Nimesil
Ukraine
Table of Contents
- INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIMESIL®
- Composition:
- Pharmacological properties.
- Clinical characteristics.
- Special precautions for use.
- Method of Administration and Dosage.
- Adverse reactions.
- Composition:
- Pharmacological properties.
- Clinical characteristics.
- Special precautions for use.
- Method of Administration and Dosage.
- Adverse reactions.
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIMESIL®
Composition:
Active ingredient: nimesulide;
1 single-dose packet of 2 g granules contains nimesulide 100 mg;
Excipients: macrogol cetylstearyl ether, sucrose, maltodextrin, citric acid anhydrous, orange flavoring.
Pharmaceutical form. Granules for oral suspension.
Main physicochemical properties: light yellow granular powder with an orange odor; after partial dissolution, the solution color is white or light yellow.
Pharmacotherapeutic group.
Nonselective 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 responsible for prostaglandin synthesis.
Pharmacokinetics.
Absorption. Nimesulide is well absorbed after oral administration. Following 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 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. Up to 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 interaction"). The main metabolite is the para-hydroxy derivative, which is also pharmacologically active. The time to detection of this metabolite in systemic circulation is short (approximately 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 the bound form. The elimination half-life ranges from 3.2 to 6 hours.
Nimesulide is primarily excreted in urine (approximately 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is excreted exclusively as a glucuronide conjugate. Approximately 29% of the administered dose is excreted in feces in metabolized form. The pharmacokinetic profile of nimesulide in elderly patients is not altered following 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 always 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.
Preclinical data obtained from standard pharmacological safety, repeat-dose toxicity, genotoxicity, and carcinogenicity studies revealed no special hazard for humans. In repeat-dose toxicity studies, nimesulide showed gastrointestinal, renal, and hepatic toxicity. In reproductive toxicity studies, when administered to pregnant females 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.
Treatment of acute pain, primary dysmenorrhea.
Nimesulide should be used only as a second-line agent.
The decision to prescribe nimesulide should be made 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) 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.
Alcoholism and drug addiction.
History of gastrointestinal bleeding or perforation related to previous use of NSAIDs.
Peptic ulcer in the active phase or history of gastrointestinal bleeding, ulcers, or perforations.
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 hemorrhagic 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 combination 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 compromised renal function), concomitant use of ACE inhibitors and cyclooxygenase inhibitors may lead to further deterioration of renal function, including 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 in 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 glipizide, theophylline, warfarin, digoxin, cimetidine, and antacids (specifically aluminum and magnesium hydroxide combination) have also been studied 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 used concomitantly with Nimesil®.
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 methotrexate serum levels and enhanced toxicity.
Due to their effect on renal prostaglandins, cyclooxygenase 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 "Dosage and 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 Nimesil® should be advised to refrain from using other analgesics.
Nimesil® contains sucrose. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medication.
During treatment with nimesulide, concomitant use of hepatotoxic drugs should be avoided, and alcohol consumption should be refrained from. The use of NSAIDs may mask fever associated with underlying bacterial infection.
Hepatic effects.
Serious liver reactions, including very rare cases with fatal outcomes, 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 who have abnormal liver function test results, should discontinue therapy. Re-administration of nimesulide to such patients is contraindicated. 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 has been reported with NSAIDs, with or without warning symptoms or a history of serious gastrointestinal events, and may be fatal. Such events can occur at any time during therapy. 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 possible dose. For these patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal 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 during the initial stages of treatment.
Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, with or without preceding symptoms or a 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 their medical 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, or antiplatelet agents such as acetylsalicylic acid, should be informed of 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, or antiplatelet agents, may trigger exacerbation of Crohn’s disease and other gastrointestinal disorders.
Effects on the cardiovascular and cerebrovascular systems.
Patients with a history of mild to moderate arterial hypertension and/or congestive heart failure require appropriate monitoring and medical consultation, as fluid retention and edema have been reported with NSAID therapy.
Clinical trials and epidemiological data suggest that the use of certain 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. There are insufficient data to exclude such risk with nimesulide.
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 risk factors for cardiovascular disease, 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, Nimesil® cannot replace acetylsalicylic acid for the prevention of cardiovascular disease.
Renal effects.
Caution is required in patients with impaired renal function or heart failure, as nimesulide use may lead to worsening renal function. If deterioration occurs, treatment should be discontinued (see also section "Interaction with other medicinal products and other forms of interaction").
Elderly patients.
Elderly patients may have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, sometimes fatal (see section "Adverse reactions"), as well as impaired renal, cardiac, and hepatic function. Therefore, appropriate clinical monitoring is recommended.
Skin reactions.
Very rare serious skin reactions, some of which are life-threatening, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAIDs (see section "Adverse reactions"). These reactions appear to occur most frequently early in the course of therapy, typically within the first month of treatment. 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. Re-administration of nimesulide is contraindicated in patients with a history of nimesulide-associated FDE (see section "Adverse reactions").
Effects on fertility.
The use of Nimesil® may impair female fertility and is not recommended for women attempting to conceive. Women experiencing difficulty conceiving or undergoing infertility investigations should consider discontinuing Nimesil® (see section "Use during pregnancy or breastfeeding").
Use during pregnancy or breastfeeding.
Pregnancy.
The 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. 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 caused increased pre- and post-implantation loss and elevated embryonic and fetal mortality. In addition, increased incidence of various fetal abnormalities, including cardiovascular defects, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.
Use of nimesulide from the 20th week of gestation may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting 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 stopping treatment. Therefore, nimesulide should not be used during the first and second trimesters unless absolutely necessary. If nimesulide is used in women attempting to conceive or during the first and second trimesters, the lowest possible dose and shortest possible duration of treatment should be prescribed.
Prenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered if nimesulide is used for several days starting from the 20th week of gestation. Pregnant women should discontinue nimesulide if oligohydramnios or ductus arteriosus constriction is detected.
During the third trimester, all prostaglandin synthesis inhibitors may cause 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, anti-aggregatory 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 non-clinical 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 difficulty conceiving or undergoing infertility investigations should discontinue nimesulide.
If pregnancy is confirmed during nimesulide treatment, the physician should be informed.
Ability to affect driving and use of machines.
Studies on the effect of nimesulide-containing medicinal products on the ability to drive or operate machinery have not been conducted. However, patients who experience dizziness, vertigo, or somnolence after taking nimesulide should refrain from driving or operating machinery.
Method of Administration and Dosage.
Dosage.
To reduce the frequency of adverse reactions, the lowest effective dose should be used for the shortest duration possible (see section "Special Instructions"). 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. Based on pharmacokinetics, dose adjustment is not necessary for patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). However, in patients with severe renal impairment (creatinine clearance < 30 mL/min), the medicinal product Nimesil® is contraindicated (see sections "Contraindications" and "Pharmacokinetics").
Hepatic impairment. Administration of the medicinal product Nimesil® is contraindicated in patients with hepatic impairment (see section "Pharmacokinetics"). Adverse reactions can be minimized by using the drug for the shortest duration necessary to control symptoms (see section "Special Instructions").
Method of Administration.
The contents of the sachet should be poured into a glass of still water. Stir with a spoon until a suspension with an orange odor is formed. The suspension should be taken immediately after mixing.
Children.
The medicinal product Nimesil® is contraindicated in children under 12 years of age.
Overdose.
Symptoms of acute nonsteroidal anti-inflammatory drug (NSAID) overdose are usually limited to apathy, 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 during therapeutic use of NSAIDs and may also occur in cases of overdose. In the event of NSAID overdose, patients should receive symptomatic and supportive treatment. There are no specific antidotes. There is no information regarding the elimination of nimesulide by hemodialysis; however, considering its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. If symptoms occur or after a 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.
Adverse reactions.
The adverse reactions listed below are based on data from controlled clinical trials* (approximately 7800 patients) and post-marketing surveillance, classified according to the following frequency categories: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10,000 – < 1/1000); very rare (< 1/10,000), including isolated cases, and frequency not known (cannot be estimated from available data).
| Disorders of the blood and lymphatic system |
Uncommon |
Anaemia*, eosinophilia* |
| Very rare |
Thrombocytopenia, pancytopenia, purpura |
|
| Immune system disorders |
Uncommon |
Increased sensitivity* |
| Very rare |
Anaphylaxis |
|
| Metabolism and nutrition disorders |
Uncommon |
Hyperkalaemia* |
| Psychiatric disorders |
Uncommon |
Feeling of fear*, nervousness*, night terrors* |
| Nervous system disorders |
Uncommon |
Dizziness* |
| Very rare |
Headache, somnolence, encephalopathy (Reye's syndrome) |
|
| Eye disorders |
Uncommon |
Blurred vision* |
| Very rare |
Visual disturbances |
|
| Ear and labyrinth disorders |
Very rare |
Vertigo (dizziness) |
| Cardiac disorders |
Uncommon |
Tachycardia* |
| Vascular disorders |
Uncommon |
Arterial hypertension* |
| Uncommon |
Hemorrhage*, blood pressure lability*, flushing* |
|
| Respiratory, thoracic and mediastinal disorders |
Uncommon |
Dyspnoea* |
| Very rare |
Asthma, bronchospasm |
|
| Gastrointestinal disorders |
Common |
Diarrhoea*, nausea*, vomiting* |
| Uncommon |
Constipation*, abdominal distension*, gastrointestinal haemorrhage, duodenal ulcer and perforation, gastric ulcer and perforation |
|
| Very rare |
Gastritis*, abdominal pain, dyspepsia, stomatitis, melaena |
|
| Hepatobiliary disorders (see section "Special warnings and precautions for use") |
Common |
Increased liver enzyme levels* |
| Very rare |
Hepatitis, fulminant hepatitis (including fatal cases), jaundice, cholestasis |
|
| Skin and subcutaneous tissue disorders |
Uncommon |
Pruritus*, rash*, increased sweating* |
| Uncommon |
Erythema*, dermatitis* |
|
| Very rare |
Urticaria, angioneurotic oedema, facial swelling, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis |
|
| Frequency not known |
Fixed drug eruption (see section "Special warnings and precautions for use") |
|
| Renal and urinary disorders |
Uncommon |
Dysuria*, haematuria* |
| Very rare |
Urinary retention*, renal failure, oliguria, interstitial nephritis |
|
| General disorders and administration site reactions |
Uncommon |
Oedema* |
| Uncommon |
Malaise*, asthenia* |
|
| Very rare |
Hypothermia |
|
| * Frequency determined from clinical trial data |
||
The most commonly observed adverse reactions are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation or bleeding, sometimes life-threatening, may occur, particularly in elderly patients (see section "Special precautions"). 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 precautions"). Gastritis has been observed less frequently. Cases of edema, arterial hypertension, and heart failure have been reported in association with NSAID therapy. Very rare cases of bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. Clinical and epidemiological studies suggest that the use of certain NSAIDs, particularly at high doses and over prolonged treatment periods, may result in a small increase in the risk of arterial thrombotic events, such as myocardial infarction or stroke (see section "Special precautions").
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.
Shelf life.
3 years. Do not use the medicinal product after the expiry date stated on the packaging.
Storage conditions.
No special storage conditions required. Keep the medicinal product out of the reach of children.
Packaging.
2 g per single-dose sachet; 9, 15, or 30 sachets in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Faine Foods and Pharmaceuticals N.T.M. S.P.A.
Manufacturer's address and place of business.
Via Grignano, 43 – 24041 Brembate (BG), Italy.
Marketing Authorization Holder.
Laboratori GIDOTTO S.p.A.
Address of Marketing Authorization Holder.
Via Livornese, 897, 56122 La Vettola (Pisa), Italy.
INSTRUCTIONS
for medical use of the medicinal product
NIMESIL®
(NIMESIL®)
Composition:
Active ingredient: nimesulide;
1 single-dose packet of 2 g granules contains 100 mg of nimesulide;
Excipients: macrogol cetostearyl ether, sucrose, maltodextrin, citric acid anhydrous, orange flavoring.
Pharmaceutical form. Granules for oral suspension.
Main physicochemical characteristics: light yellow granular powder with an orange odor; after partial dissolution, the solution is white or light yellow.
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 the synthesis of prostaglandins.
Pharmacokinetics.
Absorption. Nimesulide is well absorbed after oral administration. After a single 100 mg dose in adults, peak 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%.
Biotransformation and elimination. Nimesulide is actively metabolized in the liver via various pathways, including the cytochrome P450 isoenzyme CYP2C9. Therefore, there is a potential for drug interactions when used concomitantly with medicinal products metabolized by CYP2C9 (see section "Interaction with other medicinal products and other forms of interaction"). The main metabolite is the para-hydroxy derivative, which is also pharmacologically active. The time to appearance of 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 bound form. The elimination half-life ranges from 3.2 to 6 hours.
Nimesulide is primarily excreted in urine (approximately 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide is the main metabolite found exclusively as a glucuronide conjugate. Approximately 29% of the administered dose is excreted in feces in metabolized form. The pharmacokinetic profile of nimesulide in elderly patients is not altered after single or repeated doses.
In a short-term clinical study involving 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 up to 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.
Preclinical data obtained from standard safety pharmacology, repeated-dose toxicity, genotoxicity, and carcinogenicity studies revealed no special hazard for humans. In repeated-dose toxicity studies, nimesulide showed gastrointestinal, renal, and hepatic toxicity. In reproductive toxicity studies, embryotoxic and teratogenic effects (skeletal malformations, brain ventricle dilation) were observed in rabbits but not in rats when administered to pregnant females at non-toxic doses. In rats, increased neonatal mortality and adverse effects on fertility were observed.
Clinical characteristics.
Indications.
Treatment of acute pain, primary dysmenorrhea.
Nimesulide should only be used as a second-line agent.
The decision to prescribe nimesulide should 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) 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.
Alcoholism and drug addiction.
History of gastrointestinal bleeding or perforation related to previous use of NSAIDs.
Peptic ulcer in the active phase or history of gastrointestinal bleeding, ulcer, 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 (AII antagonists). NSAIDs may attenuate the effects of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients 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 AII antagonists. Therefore, this combination should be prescribed with caution, especially in elderly patients. Patients should receive adequate hydration. The need for monitoring renal function after initiation of concomitant therapy and periodically after its discontinuation should be evaluated.
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 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 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 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 antacid preparations (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 used concomitantly with Nimesil®.
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 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 "Dosage and administration" and the risks related to gastrointestinal and cardiovascular systems 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 Nimesil® should be advised to refrain from using other analgesics.
Nimesil® contains sucrose. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medication.
During treatment with nimesulide, concomitant use of hepatotoxic drugs should be avoided, and alcohol consumption should be refrained from. Use of NSAIDs may mask fever associated with underlying bacterial infection.
Hepatic effects.
Serious liver reactions, including very rare cases with fatal outcomes, 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, or dark urine, or those with abnormal liver function test results, should discontinue therapy. Re-administration of nimesulide is not recommended in such patients. Liver injury, mostly reversible, has been reported after short-term exposure to the drug.
Patients receiving nimesulide who develop fever and/or flu-like symptoms should discontinue treatment.
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 therapy. 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 possible dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal 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 during the initial stages of treatment.
Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, with or without preceding 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 their 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, or antiplatelet agents such as acetylsalicylic acid, should be informed of the need for caution.
If gastrointestinal bleeding or ulceration occurs in patients receiving nimesulide, treatment should be discontinued.
NSAIDs should be prescribed with caution to patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated (see section "Adverse reactions").
Concomitant use of nimesulide with other medicinal products, such as oral contraceptives, anticoagulants, or antiplatelet agents, may trigger exacerbation of Crohn’s disease and other gastrointestinal disorders.
Effects on the cardiovascular and cerebrovascular systems.
Patients with a history of mild to moderate arterial hypertension and/or congestive heart failure require appropriate monitoring and medical consultation, as fluid retention and edema have been reported with NSAID therapy.
Clinical studies and epidemiological data suggest that use of certain 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. There is insufficient data to exclude such risk with nimesulide.
Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with nimesulide only after careful assessment. A similar assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular disease, 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, Nimesil® cannot replace acetylsalicylic acid for the prevention of cardiovascular disease.
Effects on the kidneys.
Caution is required in patients with impaired renal function or heart failure, 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, in some cases even fatal (see section "Adverse reactions"), as well as impairment of renal, cardiac, and hepatic function; therefore, appropriate clinical monitoring is recommended.
Skin reactions.
Very rare serious skin reactions, some of which are life-threatening, 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 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-associated FDE (see section "Adverse reactions").
Effects on fertility.
Use of Nimesil® may impair female fertility and is not recommended for women attempting to conceive. Women experiencing difficulty conceiving or undergoing infertility investigations should consider discontinuation of Nimesil® (see section "Use during pregnancy or breastfeeding").
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. 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 therapy.
In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and elevated embryonic and fetal mortality. Furthermore, increased incidence of various fetal abnormalities, including cardiovascular malformations, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.
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 arterial duct constriction have been reported after second-trimester use, most of which resolved after treatment cessation. Therefore, nimesulide should not be used during the first and second trimesters unless absolutely necessary. If nimesulide is used in women attempting to conceive or during the first or second trimester, the lowest possible dose and shortest duration of treatment should be prescribed.
Prenatal monitoring for oligohydramnios and fetal arterial duct 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 fetal arterial duct constriction is detected.
During the third trimester, all prostaglandin synthesis inhibitors may cause the following in the fetus:
- cardiopulmonary toxicity (premature constriction/closure 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, anti-aggregatory 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.
As with other NSAIDs, medicinal products containing nimesulide are not recommended for women attempting to conceive (see section "Special precautions for use"). Women experiencing difficulty conceiving or undergoing infertility evaluation should discontinue nimesulide.
If pregnancy occurs during nimesulide use, the physician should be informed.
Ability to affect reaction speed when driving or 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.
Dosage.
To reduce the frequency of adverse reactions, the lowest effective dose for the shortest duration possible should be used (see section "Special Warnings and Precautions for Use"). 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 dose adjustment (see section "Pharmacokinetics").
Children. Medicinal products containing nimesulide are contraindicated in children under 12 years of age (see also section "Contraindications"). Based on the pharmacokinetic profile in adults and the pharmacodynamic characteristics of nimesulide, dose adjustment is not required for adolescents aged 12 to 18 years.
Renal impairment. Due to the pharmacokinetic profile, dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). However, the medicinal product Nimesil® is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Contraindications" and "Pharmacokinetics").
Hepatic impairment. Nimesil® 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 Warnings and Precautions for Use").
Method of Administration.
The contents of the sachet should be poured into a glass of non-carbonated water. Stir with a spoon until a suspension with an orange odor is obtained. The suspension should be taken immediately after mixing.
Children.
Nimesil® 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, which are generally reversible with supportive treatment. 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, considering its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. If symptoms occur or after a 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.
Adverse reactions.
The adverse reactions listed below are based on data from controlled clinical trials* (approximately 7800 patients) and post-marketing surveillance, classified according to the following frequency categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000), including rare cases, and frequency not known (cannot be estimated from the available data).
| Disorders of blood and lymphatic system |
Uncommon |
Anaemia*, eosinophilia* |
| Very rare |
Thrombocytopenia, pancytopenia, purpura |
|
| Immune system disorders |
Uncommon |
Increased sensitivity* |
| Very rare |
Anaphylaxis |
|
| Metabolism and nutrition disorders |
Uncommon |
Hyperkalaemia* |
| Psychiatric disorders |
Uncommon |
Feeling of fear*, nervousness*, night terrors* |
| Nervous system disorders |
Uncommon |
Dizziness* |
| Very rare |
Headache, somnolence, encephalopathy (Reye's syndrome) |
|
| Eye disorders |
Uncommon |
Blurred vision* |
| Very rare |
Visual disturbances |
|
| Ear and labyrinth disorders |
Very rare |
Vertigo (dizziness) |
| Cardiac disorders |
Uncommon |
Tachycardia* |
| Vascular disorders |
Uncommon |
Arterial hypertension* |
| Uncommon |
Hemorrhage*, blood pressure lability*, flushing* |
|
| Respiratory, thoracic and mediastinal disorders |
Uncommon |
Dyspnoea* |
| Very rare |
Asthma, bronchospasm |
|
| Gastrointestinal disorders |
Common |
Diarrhoea*, nausea*, vomiting* |
| Uncommon |
Constipation*, abdominal distension*, gastrointestinal haemorrhage, ulceration and perforation of the duodenum, ulceration and perforation of the stomach |
|
| Very rare |
Gastritis*, abdominal pain, dyspepsia, stomatitis, melaena |
|
| 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 |
Pruritus*, rash*, increased sweating* |
| Uncommon |
Erythema*, dermatitis* |
|
| Very rare |
Urticaria, angioneurotic oedema, facial swelling, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis |
|
| Frequency not known |
Fixed drug eruption (see section "Special precautions") |
|
| Renal and urinary disorders |
Uncommon |
Dysuria*, haematuria* |
| Very rare |
Urinary retention*, renal failure, oliguria, interstitial nephritis |
|
| General disorders and administration site conditions |
Uncommon |
Oedema* |
| Uncommon |
Malaise*, asthenia* |
|
| Very rare |
Hypothermia |
|
| * Frequency is based on clinical trial data |
||
The most commonly observed adverse reactions are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation or bleeding, sometimes life-threatening, may occur, particularly in elderly patients (see section "Special precautions for use"). Nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbation of colitis and Crohn's disease have been reported following treatment with medicinal products containing nimesulide (see section "Special precautions for use"). Gastritis has been observed less frequently. Cases of edema, arterial hypertension, and heart failure have been reported in association with NSAID therapy. Very rare cases of bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported.
Reporting of 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 are required to report any suspected adverse reactions.
Shelf life.
3 years. Do not use the medicinal product after the expiry date stated on the packaging.
Storage conditions.
No special storage conditions required. Keep the medicinal product out of the reach and sight of children.
Packaging.
2 g per single-dose sachet; 9, 15, or 30 sachets in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Laboratorios Menarini S.A.
Manufacturer's address.
Alfonso XII, 587, Badalona, Barcelona, 08918, Spain.
Marketing authorization holder.
Laboratori Guidotti S.p.A.
Address of marketing authorization holder.
Via Livornese, 897, 56122 La Vetta (Pisa), Italy.