonged use, may slightly increase the risk of arterial thrombotic events, such as myocardial infarction and stroke. There is insufficient data to exclude such risks with nimesulide use.

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

The drug should be administered with caution in patients with impaired renal function or heart failure due to the potential for worsening renal function. If the patient's condition deteriorates, treatment should be discontinued.

Elderly patients require close monitoring due to the potential for gastrointestinal bleeding and perforation, as well as worsening renal, hepatic, or cardiac function. 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.

Skin reactions.

Cases of fixed drug eruption have been reported with nimesulide use.

Nimesulide should not be re-administered to patients with a history of fixed drug eruption associated with nimesulide (see section "Adverse 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. In most cases, the risk of such reactions significantly increases if they occur within the first month of treatment. Nimesulide should be discontinued at the first signs of skin rash, mucosal lesions, or other allergic manifestations.

Use during pregnancy or breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological data suggest that use of drugs inhibiting prostaglandin synthesis during early pregnancy may increase the risk of spontaneous abortion and congenital heart defects and gastroschisis in the fetus. The absolute risk of cardiovascular malformation increased 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, nimesulide use may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after treatment initiation and is usually reversible upon discontinuation. Additionally, cases of arterial duct constriction have been reported after treatment during the second trimester, which mostly resolve after stopping treatment. Nimesulide should not be taken during the first and second trimesters of pregnancy unless absolutely necessary. If the drug is used in women trying to conceive or during the first and second trimesters of pregnancy, the lowest possible dose and shortest possible treatment duration should be selected. Prenatal monitoring for oligohydramnios may be advisable if nimesulide has been used for several days starting from the 20th week of pregnancy. Nimesulide 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 in the fetus:

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

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

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

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

As an NSAID that inhibits prostaglandin synthesis, nimesulide may cause premature closure of the ductus arteriosus, pulmonary hypertension, oliguria, oligohydramnios, increased risk of bleeding, weak labor, and peripheral edema. There have been isolated reports of renal failure in newborns whose mothers used nimesulide near the end of pregnancy. The potential risk to humans is not fully defined; therefore, nimesulide is not recommended during the first and second trimesters of pregnancy. Since it is unknown whether nimesulide is excreted in breast milk, its use is contraindicated during breastfeeding.

Nimesulide may impair fertility in women and therefore is not recommended for women trying to conceive. Women who are unable to conceive or undergoing infertility evaluation should consider discontinuing nimesulide. If pregnancy occurs during nimesulide treatment, the physician should be informed.

Ability to affect reaction speed when operating vehicles or machinery.

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

Dosage and Administration.

To minimize the potential for adverse effects, the lowest effective dose should be used for the shortest possible duration. It is recommended to take the medication after meals with sufficient amount of liquid.

The maximum duration of treatment with Nimesulide is 15 days.

Adults. 1 tablet (100 mg) twice daily.

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/h) is a contraindication for the use of Nimesulide.

Children.

Nimesulide is contraindicated in children under 12 years of age.

Overdose.

Symptoms of acute overdose with nonsteroidal anti-inflammatory drugs 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 during therapeutic use 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 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 a large dose has been ingested, 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, 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.

Blood system disorders: anaemia, eosinophilia, thrombocytopenia, pancytopenia, purpura.

Immune system disorders: hypersensitivity, anaphylaxis.

Metabolism and nutrition disorders: hyperkalaemia.

Psychiatric disorders: fear, nervousness, nightmares.

Central nervous system disorders: dizziness, headache, somnolence, encephalopathy (Reye’s syndrome).

Eye disorders: blurred vision, visual disturbances.

Ear and labyrinth disorders: vertigo.

Cardiovascular disorders: tachycardia, haemorrhage, blood pressure lability, flushing, arterial hypertension, increased risk of arterial thrombotic complications such as myocardial infarction or stroke, heart failure.

Respiratory system disorders: dyspnoea, asthma, bronchospasm.

Gastrointestinal disorders: diarrhoea; nausea; vomiting, including haematemesis; constipation; flatulence; gastritis; abdominal pain; dyspepsia; stomatitis; black stools; gastrointestinal bleeding; peptic ulcer and perforation of the stomach/duodenum; exacerbation of colitis and Crohn’s disease.

Hepatobiliary disorders: hepatitis; fulminant hepatitis, including fatal cases, jaundice; cholestasis.

Skin and subcutaneous tissue disorders: pruritus, skin rash, increased sweating, erythema, dermatitis, urticaria, angioneurotic oedema, facial swelling, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, fixed drug eruption (see section "Special precautions") — frequency unknown.

Renal and urinary disorders: dysuria, haematuria, urinary retention, renal failure, oliguria, interstitial nephritis.

General disorders: oedema, malaise, asthenia, hypothermia.

Investigations: increased liver enzymes.

Reporting suspected adverse reactions.

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

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets in blisters.

10 tablets in a blister; 1, 2, 3 or 10 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Lubnipharm".

Manufacturer's name and address.

16, Barvinkova Street, Lubny, Poltava region, 37500, Ukraine.