Instructions Nimesil granules for oral suspension 100 mg single-dose package 2 g No. 30
Composition
active ingredient: nimesulide;
1 single-dose packet of 2 g of granules contains nimesulide 100 mg;
excipients: macrogol cetostearyl ester, sucrose, maltodextrin, anhydrous citric acid, orange flavoring.
Dosage form
Granules for oral suspension.
Main physicochemical properties: light yellow granular powder with an orange odor; after partial dissolution, the color of the solution is white or light yellow.
Pharmacotherapeutic group
Non-selective non-steroidal anti-inflammatory drugs (NSAIDs). ATC code M01A X17.
Pharmacological properties
Pharmacodynamics.
Nimesulide is a nonsteroidal anti-inflammatory drug with analgesic and antipyretic properties that acts as an inhibitor of the cyclooxygenase enzyme, which is responsible for the synthesis of prostaglandins.
Pharmacokinetics.
Absorption. Nimesulide is well absorbed after oral administration. After a single dose of 100 mg of nimesulide, in adults, the maximum plasma concentration is reached after 2-3 hours and is 3-4 mg/l. The area under the concentration-time curve (AUC) is 20-35 mg h/l. No statistically significant difference was observed between these indicators and those after taking 100 mg twice a day for 7 days. Up to 97.5% of nimesulide binds to plasma proteins.
Biotransformation and elimination. Nimesulide is actively metabolized in the liver by various pathways, including the cytochrome P450 isoenzyme CYP2C9. Therefore, there is a risk of drug interactions when used simultaneously with drugs metabolized by CYP2C9 (see section "Interaction with other medicinal products and other types of interactions"). The main metabolite is the parahydroxy derivative, which is also pharmacologically active. The time to detection of this metabolite in the circulating blood is short (about 0.8 hours), but the reaction constant for its formation is low and significantly less than the absorption coefficient of nimesulide. Hydroxynimesulide is the only metabolite detected in plasma and is almost completely in bound form. The half-life is from 3.2 to 6 hours.
Nimesulide is excreted mainly in the urine (about 50% of the dose taken). Only 1-3% is excreted unchanged. Hydroxynimesulide is the main metabolite, which is found exclusively in the form of glucuronate. About 29% of the dose taken is excreted in the feces in a metabolized form. The pharmacokinetic profile of nimesulide in elderly patients does not change after a single and repeated dose.
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 concentration of nimesulide and its main metabolite was not higher than that in healthy volunteers. The AUC and half-life in patients with renal impairment were 50% higher, but were always within the range of pharmacokinetic parameters observed in healthy volunteers taking nimesulide. Repeated administration did not lead to accumulation. Nimesulide is contraindicated in patients with impaired liver function (see section "Contraindications").
Preclinical safety data.
Preclinical data obtained in standard studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential revealed no special hazard for humans. In repeated dose toxicity studies, nimesulide showed gastrointestinal, renal and hepatic toxicity. In reproductive toxicity studies, when administered to females at doses that did not cause toxicity, embryotoxic and teratogenic effects (skeletal malformations, dilatation of the cerebral ventricles) were observed in rabbits, but not in rats. In rats, increased mortality of offspring in the early postnatal period and adverse reactions regarding fertility were observed.
Indication
Treatment of acute pain, primary dysmenorrhea.
Nimesulide should only be used as a second-line drug.
The decision to prescribe nimesulide should be made based on an assessment of all risks for the individual patient.
Contraindication
Known hypersensitivity to nimesulide, to any other NSAID or to any of the excipients of the medicinal product.
History of hyperergic reactions (e.g. bronchospasm, rhinitis, urticaria) associated with the use of acetylsalicylic acid or other non-steroidal 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 associated with previous use of NSAIDs.
Peptic ulcer in the acute phase or history of gastrointestinal bleeding, ulceration or perforation.
Cerebrovascular bleeding or other hemorrhages, as well as diseases accompanied by bleeding.
Severe blood clotting disorders.
Severe heart failure.
Liver dysfunction.
Fever and/or flu-like symptoms.
Children under 12 years old.
Third trimester of pregnancy and lactation (see section “Use during pregnancy or lactation” and preclinical safety data).
Interaction with other medicinal products and other types of interactions
Pharmacodynamic interactions.
Corticosteroids: Corticosteroids may increase the risk of gastrointestinal ulceration or bleeding (see section 4.4).
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 4.4).
Anticoagulants. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special instructions"). When treating nimesulide in patients taking warfarin or similar anticoagulants or acetylsalicylic acid, there is an increased risk of bleeding complications, therefore this combination is not recommended (see also section "Special instructions") 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 necessary.
Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II antagonists (AII). NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with reduced renal function (e.g. dehydrated patients or elderly patients with compromised renal function), the 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. The possibility of such interactions should be considered in patients who need to use nimesulide-containing medicinal products together with ACE inhibitors or AII. Therefore, such a combination of drugs should be prescribed with caution, especially in elderly patients. Patients should be adequately hydrated. The need for monitoring renal function after starting concomitant treatment and periodic monitoring after its discontinuation should be considered.
Other non-steroidal anti-inflammatory drugs (NSAIDs): The concomitant use of nimesulide-containing medicinal products (see section 4.1) 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: the effect of nimesulide on the pharmacokinetics of other drugs.
Furosemide. In healthy volunteers, nimesulide temporarily weakens the effect of furosemide on sodium excretion and, to a lesser extent, potassium excretion and reduces the diuretic effect. Simultaneous use of nimesulide and furosemide leads to a decrease (by approximately 20%) in the area under the concentration-time curve (AUC) and cumulative excretion of furosemide without changing its renal clearance. The combined use of furosemide and nimesulide-containing drugs in patients with impaired renal or cardiac function requires caution (see section "Special instructions").
Lithium: NSAIDs have been reported to 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 carefully monitored.
Pharmacokinetic interactions: the effect of other drugs on the pharmacokinetics of nimesulide.
In vitro studies have shown that nimesulide is displaced from its binding sites by tolbutamide, salicylic acid and valproic acid. However, despite the possible effect on its plasma concentration, such interactions are not clinically significant.
Other interactions.
Possible pharmacokinetic interactions with glibenclamide, theophylline, warfarin, digoxin, cimetidine and antacids (namely a combination of aluminium and magnesium hydroxide) have also been investigated in vivo. No clinically significant interactions were observed.
Nimesulide inhibits the activity of the CYP2C9 enzyme. Plasma concentrations of drugs that are substrates of this enzyme may increase with simultaneous use of Nimesil.
Caution should be exercised when nimesulide is used less than 24 hours before or less than 24 hours after taking methotrexate, as it may increase the serum level of the latter and increase its toxicity.
Due to their effects on renal prostaglandins, prostaglandin synthetase inhibitors such as nimesulide may increase the nephrotoxicity of cyclosporines.
Application features
Adverse reactions can be minimized by using the lowest effective dose for the shortest period of time necessary to control symptoms (see section “Method of administration and dosage” and on gastrointestinal and cardiovascular risks below).
Concomitant use of nimesulide with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided. During therapy with Nimesil, patients should be advised to refrain from using other analgesics.
Nimesil contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
During treatment with nimesulide, it is recommended to avoid the simultaneous use of hepatotoxic drugs and to refrain from drinking alcohol. The use of NSAIDs may mask fever associated with a background bacterial infection.
Effect on the liver
Serious hepatic reactions have been reported rarely with nimesulide, including very rare fatal cases (see also section "Adverse reactions"). Patients who develop symptoms suggestive of hepatic injury during nimesulide treatment, such as anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine, or patients whose liver function tests deviate from normal values, should discontinue therapy. Nimesulide should not be re-administered to such patients. Liver injury, most of which is 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.
Effects on the gastrointestinal tract
Gastrointestinal bleeding or ulceration/perforation (with or without warning symptoms or a history of serious gastrointestinal events), which can be fatal, has been reported with all NSAIDs. The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing NSAID doses, in patients with a history of ulcer, especially if complicated by bleeding or perforation (see section 4.3), and in the elderly. In such patients, treatment should be initiated at the lowest possible dose. For these patients, as well as for those requiring concomitant low-dose acetylsalicylic acid or other drugs that increase the risk of gastrointestinal complications, combination therapy with protective agents such as misoprostol or proton pump inhibitors should be considered (see below and section 4.5).
Patients with a history of toxic gastrointestinal lesions, especially elderly patients, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), especially in the initial stages of treatment.
Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment with or without warning 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 a history of peptic ulcer, gastrointestinal bleeding, ulcerative colitis or Crohn's disease (see section 4.8).
Patients taking concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid, should be advised to exercise caution.
If bleeding or ulcers of the digestive tract occur in patients receiving nimesulide, treatment should be discontinued.
NSAIDs should be prescribed with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease), as its exacerbation is possible (see section "Adverse reactions").
Concomitant use of nimesulide with other drugs, such as oral contraceptives, anticoagulants, antiplatelet agents, may cause exacerbation of Crohn's disease and other diseases of the digestive tract.
Effects on the cardiovascular and cerebrovascular systems
Patients with hypertension and/or a history of mild to moderate congestive heart failure require appropriate monitoring and medical advice, as fluid retention and edema have been reported with NSAID therapy.
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 carried out before starting long-term treatment in patients with risk factors for cardiovascular disease, such as hypertension, hyperlipidemia, diabetes mellitus, smoking.
Since nimesulide may affect platelet function, it should be used with caution in patients with hemorrhagic diathesis (see also section "Contraindications"). However, the drug Nimesil cannot replace acetylsalicylic acid in the prevention of cardiovascular diseases.
Effects on the kidneys
Caution should be exercised in patients with impaired renal function or heart failure, as the use of nimesulide may lead to deterioration of renal function. In case of deterioration, treatment should be discontinued (see also section "Interaction with other medicinal products and other forms of interaction").
Elderly patients
Elderly patients may be more likely to experience adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, in some cases fatal (see section 4.8), and to have impaired renal, cardiac and hepatic function, and appropriate clinical monitoring is recommended.
Skin reactions
Serious skin reactions, some of which have been fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at greatest risk of developing such reactions at the start of treatment, with most reactions occurring within the first month of therapy. Nimesulide should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign 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 FDE associated with nimesulide (see section 4.8).
Impact on fertility
The use of Nimesil may impair female fertility and is not recommended in women attempting to conceive. Women who have difficulty conceiving or who are undergoing investigation for infertility should consider discontinuing Nimesil (see section "Use during pregnancy or lactation").
Use during pregnancy or breastfeeding
Pregnancy.
The use of nimesulide is contraindicated in the third trimester of pregnancy (see section "Contraindications").
Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryo/foetal development. Epidemiological data suggest that use of prostaglandin synthesis inhibitors in early pregnancy may increase the risk of miscarriage and of fetal heart defects and gastroschisis. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk is believed to increase with increasing dose and duration of therapy.
In animals, the use of a prostaglandin synthesis inhibitor has resulted in increased pre- and post-implantation losses and increased embryo-fetal mortality. In addition, it has been reported that animals treated with a prostaglandin synthesis inhibitor during organogenesis have an increased incidence of various fetal malformations, including cardiovascular malformations.
The use of nimesulide from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after the start of treatment and is usually reversible after discontinuation of the drug. In addition, cases of narrowing of the ductus arteriosus in the fetus have been reported after administration of the drug in the second trimester of pregnancy, most of which resolved after discontinuation of treatment. Therefore, during the first and second trimesters of pregnancy, nimesulide should not be taken unless absolutely necessary. If nimesulide is used in women attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose and duration of treatment should be used.
Antenatal monitoring for oligohydramnios and ductus arteriosus in the fetus should be considered in case of exposure to nimesulide for several days, starting from the 20th week of gestation. Pregnant women should discontinue nimesulide if oligohydramnios or ductus arteriosus in the fetus is detected.
In the third trimester of pregnancy, all prostaglandin synthesis inhibitors may lead to the development of the following in the fetus:
pneumocardial toxic lesion (with premature closure of the ductus arteriosus and pulmonary hypertension);
renal dysfunction, which may progress to renal failure with the development of oligohydramnios.
In the mother at the end of pregnancy and the newborn, it is possible:
suppression of uterine contractile activity, leading to delayed or prolonged labor.
Breast-feeding
It is not known whether nimesulide is excreted in human milk. Nimesulide is contraindicated during breast-feeding (see section 4.3 and preclinical safety data).
Fertility
As with other NSAIDs, nimesulide-containing products are not recommended in women attempting to conceive (see section 4.4). Women who have difficulty conceiving or are undergoing investigation of infertility should discontinue nimesulide.
If pregnancy is established while using nimesulide, the doctor should be informed.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect of medicines containing nimesulide on the ability to drive or use machines have not been conducted, however, patients who experience dizziness, vertigo or drowsiness after taking nimesulide should refrain from driving or using machines.
Method of administration and doses
Dosage
In order to reduce the frequency of adverse reactions, the minimum effective dose should be used for the shortest possible time (see section "Special instructions for use"). The maximum duration of treatment with nimesulide is 15 days.
Adults: 1 sachet (100 mg nimesulide) 2 times a day after meals.
Elderly patients: Elderly patients do not require a reduction in the daily dose (see section "Pharmacokinetics").
Children: Nimesulide-containing medicinal products are contraindicated in children under 12 years of age (see also section 4.3). Given the pharmacokinetic profile in adults and the pharmacodynamic characteristics of nimesulide, no dose adjustment is required for children aged 12 to 18 years.
Renal impairment: Based on pharmacokinetics, no dose adjustment is required in patients with mild or moderate renal impairment (creatinine clearance 30–80 ml/min), while Nimesil is contraindicated in severe renal impairment (creatinine clearance < 30 ml/min) (see sections 4.3 and 4.4).
Hepatic impairment. Nimesil is contraindicated in patients with hepatic impairment (see section 5.2). Adverse reactions can be minimised by using the drug for the shortest period of time necessary to control symptoms (see section 4.4).
Method of application
Pour the contents of the sachet into a glass of still water. Stir with a spoon until a suspension with an orange scent is obtained. Drink the suspension immediately after mixing.
Children
The drug 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 usually reversible with supportive therapy. Gastrointestinal bleeding may occur. Rarely, arterial hypertension, acute renal failure, respiratory depression and coma may occur. Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs, which may occur with overdose. In case of NSAID overdose, patients should be provided with symptomatic and supportive treatment. There are no specific antidotes. There is no information on the removal of nimesulide by hemodialysis, but taking into account its high degree of binding to plasma proteins (up to 97.5%), dialysis is unlikely to be effective in overdose. If symptoms are present or after severe overdose within 4 hours of ingestion, patients may be given 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 the high degree of protein binding. Renal and hepatic function should be monitored.
Adverse reactions
The following adverse reactions are listed based on data from controlled clinical trials* (approximately 7800 patients) and post-marketing surveillance with the following frequency classification: very common (≥ 1/10); common (≥ 1/100 - < 1/10); uncommon (≥ 1/1000 - < 1/100); rare (≥ 1/10000 - < 1/1000); very rare (< 1/10000), including rare cases, frequency unknown (cannot be estimated from the available data).
Disorders of the circulatory and lymphatic systems
Rarely
Anemia*, eosinophilia*
Very rare
Thrombocytopenia, pancytopenia, purpura
Immune system disorders
Rarely
Increased sensitivity*
Very rare
Anaphylaxis
Metabolic and nutritional disorders
Rarely
Hyperkalemia*
Mental disorders
Rarely
Feelings of fear*, nervousness*, nightmares*
Nervous system disorders
Infrequently
Dizziness*
Very rare
Headache, drowsiness, encephalopathy (Reye's syndrome)
Vision disorders
Rarely
Blurred vision*
Very rare
Vision impairment
Hearing and labyrinth disorders
Very rare
Vertigo (dizziness)
Heart disorders
Rarely
Tachycardia*
Vascular disorders
Infrequently
Arterial hypertension*
Hemorrhage*, blood pressure lability*, hot flashes*
Respiratory, thoracic and mediastinal disorders
Infrequently
Dyspnea*
Very rare
Asthma, bronchospasm
Gastrointestinal disorders
Often
Diarrhea*, nausea*, vomiting*
Infrequently
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 warnings and precautions for use")
Often
Increased liver enzymes*
Very rare
Hepatitis, fulminant hepatitis (including fatal), jaundice, cholestasis
Skin and subcutaneous tissue disorders
Infrequently
Itching*, rash*, increased sweating*
Rarely
Erythema*, dermatitis*
Very rare
Urticaria, angioedema, facial edema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis
Frequency unknown
Fixed drug eruption (see section "Special instructions")
Kidney and urinary system disorders
Rarely
Dysuria*, hematuria*
Very rare
Urinary retention*, renal failure, oliguria, interstitial nephritis
General disorders and local reactions
Infrequently
Edema*
Rarely
Malaise*, asthenia*
Very rare
Hypothermia
* Frequency determined from clinical study results
The most common adverse reactions are from the digestive tract. Peptic ulcers, perforation or bleeding in the digestive tract, which are sometimes life-threatening, especially in elderly patients, may occur (see section "Special instructions"). Nausea, vomiting, diarrhea, bloating, constipation, dyspepsia, abdominal pain, melena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported after the use of nimesulide-containing medicines (see section "Special instructions"). Gastritis has been observed less frequently. There have been reports of edema, arterial hypertension and heart failure in connection with NSAID treatment. Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely. Clinical and epidemiological studies suggest that the use of some NSAIDs, especially at high doses and during long-term treatment, may lead to a small increased risk of arterial thrombotic complications, such as myocardial infarction or stroke (see section "Special warnings and precautions for use").
Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions after the registration of a medicinal product plays an important role. This allows for continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.
Expiration date
3 years. Do not use the medicine after the expiry date stated on the packaging.
Storage conditions
No special storage conditions are required. Keep the medicine out of the reach of children.
Packaging
2 g in a single-dose sachet; 9 or 15 or 30 sachets in a cardboard box.
Vacation category
According to the recipe.
Producer
Fine Foods and Pharmaceuticals N.T.M. SPA.
Location of the manufacturer and address of its place of business.
Via Grignano, 43 – 24041 Brembate (BG), Italy.
Applicant.
Laboratori GUIDOTTI S.p.A.
Location of the applicant.
Via Livornese, 897, 56122 La Vettola (Pisa), Italy.
