Nimesulide-fitopharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIMESULIDE-PHYTOPHARM

Composition:

Active substance: nimesulide;

1 tablet contains: nimesulide 0.1 g;
Excipients: lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silicon dioxide, povidone (polyvinylpyrrolidone), sodium croscarmellose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, biconvex tablets of yellowish or yellowish-green color.

Pharmacotherapeutic group.

Non-selective non-steroidal anti-inflammatory drugs. 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. Up to 97.5% of nimesulide is bound to plasma proteins. Nimesulide is actively metabolized in the liver with the involvement of CYP2C9, an isoenzyme of cytochrome P450. The main metabolite is the 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 and primary dysmenorrhea.

Nimesulide should be used only as a second-line agent.

The decision to prescribe the drug should be based on an assessment of all risks for the individual patient.

Contraindications.

Known hypersensitivity to nimesulide or to any component of the drug. History of hypersensitivity reactions (bronchospasm, rhinitis, urticaria) associated with the use of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs). History of hepatotoxic reactions to nimesulide.

Concomitant use of other substances 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 hemorrhagic events, as well as diseases associated with bleeding tendency.

Severe coagulation disorders.

Severe heart failure.

Severe renal impairment (creatinine clearance < 30 mL/min).

Hepatic dysfunction.

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

Suspicion of acute surgical pathology.

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 lactation 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 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: NSAIDs may reduce the effectiveness 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 the development of acute renal failure, which is usually reversible. These interactions should be considered when a patient is taking nimesulide in combination with ACE inhibitors or angiotensin II antagonists. Extreme caution is required 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 and to a lesser extent the potassium excretion, as well as diminishes the diuretic effect. Concomitant use of furosemide and nimesulide in patients with impaired renal or cardiac function requires caution.

In healthy subjects, nimesulide rapidly reduces the sodium-excreting effect of furosemide and to a lesser extent the potassium excretion, and also reduces the diuretic action. Concomitant use of nimesulide and furosemide leads to a reduction (by approximately 20%) in the area under the plasma concentration-time curve (AUC) and decreased cumulative excretion of furosemide, without changes in the 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 its binding sites. However, despite a possible effect on plasma drug levels, these interactions are not considered clinically significant.

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

Nimesulide inhibits the activity of the CYP2C9 enzyme. When used concomitantly with drugs that are substrates of this enzyme, their plasma concentrations may increase. Caution is required when nimesulide is administered less than 24 hours before or less than 24 hours after methotrexate, as this may lead to increased serum levels of methotrexate and enhanced toxicity.

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

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

Special precautions for use.

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

Adverse 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 avoided. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) 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 drug should be discontinued.

Serious hepatic reactions, including fatal outcomes, have been reported with the use of nimesulide. 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, should discontinue the drug. Re-administration of nimesulide to such patients is contraindicated. After short-term use of the drug, reversible liver damage was observed in most cases.

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

In elderly patients, the frequency of adverse reactions to NSAIDs is increased, particularly the risk of gastrointestinal bleeding and perforation, which may be fatal.

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 these patients, treatment should be initiated at the lowest possible effective dose. For these patients, as well as for those taking concomitant low-dose acetylsalicylic acid or other drugs increasing the risk of gastrointestinal complications, consideration should be given to using combination therapy with protective agents, such as misoprostol or proton pump inhibitors.

Patients with gastrointestinal toxicity, particularly elderly individuals, should be informed to report any unusual gastrointestinal symptoms, especially bleeding. This is particularly important during the initial stages of treatment. Patients taking concomitant medications that may 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.

Gastrointestinal bleeding or ulceration/perforation may develop at any time during treatment, with or without preceding symptoms, both in patients with and without a history of gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued.

NSAIDs should be prescribed with caution to patients with Crohn's disease or a history of 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 lead to exacerbation of Crohn’s disease and other gastrointestinal disorders.

Patients with hypertension and/or heart failure in their medical history, 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 certain NSAIDs, especially 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 evaluation in patients with uncontrolled hypertension, acute heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Patients with cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, or smoking, should also be carefully assessed before prescribing the drug.

The drug should be used 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 increased risk of gastrointestinal bleeding and perforation, as well as deterioration in renal, hepatic, or cardiac function. Since nimesulide may affect platelet function, it should be used with caution in patients with hemorrhagic diathesis. However, nimesulide does not replace acetylsalicylic acid for the prevention of cardiovascular diseases.

Rare cases of severe skin reactions have been reported with NSAID use, some of which may be life-threatening, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The risk of such reactions is particularly high if a reaction occurred during a previous course of treatment, which in most cases appeared within the first month of therapy. 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 the use of nimesulide.

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

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

The medicinal product contains lactose and therefore should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

If a patient has intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.

Use during pregnancy or breastfeeding.

Fertility. The use of nimesulide may impair female fertility and is not recommended for women planning to become pregnant. Nimesulide is not recommended for women experiencing difficulty conceiving or undergoing infertility evaluation. If pregnancy occurs during nimesulide treatment, the physician should be informed.

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 the 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 increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of treatment. Starting from the 20th week of gestation, the use of nimesulide may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after the start of treatment and is usually reversible upon discontinuation of therapy. Additionally, there have been reports of arterial duct constriction after treatment during the second trimester, which in most cases resolved after discontinuation of therapy. Therefore, nimesulide should not be used during the first and second trimesters of pregnancy unless absolutely necessary. If the drug 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 selected. Prenatal monitoring for oligohydramnios and arterial duct constriction may be advisable after several days of nimesulide exposure, starting from the 20th gestational week. The drug 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 losses 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. The drug is contraindicated during the third trimester of pregnancy.

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

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction (see above).

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

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

Therefore, nimesulide is contraindicated throughout the third trimester of pregnancy (see section "Contraindications").

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

Ability to affect reaction speed when driving 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 drowsiness after taking nimesulide should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage

To prevent the occurrence and reduce the severity of adverse reactions, the drug should be taken for the shortest possible duration and at the lowest effective dose. The drug should be prescribed only after careful assessment of the risk/benefit ratio.

The maximum duration of treatment with nimesulide is 15 days.

The drug should be taken orally after meals with sufficient fluid. Adults. The recommended dose is 100 mg twice daily after meals. Elderly patients. Dose adjustment is not required. Children aged 12 years and older. Dose adjustment is not required.

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

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

Children.

The drug 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 of acute overdose with nonsteroidal anti-inflammatory drugs (NSAIDs) are usually limited to the following manifestations: apathy, drowsiness, nausea, vomiting, 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. Cases of anaphylactoid reactions have been reported during the use of therapeutic doses of NSAIDs as well as in cases of overdose.

Treatment: 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 are present or a large dose has been ingested, within 4 hours of drug intake, patients may be given: induced emesis 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.

There is no specific antidote.

Adverse reactions.

The following classification is used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), 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, ulceration 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.

Cardiovascular disorders: rare – tachycardia; uncommon – arterial hypertension; rare – hemorrhage, fluctuations in blood pressure, 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 (see section "Special instructions").

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

Laboratory findings: common – increased liver enzyme levels.

Adverse reactions from the gastrointestinal tract are most commonly observed during the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Peptic ulcers, gastrointestinal perforations or bleeding, sometimes life-threatening, may occur, particularly in elderly patients. Reports have been received regarding the following adverse reactions after using this class of drugs: nausea, vomiting, diarrhea, bloating, 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 with NSAID use. Data indicate that some NSAIDs, particularly at high doses and with prolonged use, may slightly increase the risk of arterial thrombotic complications, such as myocardial infarction or stroke.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging. 12 tablets per blister, in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "FITOPHARM".

Manufacturer's address and location.

2 Sybirtseva Street, Bakhmut, Donetsk region, 84500, Ukraine.

Marketing Authorization Holder. JSC "FITOPHARM".

Address of the Marketing Authorization Holder.

7, Verkhovnoї Rady Boulevard, Kyiv, 02100, Ukraine, floor 3, room 18.