Nimesulide

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Nimesulide (Nimesulide)

Composition:

Active substance: nimesulide;

1 tablet contains: nimesulide 100 mg (0.1 g);

Excipients: lactose monohydrate, corn starch, magnesium stearate, colloidal anhydrous silicon dioxide, talc, microcrystalline cellulose.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets from light yellow to greenish-yellow in color.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01A X17.

Pharmacological Properties

Pharmacodynamics.

A non-steroidal anti-inflammatory drug with analgesic and antipyretic properties, it acts as an inhibitor of the enzyme cyclooxygenase involved in prostaglandin synthesis.

Pharmacokinetics.

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

Plasma protein binding is up to 97.5%.

Nimesulide is extensively metabolized in the liver via various pathways, including cytochrome P450 (CYP) isoenzymes, particularly CYP2C9. Therefore, there is a potential for interaction with concomitantly administered drugs that are also metabolized by CYP2C9. The main metabolite, 4-hydroxynimesulide, is also pharmacologically active. The time to appearance of this metabolite in blood is short (approximately 0.8 hours), but its formation rate constant is low and significantly lower than the absorption rate constant of nimesulide.

Hydroxynimesulide is almost completely conjugated and is the only metabolite detected in blood plasma. Its elimination half-life (T_1/2) ranges from 3.2 to 6 hours.

Nimesulide is primarily excreted via the urine (approximately 50% of the administered dose), of which only 1–3% is excreted unchanged. The main metabolite, hydroxynimesulide, is found in urine solely as a glucuronide conjugate. Approximately 29% of the dose is excreted in feces following metabolism.

The kinetic profile of nimesulide remains unchanged after single or repeated doses in elderly patients.

Acute clinical studies have shown that in patients with mild to moderate renal impairment (creatinine clearance of 30–80 mL/min), the maximum plasma concentrations of nimesulide and its main metabolite are not higher than those in healthy volunteers. The AUC and T_1/2 were increased by approximately 50%, but remained within the kinetic range observed in healthy volunteers.

Repeated administration does not lead to accumulation.

Clinical Characteristics.

Indications.

Treatment of acute pain, primary dysmenorrhea. Nimesulide should be used only as a second-line agent. The decision to prescribe Nimesulide must be based on an assessment of all risks for the individual patient.

Contraindications.

Hypersensitivity to the active substance or to any component of the drug. Hypersensitivity reactions (bronchospasm, rhinitis, urticaria) to acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs in medical history. Hepatotoxic reactions to the drug in medical history. Concomitant use with potentially hepatotoxic agents. Alcoholism, drug addiction. Active peptic ulcer disease of the stomach or duodenum, history of recurrent peptic ulcers or gastrointestinal bleeding, or bleeding associated with other diseases, history of perforations. Severe disorders of blood coagulation. Severe heart failure. Severe renal impairment (creatinine clearance <30 mL/min). Hepatic insufficiency. Elevated body temperature and flu-like symptoms. Suspicion of acute surgical pathology. History of cerebrovascular hemorrhage or other hemorrhages.

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 bleeding.

Anticoagulants: nonsteroidal anti-inflammatory drugs may enhance the effect 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.

Nonsteroidal anti-inflammatory drugs 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 substances that inhibit the cyclooxygenase system may lead to further deterioration of renal function and the 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 is required when using this combination, 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, 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-excreting effect, and also reduces diuresis. Concomitant use 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 the renal clearance of furosemide.

Pharmacokinetic interactions with other medicinal products.

There have been reports that nonsteroidal anti-inflammatory drugs 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 co-administered with drugs 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 increased toxicity. Due to effects 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. Despite these interactions being identified in plasma, the described effects have not been observed during clinical use of the drug.

Special precautions for use.

To reduce the risk of adverse effects, the lowest effective dose should be used for the shortest duration necessary. If the patient's condition does not improve, treatment should be discontinued.

There have been isolated reports of serious hepatic reactions, including fatal outcomes (see "Adverse reactions"). In patients receiving nimesulide who develop symptoms indicating liver injury (anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine), or in patients with abnormal liver function test results, the drug should be discontinued immediately. Nimesulide is contraindicated in such patients thereafter. In most cases, reversible liver injury has been observed after short-term use of the drug.

During nimesulide therapy, concomitant use of hepatotoxic drugs and alcohol should be avoided due to an increased risk of hepatic reactions.

Patients should be advised to avoid using other analgesic agents during nimesulide treatment. Concomitant use of different nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors, is not recommended.

The use of NSAIDs may mask fever associated with underlying bacterial infection. If fever or influenza-like symptoms occur in patients taking nimesulide, the drug should be discontinued.

Gastrointestinal ulceration, bleeding, or perforation may be life-threatening, particularly in patients with a history of such events during treatment with any other NSAID (regardless of time elapsed). The risk of these 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. In such patients, treatment should be initiated at the lowest possible effective dose. For these patients, as well as for those receiving concomitant 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, particularly elderly patients, should report any unusual gastrointestinal symptoms, especially signs of bleeding. This is particularly important during the initial stages of treatment. Patients receiving concomitant medications that may increase the risk of ulceration or bleeding—such as corticosteroids, anticoagulants, selective serotonin reuptake inhibitors, or antiplatelet agents (including acetylsalicylic acid)—should be informed about the need for caution when using nimesulide.

Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, often without preceding warning symptoms, and even in patients without prior gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued.

NSAIDs should be used with caution in patients with a history of Crohn’s disease or ulcerative colitis, as nimesulide may provoke exacerbations.

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

Patients experiencing fluid retention and edema due to NSAID use require appropriate monitoring and medical consultation. If renal function deteriorates, the drug should be discontinued (see "Interaction with other medicinal products and other forms of interaction").

Adverse effects of the drug occur most frequently in elderly patients, including gastrointestinal bleeding and perforation—which may be life-threatening—renal, cardiac, and hepatic dysfunction. Therefore, regular clinical monitoring is recommended.

Clinical studies and epidemiological data suggest that some NSAIDs, particularly at high doses and with prolonged use, may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction and stroke. However, data are insufficient to exclude such risks with nimesulide.

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

Since nimesulide may affect platelet function, it should be used cautiously in patients with hemorrhagic diathesis (see "Contraindications"). However, nimesulide should not be used as a substitute for acetylsalicylic acid for cardiovascular prophylaxis.

Nimesulide tablets contain lactose and therefore should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Rare cases of severe skin reactions have been reported with NSAIDs, some of which may be life-threatening, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In most cases, the risk of such reactions is significantly increased 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.

Cases of fixed drug eruption have been reported with nimesulide.

Nimesulide should not be re-administered to patients with a history of fixed drug eruption associated with its prior use (see section "Adverse reactions").

Nimesulide should be used with caution in patients with renal impairment or heart failure due to the potential for worsening renal function. If the patient's condition deteriorates, treatment should be discontinued.

Use during pregnancy or breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological data suggest that use of prostaglandin synthesis inhibitors during early pregnancy may increase the risk of spontaneous abortion and 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 gestation, use of the drug may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction after second-trimester exposure, which in most cases resolved after stopping treatment. The drug should not be used during the first and second trimesters unless absolutely necessary. If used in women attempting to conceive or during the first or second trimester, the lowest possible dose and shortest possible duration of treatment should be prescribed. Prenatal monitoring for oligohydramnios and arterial duct constriction may be advisable after drug exposure, starting from the 20th gestational week. Treatment should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors may cause in the fetus:

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

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

• prolonged bleeding time and antiplatelet 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.

As 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 whose mothers used nimesulide late in pregnancy. Animal studies have shown atypical reproductive toxicity, but reliable human data on nimesulide use during pregnancy are lacking. The potential risk to humans is not established; 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 female fertility and is therefore not recommended for women attempting to conceive. Women experiencing infertility 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 driving vehicles or operating machinery.

The effect of nimesulide on the ability to drive vehicles or perform tasks requiring high attention has not been studied. However, patients who experience dizziness or somnolence after taking nimesulide should refrain from driving or performing tasks requiring high concentration.

Dosage and Administration

Nimesulide should be prescribed only after a careful assessment of the risk/benefit ratio.

Use the lowest effective dose for the shortest duration necessary to minimize side effects.

The maximum duration of treatment with nimesulide is 15 days.

Tablets are for oral administration.

Adults. The recommended dose is 100 mg twice daily after meals.

Elderly patients. Dose adjustment is not required.

Adolescents (aged 12 to 18 years). Dose adjustment is not required.

Patients with impaired renal function. Based on the pharmacokinetics of the drug, dosage adjustment is not necessary in patients with mild to moderate renal impairment (creatinine clearance of 30–80 mL/min). The use of the drug is contraindicated in severe renal impairment (creatinine clearance <30 mL/min).

Patients with impaired hepatic function. The use of 100 mg nimesulide tablets for the treatment of patients with liver insufficiency is contraindicated (see "Contraindications").

Children. The drug is not recommended for use in children under 12 years of age.

Overdose. Symptoms of acute overdose with nonsteroidal anti-inflammatory drugs are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain. These symptoms are usually reversible with appropriate supportive treatment. Gastrointestinal bleeding may occur. Less frequently, arterial hypertension, acute renal failure, respiratory depression, and coma may be observed. Anaphylactoid reactions have been reported during therapeutic use of nonsteroidal anti-inflammatory drugs and may also occur in overdose.

After overdose with a nonsteroidal anti-inflammatory drug, patients require symptomatic and supportive treatment. There is no specific antidote. Information regarding the elimination of nimesulide by hemodialysis is lacking; however, due to its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. In patients who have ingested a high dose of nimesulide within the previous 4 hours, induction of vomiting and/or administration of activated charcoal (60–100 mg for adults) and/or an osmotic laxative is recommended. Forced diuresis, urinary alkalinization, hemodialysis, or hemoperfusion are unlikely to be effective due to the high degree of protein binding.

Careful monitoring of renal and hepatic function is required.

Side effects.

The adverse reactions listed below are based on data from controlled clinical studies* (approximately 7,800 patients) and post-marketing surveillance. The frequency of adverse effects was defined as follows: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated cases.

Shelf life. 3 years.

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

Keep out of the reach of children.

Packaging. 10 tablets per blister, 1 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Private joint-stock company "Lekhim-Kharkiv". PJSC "Tekhnolog".

Manufacturer's address and location of business activities.

36 Severina Pototskoho Street, Kharkiv, Kharkiv region, 61115, Ukraine.

8 Stara Prorizna Street, Uman, Cherkasy region, 20300, Ukraine.