Nimesulide® granules

Instructions for use Nimesulide® granules

International Nonproprietary Name: Nimesulide

Trade Name: Nimesulide

Dosage Form: granules for the preparation of an oral suspension

One sachet contains:

Active substance: nimesulide (calculated as 100% substance) 100.0 mg;

Excipients: orange flavor - 42.0 mg, citric acid - 30.0 mg, maltodextrin - 15.0 mg, macrogol cetostearyl ether - 8.0 mg, sucrose - up to a weight of 2000.0 mg.

Description

A mixture of powder and granules from almost white to light yellow in color, with an orange odor. Color heterogeneity is allowed.

The prepared suspension is from white to light yellow in color, with an orange odor.

Pharmacotherapeutic group: nonsteroidal anti-inflammatory drug (NSAID).

ATC Code: M01AX17

Pharmacological properties

Pharmacodynamics:

Nimesulide is a nonsteroidal anti-inflammatory drug from the sulfonamide class. It has anti-inflammatory, analgesic, and antipyretic effects. Unlike non-selective NSAIDs, nimesulide primarily inhibits cyclooxygenase-2 (COX-2), inhibits prostaglandin synthesis at the site of inflammation; it has a less pronounced inhibitory effect on cyclooxygenase-1 (COX-1).

Pharmacokinetics:

Absorption

Nimesulide is well absorbed from the gastrointestinal tract (GIT).

The maximum plasma concentration (C_max) after a single oral dose of nimesulide (100 mg) is reached on average after 2-3 hours and is 3-4 mg/L.

Distribution

Plasma protein binding is up to 97.5 %.

Penetrates into tissues of the female reproductive organs, where after a single dose its concentration is about 40 % of the plasma concentration. Penetrates well into the acidic environment of the inflammation site (40 %), synovial fluid (43 %). Easily crosses histohematic barriers.

Metabolism

Nimesulide is actively metabolized in the liver by the cytochrome P450 (CYP)2C9 isoenzyme. There is a possibility of drug interaction of nimesulide when used concomitantly with drugs metabolized by the CYP2C9 isoenzyme. The main metabolite is the pharmacologically active parahydroxy derivative of nimesulide - hydroxynimesulide, found in plasma mainly in conjugated form, as a glucuronide.

Excretion

The half-life (T_1/2) of nimesulide is about 1.56-4.95 hours, hydroxynimesulide - 2.89-4.78 hours. Nimesulide is eliminated from the body mainly by the kidneys (about 50 % of the administered dose). Hydroxynimesulide is excreted by the kidneys (65 %) and with bile (35 %), and undergoes enterohepatic recirculation.

Use in elderly patients

The pharmacokinetic profile of nimesulide in elderly individuals does not change with single and multiple/repeated doses.

Use in patients with renal disease

In a short-term study conducted in patients with mild to moderate renal impairment (creatinine clearance 30-60 ml/min), the C_max of nimesulide and its main metabolite were no higher than in healthy volunteers.

AUC and T_1/2 were 50 % higher but were within the range of AUC and T_1/2 values observed in healthy volunteers taking nimesulide. Repeated administration did not lead to accumulation of nimesulide.

Indications for use

Therapy of acute pain:

• pain in the lower back and/or lumbar region;
• pain syndrome associated with musculoskeletal disorders, including tendinitis, bursitis;
• pain from bruises, sprains, and joint dislocations;
• toothache;
• symptomatic treatment of osteoarthritis with pain syndrome;
• primary dysmenorrhea. The drug is intended for symptomatic therapy, to reduce pain and inflammation at the time of use; it does not affect the progression of the disease. Nimesulide is recommended for therapy as a second-line drug.

Contraindications

• hypersensitivity to nimesulide or other components of the drug;
• complete or incomplete combination of bronchial asthma, recurrent nasal polyposis, paranasal sinusitis and intolerance to acetylsalicylic acid and other NSAIDs (including history);
• history of hepatotoxic reactions to nimesulide;
• concurrent use with other drugs with potential hepatotoxicity (e.g., other NSAIDs);
• chronic inflammatory bowel diseases (Crohn's disease, ulcerative colitis) in the acute phase;
• post coronary artery bypass graft period;
• febrile syndrome in colds and acute respiratory viral infections;
• suspected acute surgical pathology;
• peptic ulcer of the stomach or duodenum in the acute phase;
• erosive-ulcerative lesions of the gastrointestinal tract in the acute phase;
• history of erosive-ulcerative lesions of the gastrointestinal tract;
• history of perforations or gastrointestinal bleeding, including associated with previous NSAID therapy;
• history of cerebrovascular bleeding, other active bleeding or diseases accompanied by increased bleeding tendency;
• severe coagulation disorders;
• severe heart failure;
• severe renal failure (creatinine clearance less than 30 ml/min);
• progressive kidney disease;
• confirmed hyperkalemia;
• hepatic insufficiency, active liver disease;
• children under 12 years of age;
• pregnancy and breastfeeding period;
• alcoholism, drug dependence, sucrase/isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption, as the drug contains sucrose;

With caution

• arterial hypertension;
• ischemic heart disease;
• cerebrovascular diseases;
• severe heart failure;
• dyslipidemia/hyperlipidemia;
• diabetes mellitus;
• peripheral arterial disease;
• hemorrhagic diathesis;
• smoking;
• renal insufficiency (creatinine clearance 30-60 ml/min);
• history of erosive-ulcerative lesions of the gastrointestinal tract, presence of Helicobacter pylori;
• elderly age;
• long-term use of nonsteroidal anti-inflammatory drugs;
• frequent alcohol consumption, severe somatic diseases, systemic lupus erythematosus (SLE) and other systemic connective tissue diseases;
• concomitant therapy with the following drugs: anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid, clopidogrel), oral glucocorticosteroids (e.g., prednisolone), selective serotonin reuptake inhibitors (e.g., citalopram, fluoxetine, paroxetine, sertraline).

Use during pregnancy and breastfeeding

Pregnancy

Like other drugs from the NSAID class that inhibit prostaglandin synthesis, nimesulide may adversely affect the course of pregnancy and/or embryonic development and may lead to premature closure of the ductus arteriosus, pulmonary artery hypertension in the fetus, impaired renal function, which may progress to renal failure with oliguria in the fetus, increased risk of bleeding, reduced uterine contractility, and the occurrence of peripheral edema in the mother. The use of nimesulide during pregnancy is contraindicated.

Breastfeeding period

The use of nimesulide during breastfeeding is contraindicated.

Dosage and Administration

Before use, the Nimesulide powder must be diluted in liquid to obtain a suspension. To do this, open the sachet, pour the contents into a glass, and add boiled but cooled to room temperature water in an amount of at least 100 ml. The resulting mixture must be stirred thoroughly until the drug is completely dissolved. After this, the suspension can be used.

IMPORTANT! Storage of the prepared suspension is not allowed! The drug should be diluted immediately before use.

Nimesulide powder is taken orally, preferably after meals.

Orally. For adults and children over 12 years old (body weight over 40 kg), 100 mg twice daily is prescribed. Take after meals with a sufficient amount of water. The maximum daily dose for adults and children over 12 years is 200 mg.

Elderly patients: No dose adjustment is required when treating elderly patients.

Patients with renal impairment: In patients with mild to moderate renal impairment (creatinine clearance 30-60 ml/min), no dose adjustment is required. Nimesulide is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

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

Course of treatment: As prescribed by a physician. To reduce the likelihood of adverse effects, it is recommended to use the lowest effective dose for the shortest possible duration. The maximum duration of treatment with nimesulide is 15 days.

Instructions for use of Nimesulide powder for children

To avoid adverse effects and reduce health risks, the drug is not prescribed to children under 12 years of age. For children who have reached 12 years of age, the powder can be given according to the same treatment regimen recommended for adults.

IMPORTANT! If a dose is missed, do not double the next dose. If there is a long break in taking the drug, it is necessary to consult a doctor and, if necessary, resume the treatment regimen or adjust it.

Adverse reactions

The frequency of adverse effects is classified according to incidence: Very common (>1/10), Common (from ≥ 1/100 to < 1/10), Uncommon (from ≥ 1/1000 to < 1/100), Rare (from ≥ 1/10000 to < 1/1000), Very rare (< 1/10000), Frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders: Rare - anemia, eosinophilia, hemorrhages; Very rare - thrombocytopenia, pancytopenia, thrombocytopenic purpura, prolonged bleeding time.

Immune system disorders: Rare - hypersensitivity reactions; Very rare - anaphylactoid reactions.

Psychiatric disorders: Rare - feeling of fear, nervousness, nightmarish dreams.

Nervous system disorders: Uncommon - dizziness; Very rare - headache, drowsiness, encephalopathy (Reye's syndrome).

Eye disorders: Rare - blurred vision; Very rare - visual impairment.

Ear and labyrinth disorders: Very rare - vertigo.

Cardiac disorders: Rare - tachycardia, palpitations.

Vascular disorders: Uncommon - increased blood pressure; Rare -lability of blood pressure, flushing.

Respiratory, thoracic and mediastinal disorders: Uncommon - dyspnea; Very rare – exacerbation of bronchial asthma, bronchospasm.

Gastrointestinal disorders: Common – diarrhea, nausea, vomiting; Uncommon - constipation, flatulence, gastritis, gastrointestinal bleeding, ulcer and/or perforation of the stomach or duodenum; Very rare – abdominal pain, dyspepsia, stomatitis, tarry stools.

Hepatobiliary disorders: Common – increased activity of "liver" enzymes; Very rare – hepatitis, fulminant hepatitis (including fatal outcomes), jaundice, cholestasis.

Skin and subcutaneous tissue disorders: Uncommon - pruritus, skin rash, increased sweating; Rare - erythema, dermatitis; Very rare - urticaria, angioedema, facial edema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

Renal and urinary disorders: Rare - dysuria, hematuria, urinary retention; Very rare - renal failure, oliguria, interstitial nephritis, hyperkalemia.

General disorders and administration site conditions: Uncommon - peripheral edema; Rare – malaise, asthenia; Very rare – hypothermia.

Overdose

Symptoms: Apathy, drowsiness, nausea, vomiting, epigastric pain. These symptoms are usually reversible with supportive and symptomatic therapy. Increased blood pressure, occurrence of gastrointestinal bleeding, acute renal failure, respiratory depression, coma, anaphylactoid reactions are possible.

Treatment: Supportive and symptomatic therapy. There is no specific antidote. If symptoms of overdose occur within 4 hours of ingestion, induce vomiting and/or administer activated charcoal (60 to 100 g for an adult) and/or an osmotic laxative. Forced diuresis, hemodialysis, hemoperfusion, and urine alkalinization are ineffective due to the high degree of protein binding of nimesulide (up to 97.5 %). Monitoring of renal and liver function is necessary.

Drug interactions

Glucocorticosteroids increase the risk of erosive-ulcerative lesions of the gastrointestinal tract or bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, increase the risk of gastrointestinal bleeding.

Anticoagulants. NSAIDs may enhance the effect of anticoagulants such as warfarin, or drugs with antiplatelet action, such as acetylsalicylic acid. Due to the increased risk of bleeding, such combination is not recommended and is contraindicated in patients with severe coagulation disorders. If combined therapy cannot be avoided, careful monitoring of blood coagulation parameters is necessary.

Other nonsteroidal anti-inflammatory drugs (NSAIDs): Concurrent use of nimesulide-containing preparations with other NSAIDs, including acetylsalicylic acid in a single dose greater than 1 g or a daily dose greater than 3 g, is not recommended.

Diuretics. NSAIDs may reduce the effect of diuretics. In healthy volunteers, nimesulide temporarily reduced sodium excretion under the influence of furosemide, to a lesser extent potassium excretion, and reduced the diuretic effect itself. Concurrent use of nimesulide and furosemide leads to an approximate 20 % decrease in the area under the concentration-time curve (AUC) and a reduction in the cumulative excretion of furosemide without changing the renal clearance of furosemide. Concurrent use of furosemide and nimesulide requires caution in patients with renal or cardiac insufficiency.

ACE inhibitors and angiotensin II receptor antagonists. NSAIDs may reduce the effect of antihypertensive drugs. In patients with mild to moderate renal insufficiency (creatinine clearance 30-60 ml/min), concurrent use of ACE inhibitors, angiotensin II receptor antagonists and agents that suppress the cyclooxygenase system (NSAIDs, antiplatelet agents) may lead to further deterioration of renal function and the occurrence of acute renal failure, which is usually reversible. These interactions should be considered in patients taking nimesulide in combination with ACE inhibitors or angiotensin II receptor antagonists. Therefore, concurrent use of these drugs should be done with caution, especially in elderly patients. Patients should receive sufficient fluids, and renal function should be carefully monitored after initiation of concurrent use.

Mifepristone. Due to the theoretical risk of changes in the effectiveness of mifepristone under the influence of prostaglandin synthesis inhibitors, NSAIDs should not be used earlier than 8-12 days after discontinuation of mifepristone.

There is evidence that NSAIDs reduce the clearance of lithium, leading to increased plasma lithium concentrations and its toxicity. When using nimesulide in patients on lithium therapy, regular monitoring of plasma lithium concentration should be performed.

Clinically significant interactions with glibenclamide, theophylline, digoxin, cimetidine and antacid preparations (e.g., combination of aluminum and magnesium hydroxides) have not been observed.

Nimesulide inhibits the activity of the CYP2C9 isoenzyme. When used concurrently with nimesulide with drugs that are substrates of this enzyme, the plasma concentration of the latter may increase.

Caution is required if nimesulide is administered less than 24 hours before or after methotrexate intake, as in such cases the plasma level of methotrexate and, accordingly, its toxic effects may increase.

Due to the effect on renal prostaglandins, prostaglandin synthetase inhibitors, which include nimesulide, may increase the nephrotoxicity of cyclosporine. In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid and valproic acid. Although these interactions were determined in plasma, these effects have not been observed in clinical use of the drug.

Special warnings and precautions

Undesirable adverse effects can be minimized by using the drug at the lowest effective dose for the shortest duration necessary to relieve pain.

There are reports of very rare cases of serious liver reactions, including fatal cases, associated with the use of nimesulide-containing preparations. If symptoms resembling signs of liver damage (anorexia, pruritus, jaundice, nausea, vomiting, abdominal pain, dark urine, increased activity of "liver" transaminases) occur, nimesulide should be discontinued immediately and a doctor should be consulted. Re-administration of nimesulide in such patients is contraindicated. After 2 weeks of drug use, monitoring of liver function indicators ("transaminases") is necessary. Liver reactions, mostly reversible, have been reported with short-term use of the drug. During the use of nimesulide, the patient should refrain from taking other analgesics, including NSAIDs (including selective COX-2 inhibitors).

Nimesulide should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as these conditions may be exacerbated. The risk of gastrointestinal bleeding, peptic ulcer/perforation of the stomach or duodenum is increased in patients with a history of ulcerative gastrointestinal lesions (ulcerative colitis, Crohn's disease), as well as in elderly patients, with increasing doses of NSAIDs, so treatment should be started at the lowest possible dose. Such patients, as well as patients requiring concurrent use of low doses of acetylsalicylic acid or other agents that increase the risk of gastrointestinal complications, are recommended to additionally take gastroprotective agents (misoprostol or proton pump inhibitors). Patients with a history of gastrointestinal diseases, especially elderly patients, should report any new gastrointestinal symptoms (especially symptoms that may indicate possible gastrointestinal bleeding) to their doctor. Nimesulide should be prescribed with caution to patients taking drugs that increase the risk of ulceration or bleeding (oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid). If gastrointestinal bleeding or ulcerative gastrointestinal lesions occur in patients taking nimesulide, treatment with the drug must be stopped immediately.

Given reports of visual disturbances in patients taking other NSAIDs, if any visual disturbance occurs, nimesulide should be discontinued immediately and an ophthalmological examination performed.

The drug may cause fluid retention in tissues, therefore nimesulide should be used with particular caution in patients with arterial hypertension, renal and/or cardiac insufficiency, ischemic heart disease, peripheral arterial disease and/or cerebrovascular diseases, with risk factors for cardiovascular diseases (e.g., hyperlipidemia, diabetes mellitus, smokers). If the condition worsens, treatment with nimesulide must be discontinued.

Clinical studies and epidemiological data suggest that NSAIDs, especially in high doses and with long-term use, may lead to a slight increase in the risk of myocardial infarction or stroke. There is insufficient data to exclude the risk of such events with the use of nimesulide.

If signs of a "cold" or acute respiratory viral infection appear during the use of nimesulide, the drug should be discontinued.

Nimesulide may alter platelet properties, so caution should be exercised when using the drug in persons with hemorrhagic diathesis; however, the drug does not replace the prophylactic effect of acetylsalicylic acid in cardiovascular diseases.

Elderly patients are particularly susceptible to adverse reactions to NSAIDs, including the risk of gastrointestinal bleeding and perforations, which are life-threatening, and decreased renal, liver, and heart function. When taking nimesulide, proper clinical monitoring is necessary for this category of patients.

There are reports of rare cases of skin reactions (such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) with NSAIDs, including nimesulide. At the first appearance of skin rash, mucosal lesions, or other signs of an allergic reaction, nimesulide should be discontinued immediately.

The use of the drug may adversely affect female fertility and is not recommended for women planning pregnancy.

Effects on ability to drive and use machines

The effect of nimesulide on the ability to drive vehicles and operate machinery has not been studied; however, given the undesirable reactions from the nervous system (dizziness, drowsiness), one should refrain from driving vehicles and operating machinery.

Dosage form

Granules for the preparation of an oral suspension, 100 mg.

2.0 g in single-use sachets made of multilayer packaging material (polyethylene terephthalate-polypropylene-aluminum-polyethylene).

10, 20 or 30 sachets, together with the instructions for use, are placed in a cardboard carton.

Physicochemical properties of the drug

Nimesulide powder is white to light with a slight yellowish tint. The crystals are uniform, have a slight specific odor, have the same shape and size. When diluted, the drug should have a powdery consistency; the presence of large lumps and stuck granules is not allowed.

To obtain an oral solution, Nimesulide powder is dissolved in cold boiled water. The granules are stirred until completely dissolved. The resulting suspension is white or white-yellow in color with a pleasant odor and taste.

Storage conditions

At a temperature not exceeding 25 °C. Keep out of reach of children.

Prescription status

By prescription.

Shelf life

2 years. Do not use after the expiration date printed on the packaging.

Name and address of the legal entity in whose name the registration certificate is issued / Organization accepting claims:

JSC "AVVA RUS", Russia

121614,  Moscow, Krylatskie Kholmy st., 30, building 9.

Tel/Fax: +7 (495) 956-75-54.

avva.com.ru

Production site address:

JSC "AVVA RUS", Russia, 610044, Kirov region, Kirov, Luganskaya st., 53a

Tel.: +7 (8332) 25-12-29; +7 (495) 956-75-54.

Where to buy Nimesulide and how much does it cost?

The drug is distributed exclusively through pharmacies. To purchase it, it is necessary to obtain a prescription from a doctor in advance. Without this document, the pharmacist has the right to refuse to dispense the medicine from the pharmacy.

The price of the drug varies depending on the region of distribution and the specifics of the particular pharmacy's pricing. The right to set the final price remains with the pharmacy.

When purchasing the drug in a retail network, it is necessary to verify its authenticity by studying the instructions for use of Nimesulide powder, familiarize yourself with the existing contraindications and restrictions on use, and ensure that the expiration dates are observed. The drug is taken according to the regimen recommended by the doctor. If any undesirable reactions of the body are detected, it is necessary to immediately stop taking the powder and seek medical help.