Nimesulide-SZ (Granules) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

ATC Code

M01AX17 (Nimesulide)

Active Substance

Nimesulide (Rec.INN registered by WHO)

Dosage Form

Nimesulide-SZ

Granules for the preparation of an oral suspension 100 mg/1 pkg.: pkg. 2 g 4, 10, 20, 30, or 50 pcs.

Dosage Form, Packaging, and Composition

Granules for the preparation of an oral suspension in the form of a light yellow mixture, with an orange odor.

Excipients: povidone K-30 (medium molecular weight polyvinylpyrrolidone) – 35 mg, lactose monohydrate (milk sugar) – 1663 mg, crospovidone (Kollidon CL-M) – 120 mg, aspartame – 10 mg, citric acid – 30 mg, orange flavor – 42 mg.

2 g – three-layer bags (4) – cardboard packs.
2 g – three-layer bags (10) – cardboard packs.
2 g – three-layer bags (20) – cardboard packs.
2 g – three-layer bags (30) – cardboard packs.
2 g – three-layer bags (50) – cardboard packs.

Clinical-Pharmacological Group

NSAID. Selective COX-2 inhibitor

Pharmacotherapeutic Group

NSAID

Pharmacological Action

NSAID from the sulfonanilide class. It has anti-inflammatory, analgesic, and antipyretic effects. Unlike non-selective NSAIDs, Nimesulide mainly inhibits COX-2, inhibits the synthesis of prostaglandins at the site of inflammation; it has a less pronounced inhibitory effect on COX-1.

Pharmacokinetics

Absorption and Distribution

Nimesulide is well absorbed from the gastrointestinal tract. C_max in blood plasma after oral administration of a single dose of nimesulide, which is 100 mg, is reached on average after 2-3 hours and is 3-4 mg/l. AUC – 20-35 mg×h/l.

Binding to blood plasma proteins is up to 97.5%. It penetrates into the tissues of the female genital organs, where after a single dose its concentration is about 40% of the concentration in plasma. It penetrates well into the acidic environment of the inflammation site (40%), synovial fluid (43%). It easily passes through histohematic barriers.

Repeated use did not lead to the accumulation of nimesulide.

Metabolism

It is metabolized in the liver by the cytochrome P450 (CYP) 2C9 isoenzyme. The main metabolite is the pharmacologically active parahydroxy derivative of nimesulide – hydroxynimesulide, which is found in blood plasma mainly in the form of glucuronate.

Excretion

T_1/2 of nimesulide is about 1.56-4.95 hours, of hydroxynimesulide – 2.89-4.78 hours.

Nimesulide is excreted from the body mainly with urine (about 50% of the dose taken), hydroxynimesulide is excreted with urine (65%) and with bile (35%), and undergoes enterohepatic recirculation.

Pharmacokinetics in Special Patient Groups

The pharmacokinetic profile of nimesulide in the elderly and in patients with mild to moderate renal failure does not change with the use of single and multiple/repeated doses.

In a study conducted in patients with mild to moderate renal failure (CC 30-80 ml/min), the C_max of nimesulide and its main metabolite were not 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 while taking nimesulide.

Indications

• Acute pain (back pain, lower back pain; pain syndrome in injuries and diseases of the musculoskeletal system, including bruises, sprains and dislocations of joints, tendinitis, bursitis; toothache);
• Symptomatic treatment of osteoarthritis (osteoarthritis) with pain syndrome;
• Primary dysmenorrhea.

The drug is intended for symptomatic therapy, reducing pain and inflammation at the time of use; Nimesulide is recommended for therapy as a second-line drug.

ICD codes

Dosage Regimen

The drug is taken orally. The contents of the sachet are dissolved in approximately 100 ml of water at room temperature (a white or light yellow suspension is formed). The prepared solution is not subject to storage.

The drug Nimesulide-SZ is used only for the treatment of patients over 12 years of age.

Adults and children over 12 years of age (body weight more than 40 kg) 1 sachet 2 times/day, after meals.

The maximum daily dose for adults and children over 12 years of age is 200 mg.

The maximum duration of the course of treatment is 15 days.

When treating elderly patients, the need for adjustment of the daily dose is determined by the doctor based on the possibility of interaction with other drugs.

In patients with mild to moderate renal failure (CC 30-60 ml/min) no dose adjustment is required, patients with severe renal failure (CC <30 ml/min) the drug Nimesulide-SZ is contraindicated.

The use of the drug Nimesulide-SZ in patients with hepatic insufficiency is contraindicated.

To reduce the likelihood of adverse reactions, it is recommended to take the minimum effective dose for the shortest possible time.

Adverse Reactions

The frequency of adverse reactions in accordance with WHO recommendations depending on the occurrence of the case: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), including isolated reports.

From the blood and lymphatic system rarely – anemia, eosinophilia, hemorrhages; very rarely – thrombocytopenia, pancytopenia, thrombocytopenic purpura.

From the immune system rarely – hypersensitivity reactions; very rarely – anaphylactoid reactions.

From the skin and subcutaneous tissues uncommon – itching, skin rash, increased sweating; rarely – erythema, dermatitis; very rarely – urticaria, angioedema, facial edema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

From the nervous system uncommon – dizziness; very rarely – headache, drowsiness, encephalopathy (Reye’s syndrome).

Mental disorders rarely – feeling of fear, nervousness, nightmares.

From the organ of vision rarely – blurred vision; very rarely – visual impairment.

From the organ of hearing and labyrinthine disorders very rarely – vertigo.

From the cardiovascular system uncommon – increased blood pressure; rarely – tachycardia, blood pressure lability, “flushes” of blood to the skin of the face, palpitations.

From the respiratory system uncommon – shortness of breath; very rarely – exacerbation of bronchial asthma, bronchospasm.

From the digestive system often – diarrhea, nausea, vomiting; uncommon – constipation, flatulence, gastritis, gastrointestinal bleeding, ulcer and/or perforation of the stomach or duodenum; very rarely – abdominal pain, dyspepsia, stomatitis, tarry stools.

From the liver and biliary tract often – increased activity of liver enzymes; very rarely – hepatitis, fulminant hepatitis (including fatal outcomes), jaundice, cholestasis.

From the urinary system rarely – dysuria, hematuria, urinary retention; very rarely – renal failure, oliguria, interstitial nephritis.

From water and electrolyte metabolism rarely – hyperkalemia.

Other uncommon – peripheral edema; rarely – malaise, asthenia; very rarely – hypothermia.

Contraindications

• Hypersensitivity to nimesulide or any of the excipients of the drug;
• History of hyperergic reactions (bronchospasm, rhinitis, urticaria) associated with the use of acetylsalicylic acid or other NSAIDs, including nimesulide;
• Complete or incomplete combination of bronchial asthma, recurrent nasal polyposis or paranasal sinus polyposis with intolerance to acetylsalicylic acid and other NSAIDs (including in history);
• History of hepatotoxic reactions to Nimesulide;
• Simultaneous use with other drugs with potential hepatotoxicity (for example, other NSAIDs);
• Chronic inflammatory bowel diseases (Crohn’s disease, ulcerative colitis) in the acute phase;
• Period after coronary artery bypass surgery;
• Febrile syndrome with colds and acute respiratory viral infections;
• Suspicion of acute surgical pathology;
• Gastric or duodenal ulcer in the acute phase, erosive and ulcerative lesions of the gastrointestinal tract, perforations or gastrointestinal bleeding in history;
• History of cerebrovascular bleeding or other diseases accompanied by increased bleeding;
• Severe blood clotting disorders;
• Severe heart failure;
• Severe renal failure (CC <30 ml/min), confirmed hyperkalemia;
• Hepatic insufficiency, active liver disease;
• Children under 12 years of age;
• Pregnancy;
• Breastfeeding period;
• Alcoholism, drug addiction;
• Hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

With caution

Arterial hypertension, diabetes mellitus, compensated heart failure, coronary artery disease, cerebrovascular diseases, dyslipidemia/hyperlipidemia, peripheral arterial diseases, hemorrhagic diathesis, smoking, CC 30-60 ml/min.

History of gastrointestinal ulcer; history of Helicobacter pylori infection; elderly age; long-term prior use of NSAIDs; severe somatic diseases.

Simultaneous use with the following drugs: anticoagulants (for example, warfarin), antiplatelet agents (for example, acetylsalicylic acid, clopidogrel), oral corticosteroids (for example, prednisolone), selective serotonin reuptake inhibitors (for example, citalopram, fluoxetine, paroxetine, sertraline).

Use in Pregnancy and Lactation

Pregnancy

Like other drugs from the NSAID class that inhibit the synthesis of prostaglandins, Nimesulide may adversely affect the course of pregnancy and/or the development of the embryo and may lead to premature closure of the arterial duct, hypertension in the fetal pulmonary artery system, impaired renal function, which may progress to renal failure with oliguria in the fetus, to an increased risk of bleeding, decreased uterine contractility, and the occurrence of peripheral edema in the mother.

Data obtained from epidemiological studies indicate a possible increase in the risk of spontaneous abortion, the risk of heart defects and gastroschisis when using prostaglandin synthesis blocking agents in early pregnancy. The absolute risk of developing a cardiovascular system abnormality increases from approximately 1% to 1.5%. The risk is believed to increase with increasing dose and duration of use.

When using NSAIDs in women starting from the 20th week of pregnancy, oligohydramnios and/or kidney pathology in newborns (neonatal renal dysfunction) may develop.

The use of the drug Nimesulide-SZ during pregnancy is contraindicated.

Breastfeeding period

The use of the drug Nimesulide-SZ during breastfeeding is contraindicated.

Fertility

The use of nimesulide may adversely affect female fertility and is not recommended for women planning pregnancy. When planning a pregnancy, it is necessary to consult with the attending physician.

Use in Hepatic Impairment

The use of the drug is contraindicated in hepatic insufficiency or any active liver disease.

Use in Renal Impairment

In patients with mild to moderate renal failure (CC 30-60 ml/min), no dose adjustment is required.

In patients with severe renal failure (CC <30 ml/min), the drug Nimesulide-SZ is contraindicated.

Pediatric Use

The use of the drug is contraindicated in children under 12 years of age.

Geriatric Use

When treating elderly patients, the need for adjustment of the daily dose is determined by the doctor based on the possibility of interaction with other drugs.

Special Precautions

Adverse reactions can be minimized by using the drug at the minimum effective dose for the minimum duration of use necessary to relieve pain.

There are data on very rare cases of serious liver reactions, including cases of death, associated with the use of nimesulide-containing drugs. If symptoms similar to signs of liver damage appear (anorexia, skin itching, yellowing of the skin, nausea, vomiting, abdominal pain, dark urine, increased activity of liver transaminases), the patient should immediately stop using the drug Nimesulide-SZ and consult a doctor. Repeated use of the drug Nimesulide-SZ in such patients is contraindicated. Liver reactions are reported, which in most cases are reversible, with short-term use of the drug.

During the use of the drug Nimesulide-SZ, the patient should refrain from taking other analgesics, including NSAIDs (including selective COX-2 inhibitors).

The drug Nimesulide-SZ should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn’s disease), since an exacerbation of these diseases is possible.

The risk of gastrointestinal bleeding, peptic ulcer/perforation of the stomach or duodenum increases in patients with a history of gastrointestinal ulcerative lesions (ulcerative colitis, Crohn’s disease), as well as in elderly patients, with an increase in the dose of NSAIDs, so treatment should be started with the lowest possible dose. Such patients, as well as patients who require simultaneous use of low-dose acetylsalicylic acid or other agents that increase the risk of gastrointestinal complications, are recommended to additionally prescribe gastroprotectors (misoprostol or proton pump inhibitors). Patients with a history of gastrointestinal disease, especially elderly patients, should inform the doctor about any newly emerging gastrointestinal symptoms (especially symptoms that may indicate possible gastrointestinal bleeding).

The drug Nimesulide-SZ should be prescribed with caution to patients taking drugs that increase the risk of ulceration or bleeding (oral corticosteroids, anticoagulants, for example warfarin, selective serotonin reuptake inhibitors or antiplatelet agents, for example, acetylsalicylic acid).

In case of gastrointestinal bleeding or gastrointestinal ulceration in patients taking the drug Nimesulide-SZ, treatment with the drug must be stopped immediately.

Given reports of visual impairment in patients taking other NSAIDs, if any visual impairment occurs, the use of the drug Nimesulide-SZ should be stopped immediately and an ophthalmological examination should be performed.

The drug can cause fluid retention in the body, so patients with arterial hypertension, renal and/or heart failure, coronary artery disease, peripheral arterial disease and/or cerebrovascular diseases, with the presence of risk factors for the development of cardiovascular diseases (for example, hyperlipidemia, diabetes mellitus, smokers) the drug Nimesulide-SZ should be used with particular caution. In case of deterioration of the condition, treatment with the drug Nimesulide-SZ must be discontinued.

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

The preparation contains lactose monohydrate (milk sugar), which should be taken into account by patients suffering from diabetes mellitus (0.14-0.16 BU per 100 mg of the preparation) and persons on a low-calorie diet. Nimesulide-SZ is not recommended for patients with lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

If signs of a cold or acute respiratory viral infection appear during the use of Nimesulide-SZ, the administration of the preparation should be discontinued.

Nimesulide may alter platelet properties, therefore caution should be exercised when using the preparation in persons with hemorrhagic diathesis; however, the preparation 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 to the patient, and decreased renal, hepatic and cardiac function. When taking Nimesulide-SZ in this category of patients, proper clinical monitoring is necessary.

There are data on the occurrence in rare cases of skin reactions (such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) when taking NSAIDs, including nimesulide. At the first appearance of skin rash, mucosal lesions or other signs of an allergic reaction, the administration of Nimesulide-SZ should be stopped immediately.

Effect on the ability to drive vehicles and mechanisms

The effect of Nimesulide-SZ on the ability to drive vehicles and mechanisms has not been studied, therefore, during the period of using Nimesulide-SZ, caution should be exercised when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

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

Treatment symptomatic and supportive therapy. There is no specific antidote. If overdose occurred within the last 4 hours, it is necessary to induce vomiting and/or provide intake of activated charcoal (from 60 to 100 g for an adult) and/or an osmotic laxative. Forced diuresis, hemodialysis, hemoperfusion, urine alkalinization are ineffective due to the high degree of nimesulide binding to plasma proteins (up to 97.5%). Monitoring of renal and hepatic function is necessary.

Drug Interactions

Corticosteroids increase the risk of gastrointestinal ulcer or bleeding.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs), for example, fluoxetine, increase the risk of gastrointestinal bleeding.

NSAIDs may enhance the effect of anticoagulants such as warfarin. Due to the increased risk of bleeding, such combination is contraindicated in patients with severe coagulation disorders. If combined therapy still cannot be avoided, careful monitoring of blood coagulation parameters is necessary.

Diuretics

NSAIDs may reduce the effect of diuretics.

In healthy volunteers, nimesulide temporarily reduces sodium excretion under the action of furosemide, to a lesser extent – potassium excretion, and reduces the diuretic effect itself.

Concomitant use of nimesulide and furosemide leads to a decrease (approximately by 20%) in AUC and a decrease in the cumulative excretion of furosemide without changing the renal clearance of furosemide.

Concomitant 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 30-80 ml/min), concomitant use of ACE inhibitors, angiotensin II receptor antagonists and agents that suppress the COX system (NSAIDs, antiplatelet agents) may lead to further deterioration of renal function and the occurrence of acute renal failure, which is usually reversible. This interaction should be taken into account in patients taking Nimesulide in combination with ACE inhibitors or angiotensin II receptor antagonists. Therefore, the concomitant use of these drugs should be carried out with caution, especially in elderly patients. Patients should receive sufficient fluids, and renal function should be carefully monitored after the start of concomitant use.

Mifepristone

Theoretically, a decrease in the effectiveness of mifepristone and prostaglandin analogues is possible when used concomitantly with NSAIDs (including acetylsalicylic acid) due to the antiprostaglandin action of the latter. Limited data show that the use of NSAIDs on the day of prostaglandin analogue use does not adversely affect the effect of mifepristone or prostaglandin analogue on cervical dilation, uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy.

Lithium preparations

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

Clinically significant interaction with glibenclamide, theophylline, digoxin, cimetidine and antacid preparations (for example, a combination of aluminum hydroxide and magnesium hydroxide) was not observed.

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

Caution is required when prescribing nimesulide less than 24 hours before or after the use of methotrexate, since in such cases the plasma concentration of methotrexate and, accordingly, toxic effects may increase.

Due to the effect on renal prostaglandins, prostaglandin synthetase inhibitors, which include Nimesulide, may increase the nephrotoxicity of cyclosporine.

Storage Conditions

The preparation should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The preparation is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.