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

Composition:

Active substance: nimesulide;

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

Excipients: polyethylene glycol cetostearyl ether, maltodextrin, anhydrous citric acid, orange flavor, crystalline sugar.

Pharmaceutical form. Granules for oral suspension.

Main physico-chemical characteristics: granules of light yellow to yellow color.

Pharmacotherapeutic group. Non-selective non-steroidal anti-inflammatory drugs.

ATC code M01AX17.

Pharmacological Properties

Pharmacodynamics. The medicinal product Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) of the methanesulfonanilide group, exhibiting anti-inflammatory, analgesic, and antipyretic effects. The therapeutic action 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 humans after oral administration. After a single 100 mg dose in adults, maximum plasma concentration is reached within 2–3 hours and amounts to 3–4 mg/L. The area under the plasma 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. Nimesulide is bound to plasma proteins by up to 97.5%. Nimesulide is actively metabolized in the liver by 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 types of interactions"). The main metabolite is the para-hydroxy derivative, which also possesses pharmacological activity. The time to detect this metabolite in circulating blood is short (approximately 0.8 hours), but the rate constant of its formation is low and significantly lower than the absorption coefficient of nimesulide. Hydroxynimesulide is the only metabolite detected in plasma and is almost entirely present in a conjugated 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, in which 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 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").

Preclinical Safety Data

According to preclinical data obtained from standard studies on pharmacological safety, repeated-dose toxicity, genotoxicity, and carcinogenic potential, no specific hazard to humans was identified. In repeated-dose toxicity studies, nimesulide showed gastrointestinal, renal, and hepatic toxicity. In reproductive toxicity studies, when administered to female 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. For the treatment of acute pain, primary dysmenorrhea.

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

Contraindications. Hypersensitivity to nimesulide, 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 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 disorders associated with bleeding tendency.

Severe disorders of blood coagulation.

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 lactation 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. Treatment with nimesulide in patients taking warfarin or similar anticoagulants or acetylsalicylic acid is associated with 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 attenuate the effect 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 agents inhibiting 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 nimesulide in combination with ACE inhibitors or angiotensin II antagonists. Extreme caution is required when using such a combination, especially in elderly patients. Patients should receive adequate hydration, and renal function should be closely monitored after initiation of such combination therapy and periodically after its discontinuation.

Nimesulide temporarily reduces the sodium-excreting effect of furosemide and to a lesser extent its potassium-excreting effect, as well as diminishes the diuretic effect. 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. Concomitant use of furosemide and nimesulide 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 nimesulide to patients receiving lithium therapy, plasma lithium levels should be monitored frequently.

No clinically significant interaction has been observed in vivo with glipizide, theophylline, warfarin, digoxin, cimetidine, and antacid agents (aluminum and magnesium hydroxide combination). 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 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, 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 these interactions being identified in plasma, such effects have not been observed during clinical use of the medicinal product and are not clinically significant.

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 there is no therapeutic response, treatment with the drug should be discontinued.

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 flu-like symptoms in patients receiving nimesulide, the drug should be discontinued.

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

Hepatic effects. During treatment with nimesulide, concomitant use of hepatotoxic drugs should be avoided, and alcohol consumption should be refrained from. Serious hepatic reactions, including fatal outcomes, have been reported during treatment with 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, must discontinue the drug. Re-administration of nimesulide to such patients is contraindicated. Liver injury, mostly 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 effective dose. For these patients, as well as for those concurrently taking low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risk, consideration should be given to concomitant use of 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, regardless of prior 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 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 receiving concomitant medications that increase the risk of ulceration or bleeding, such as corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents (e.g., acetylsalicylic acid), should be informed of the need for caution when using nimesulide.

If gastrointestinal bleeding or ulceration occurs in a patient receiving nimesulide, treatment should be discontinued.

Concomitant use of nimesulide with other drugs 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, or those who develop fluid retention and edema during NSAID treatment, require appropriate monitoring and physician consultation.

Clinical studies 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 are insufficient data to exclude such risk with nimesulide.

Nimesulide should be prescribed with caution after careful benefit-risk assessment in patients with uncontrolled 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 with caution in patients with hemorrhagic diathesis. However, nimesulide does not substitute for acetylsalicylic acid in the prevention of cardiovascular disease.

Renal effects. The drug should be used with caution in patients with impaired renal function or heart failure due to the risk of worsening renal function. If deterioration occurs, treatment should be discontinued.

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

Skin reactions. Rare cases of severe skin reactions, some of which may be fatal, have been reported with NSAIDs, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The risk of such reactions increases significantly if they occur within the first month of treatment. Nimesulide must 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. 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 attempting to conceive. Nimesulide is not recommended for women experiencing difficulty in conceiving or undergoing infertility investigations.

Important information about excipients. Nimesulide contains sucrose. Patients with known sugar intolerance should consult their physician before taking this medication.

This product is contraindicated in 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 fetal congenital heart defects and gastroschisis. 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.

In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and increased embryonic and fetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various fetal malformations, including cardiovascular defects, has been observed. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction may be advisable after several days of nimesulide exposure starting from the 20th gestational week. Treatment with nimesulide should be discontinued if these pregnancy or fetal abnormalities are detected.

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

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

cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
renal dysfunction, which may progress to renal failure with oliguria.

At the end of pregnancy, in both mother and fetus, 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.

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. There are reports of renal failure in newborns whose mothers used nimesulide near the end of pregnancy.

Breastfeeding. Since it is unknown whether nimesulide is excreted in 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

No studies on the effect of nimesulide on the ability to drive or operate machinery have been conducted. However, if patients experience headache, dizziness, vertigo, or somnolence during nimesulide treatment, they should refrain from driving or operating machinery.

Dosage and Administration

To minimize the potential for adverse effects, the lowest effective dose should be used for the shortest duration possible.

The medicinal product should be taken after food. The contents of the sachet should be poured into a glass, dissolved in water, and taken orally.

The maximum duration of treatment with Nimesulide is 15 days.

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

Elderly patients: Dose adjustment is not required.

Children aged 12 years and older: 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). However, severe renal impairment (creatinine clearance < 30 mL/min) is a contraindication for the use of Nimesulide.

Patients with hepatic impairment: The use of Nimesulide is contraindicated in patients with hepatic impairment.

Children: Nimesulide is contraindicated in children under 12 years of age.

Overdose: Symptoms of acute 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 with therapeutic doses of NSAIDs as well as in cases of NSAID 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 if a large dose has been ingested within the past 4 hours, vomiting may be induced and/or activated charcoal (60–100 g for adults) and an osmotic laxative may be administered. 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.

Adverse Reactions

All adverse reactions are listed by organ systems and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from 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 bleeding, ulceration and perforation of the duodenum or stomach; 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.

Cardiovascular disorders: uncommon — arterial hypertension; rare — tachycardia, 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: uncommon — 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.

Investigations: common — increased liver enzymes.

The most commonly observed adverse reactions during NSAID use are gastrointestinal disorders. Peptic ulcers, gastrointestinal perforation or bleeding, sometimes fatal, may occur, particularly in elderly patients (see section "Special Warnings and Precautions for Use"). After administration of medicinal products containing nimesulide, 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 Warnings and Precautions for Use"). Gastritis has been reported less frequently. Cases of edema, arterial hypertension, and heart failure have been reported in association with NSAID therapy. Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely.

Clinical and epidemiological studies suggest that certain NSAIDs, particularly at high doses and with prolonged use, may increase the risk of arterial thrombotic events, such as myocardial infarction or stroke.

Reporting suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report any suspected adverse reactions and/or lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at: 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. 2 g granules in sachets; 30 sachets per box.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of operations. 13 Boryspylska Street, Kyiv, 02093, Ukraine.