Nimesulide

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

Composition:

Active substance: nimesulide;

1 sachet (2 g) contains nimesulide 100 mg;

Excipients: polyethylene glycol (macrogol) cetostearyl ether, sucrose, glucose, corn starch, anhydrous citric acid (E 330), lemon flavoring.

Pharmaceutical form. Granular powder for oral suspension.

Main physicochemical properties: granular powder from almost white to light yellow in color with a citrus aroma; yellow specks may be present. After partial dissolution, the suspension is white or light yellow in color.

Pharmacotherapeutic group.

Non-selective non-steroidal anti-inflammatory drugs (NSAIDs).

ATC code M01AX17.

Pharmacological properties.

Pharmacodynamics.

Nimesulide is a non-steroidal anti-inflammatory agent with analgesic and antipyretic properties, acting as an inhibitor of the enzyme cyclooxygenase, which is responsible for prostaglandin synthesis.

Pharmacokinetics.

Absorption. Nimesulide is well absorbed after oral administration. Following a single 100 mg dose of nimesulide 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. Approximately 97.5% of nimesulide is bound to plasma proteins.

Biotransformation and elimination. Nimesulide is actively metabolized in the liver via multiple pathways, including the cytochrome P450 isoenzyme CYP2C9. Therefore, there is a potential risk of drug interactions when nimesulide is used concomitantly with medicinal products metabolized by CYP2C9 (see section "Interaction with other medicinal products and other forms of interactions"). The main metabolite is para-hydroxy derivative, which is also pharmacologically active. The time to detection of this metabolite in systemic circulation is short (about 0.8 hours), but the rate constant of its formation is low and significantly less than the absorption coefficient of nimesulide. Hydroxynimesulide is the only metabolite detected in plasma and is almost entirely present in conjugated form. The elimination half-life ranges from 3.2 to 6 hours.

Nimesulide is primarily excreted via the urine (about 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is exclusively excreted as glucuronide conjugate. Approximately 29% of the administered dose is excreted in the feces in metabolized form. The pharmacokinetic profile of nimesulide in elderly patients is not altered after single or repeated administration.

In a short-term experimental study conducted in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min) and healthy volunteers, the maximum plasma concentrations of nimesulide and its main metabolite in patients were not higher than those in healthy volunteers. AUC and elimination half-life in patients with renal impairment were approximately 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").

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.

Known hypersensitivity to nimesulide, to any other NSAID, or to any of the excipients of the medicinal product.

History of hypersensitivity reactions (e.g. bronchospasm, rhinitis, urticaria, nasal polyps) 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 dependence.

History of gastrointestinal bleeding or perforation related to previous use of NSAIDs.

Peptic ulcer in the active phase or history of gastrointestinal bleeding, ulceration, or perforation.

Cerebrovascular hemorrhage or other bleeding disorders, as well as diseases associated with bleeding tendencies.

Severe coagulation disorders.

Severe heart failure.

Severe renal impairment.

Hepatic dysfunction.

Fever and/or flu-like symptoms.

Children under 12 years of age.

Third trimester of pregnancy and breastfeeding period (see section "Use during pregnancy or breastfeeding" and preclinical safety data).

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Corticosteroids. Corticosteroids may increase the risk of gastrointestinal ulceration or bleeding (see section "Special precautions for use").

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs) increase the risk of gastrointestinal ulceration or bleeding (see section "Special precautions for use").

Anticoagulants. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special precautions for use"). In patients treated with nimesulide who are also taking warfarin or similar anticoagulants or acetylsalicylic acid, there is an increased risk of bleeding complications; therefore, such combination is not recommended (see also section "Special precautions for use") and is contraindicated in patients with severe coagulation disorders (see also section "Contraindications"). If combined therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (ARBs). NSAIDs may attenuate the effect of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of ACE inhibitors and cyclooxygenase inhibitors may lead to further deterioration of renal function, including the development of acute renal failure, which is usually reversible. Such interactions should be considered in patients receiving medicinal products containing nimesulide together with ACE inhibitors or ARBs. Therefore, this combination should be prescribed with caution, especially in elderly patients. Patients should receive adequate hydration. Renal function should be monitored after initiation of concomitant therapy and periodically after its discontinuation.

Other nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant use of medicinal products containing nimesulide (see section "Clinical characteristics") with other NSAIDs, including acetylsalicylic acid at anti-inflammatory doses (≥ 1 g as a single dose or ≥ 3 g per day), is not recommended.

Pharmacokinetic interactions: effect of nimesulide on the pharmacokinetics of other medicinal products.

Furosemide. In healthy volunteers, nimesulide transiently reduces furosemide-induced sodium excretion and, to a lesser extent, potassium excretion, and decreases the diuretic effect. Concomitant administration of nimesulide and furosemide results in a reduction (by approximately 20%) in the area under the plasma concentration-time curve (AUC) and cumulative excretion of furosemide, without changes in its renal clearance. Concomitant use of furosemide and medicinal products containing nimesulide in patients with impaired renal or cardiac function requires caution (see section "Special precautions for use").

Lithium. There have been reports that NSAIDs reduce lithium clearance, leading to increased plasma lithium levels and lithium toxicity. When nimesulide is prescribed to a patient receiving lithium therapy, plasma lithium levels should be closely monitored.

Pharmacokinetic interactions: effect of other medicinal products on the pharmacokinetics of nimesulide.

In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid, and valproic acid. However, despite a possible effect on its plasma concentration, such interactions have no clinical significance.

Other interactions.

Pharmacokinetic interactions with glyburide (glibenclamide), theophylline, warfarin, digoxin, cimetidine, and antacids (specifically, aluminum and magnesium hydroxide combination) have also been investigated in vivo. No clinically significant interactions were observed.

Nimesulide inhibits the activity of the CYP2C9 enzyme. Plasma concentrations of medicinal products that are substrates of this enzyme may increase when nimesulide is administered concomitantly.

Caution is required when nimesulide must be 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 its effect on renal prostaglandins, prostaglandin synthase inhibitors such as nimesulide may increase the nephrotoxicity of cyclosporine.

Special precautions for use.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Posology and method of administration" and the risks related to the gastrointestinal tract and cardiovascular system below).

If no therapeutic effect is observed, treatment should be discontinued.

Concomitant use of nimesulide with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided. Patients receiving nimesulide should be advised to refrain from using other analgesics.

During treatment with nimesulide, concomitant use of hepatotoxic drugs should be avoided and alcohol consumption should be refrained from. NSAIDs may mask fever associated with underlying bacterial infection.

Hepatic effects.

Serious hepatic reactions, including very rare fatal cases, have been reported with nimesulide (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury during treatment with nimesulide, such as anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine, or those with abnormal liver function test results, should discontinue therapy. Nimesulide should not be re-administered to such patients. Liver injury, mostly reversible, has been reported after short-term exposure to the drug.

Patients taking nimesulide who develop fever and/or flu-like symptoms should discontinue treatment.

Gastrointestinal effects.

Gastrointestinal bleeding or ulceration/perforation (with or without warning symptoms or history of serious gastrointestinal events) have been reported with all NSAIDs, which may be fatal and 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. Such patients should be initiated on the lowest possible dose. For these patients, as well as for those requiring concomitant use of 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 (see below and section "Interaction with other medicinal products and other forms of interaction").

Patients with a history of gastrointestinal toxicity, particularly elderly patients, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly in the initial stages of treatment.

Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, with or without warning symptoms or 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 (see section "Adverse reactions").

Patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants like warfarin, selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents such as acetylsalicylic acid, should be informed about the need for caution.

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

NSAIDs should be used with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease), as exacerbation is possible (see section "Adverse reactions").

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

Cardiovascular and cerebrovascular effects.

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and physician consultation, as fluid retention and edema have been reported with NSAID therapy.

Clinical trials and epidemiological data suggest that use of some NSAIDs, particularly at high doses and during long-term treatment, may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction or stroke. Data to exclude such risk with nimesulide are insufficient.

Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with nimesulide after careful assessment. A similar assessment should be performed before initiating long-term treatment in patients with cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, or smoking.

Since nimesulide may affect platelet function, it should be used with caution in patients with hemorrhagic diathesis (see also section "Contraindications"). However, nimesulide cannot replace acetylsalicylic acid in the prevention of cardiovascular diseases.

Renal effects.

Patients with impaired renal function or heart failure should be treated with caution, as nimesulide use may lead to worsening of renal function. If deterioration occurs, treatment should be discontinued (see also section "Interaction with other medicinal products and other forms of interaction").

Elderly patients.

In elderly patients, the frequency of adverse reactions to NSAIDs may be increased, particularly gastrointestinal bleeding and perforation, sometimes fatal (see section "Adverse reactions"), as well as impairment of renal, cardiac, and hepatic function; therefore, appropriate clinical monitoring is recommended.

Skin reactions.

Very rarely, serious skin reactions, some of which are potentially fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAIDs (see section "Adverse reactions"). It appears that patients are at greatest risk of such reactions early in the course of treatment, with most cases occurring within the first month of therapy. Nimesulide should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Cases of fixed drug eruption (FDE) have been reported with nimesulide. Nimesulide should not be re-administered to patients with a history of nimesulide-related FDE (see section "Adverse reactions").

Nimesulide contains sucrose. If a patient has known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy.

Use of nimesulide is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest that use of prostaglandin synthesis inhibitors during early pregnancy may increase the risk of miscarriage 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.

In animal studies, prostaglandin synthesis inhibitors caused 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 fetal malformations, including cardiovascular, has been reported.

Use of nimesulide from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal ductus arteriosus constriction have been reported after second-trimester use, most of which resolved after discontinuation of treatment. Therefore, nimesulide should not be used during the first and second trimesters of pregnancy unless strictly necessary. If nimesulide 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 prescribed.

Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered if nimesulide is used for several days starting from the 20th gestational week. Pregnant women should discontinue nimesulide if oligohydramnios or ductus arteriosus constriction is detected.

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

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

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

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

Breastfeeding.

It is unknown whether nimesulide passes into human breast milk. Nimesulide is contraindicated during breastfeeding (see section "Contraindications" and preclinical safety data).

Fertility.

Like other NSAIDs, nimesulide-containing medicinal products are not recommended for women attempting to conceive (see section "Special precautions for use"). Women experiencing difficulties in becoming pregnant or undergoing fertility investigations should discontinue nimesulide.

If pregnancy is confirmed during nimesulide treatment, the physician should be informed.

Ability to influence driving and operating machinery.

Studies on the effect of nimesulide-containing medicinal products on the ability to drive or operate machinery have not been conducted. However, patients experiencing dizziness, vertigo, or somnolence after taking nimesulide should refrain from driving or operating machinery.

Method of Administration and Dosage.

Dosing.

To reduce the frequency of adverse reactions, the minimum effective dose should be used for the shortest duration possible (see section "Special Precautions"). The maximum duration of treatment with nimesulide is 15 days.

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

Elderly patients. Elderly patients do not require a reduction in daily dose (see section "Pharmacokinetics").

Children. Medicinal products containing nimesulide are contraindicated in children under 12 years of age (see also section "Contraindications"). Considering the pharmacokinetic profile in adults and the pharmacodynamic characteristics of nimesulide, dose adjustment is not required for children aged 12 to 18 years.

Renal impairment. Given the pharmacokinetic profile, dose adjustment is not necessary in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). However, nimesulide is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Contraindications" and "Pharmacokinetics").

Hepatic impairment. The use of nimesulide is contraindicated in patients with hepatic dysfunction (see section "Pharmacokinetics"). Adverse reactions can be minimized by using the drug for the shortest duration necessary to control symptoms (see section "Special Precautions").

Method of administration.

The contents of the sachet should be poured into a glass of still water and stirred with a spoon until a suspension is formed. The suspension should be consumed immediately after mixing.

Children.

Nimesulide is contraindicated in children under 12 years of age.

Overdose.

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive therapy. Gastrointestinal bleeding may occur. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma may develop. Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs and may also occur in overdose. In case of NSAID overdose, symptomatic and supportive treatment should be provided. There are no specific antidotes. There is no information regarding the elimination of nimesulide by hemodialysis; however, due to its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. If symptoms occur or in cases of significant overdose 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, urine alkalinization, hemodialysis, or hemoperfusion may be ineffective due to high protein binding. Renal and hepatic functions should be monitored.

Side effects

The adverse reactions listed below are based on data from controlled clinical trials* (approximately 7,800 patients) and post-marketing surveillance, classified according to the following frequency categories: 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), including isolated cases, and frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Rare
Anemia*, eosinophilia*.

Very rare
Thrombocytopenia, pancytopenia, purpura.

Immune system disorders

Rare
Hypersensitivity*.

Very rare
Anaphylaxis.

Metabolism and nutrition disorders

Rare
Hyperkalemia*.

Psychiatric disorders

Rare
Fear*, nervousness*, night terrors*.

Nervous system disorders

Uncommon
Dizziness*.

Very rare
Headache, somnolence, encephalopathy (Reye's syndrome).

Eye disorders

Rare
Blurred vision*.

Very rare
Visual disturbances.

Ear and labyrinth disorders

Very rare
Vertigo (dizziness).

Cardiac disorders

Rare
Tachycardia*.

Vascular disorders

Uncommon
Arterial hypertension*.

Rare
Hemorrhage*, blood pressure lability*, flushing*.

Respiratory, thoracic and mediastinal disorders

Uncommon
Dyspnea*.

Very rare
Asthma, bronchospasm.

Gastrointestinal disorders

Common
Diarrhea*, nausea*, vomiting*.

Uncommon
Constipation*, abdominal distension*, gastrointestinal bleeding, duodenal ulcer and perforation, gastric ulcer and perforation.

Very rare
Gastritis*, abdominal pain, dyspepsia, stomatitis, melena.

Hepatobiliary disorders (see section "Special precautions")

Common
Increased liver enzyme levels*.

Very rare
Hepatitis, fulminant hepatitis (including fatal cases), jaundice, cholestasis.

Skin and subcutaneous tissue disorders

Uncommon
Itching*, 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 precautions").

Renal and urinary disorders

Rare
Dysuria*, hematuria*.

Very rare
Urinary retention*, renal failure, oliguria, interstitial nephritis.

General disorders and administration site conditions

Uncommon
Edema*.

Rare
Malaise*, asthenia*.

Very rare
Hypothermia.

* Frequency determined from clinical trial results.

Gastrointestinal adverse reactions are the most commonly observed. Peptic ulcers, gastrointestinal perforation, or gastrointestinal bleeding, sometimes life-threatening, may occur, particularly in elderly patients (see section "Special precautions"). Following administration of medicinal products containing nimesulide, cases of 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 precautions"). Gastritis has been observed 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 the use of certain NSAIDs, particularly at high doses and for prolonged durations, may be associated with a small increase in the risk of arterial thrombotic events such as myocardial infarction or stroke (see section "Special precautions").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 3 years.

Do not use after the expiry date.

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 in sachets, 10 (1x10) sachets or 30 (1x30) sachets in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

PJSC "CHEMICAL PHARMACEUTICAL PLANT "CHERVONA ZIRKA"

Manufacturer's address and place of business.

1, Gordienkovska Street, Kharkiv, Kharkiv Oblast, 61010, Ukraine