Nimesulide, 100 mg 2 g 30 pcs

Pharmacotherapeutic group: Non-steroidal anti-inflammatory drug (NSAID).

ATX code: M01AX17.

Pharmacological properties

Pharmacodynamics:

Nimesulide is a nonsteroidal anti-inflammatory agent of the sulfonamide class. It has anti-inflammatory, analgesic and antipyretic effects. Unlike non-selective NSAIDs, nimesulide mainly inhibits cyclooxygenase-2 (COX-2), inhibits the synthesis of prostaglandins in the inflammation focus; it has less pronounced inhibitory effect on cyclooxygenase-1 (COX-1).

Pharmacokinetics:

Assimilation

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

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

Distribution

The binding to plasma proteins is up to 97.5%.

It penetrates into the tissues of the female genitalia, where after a single administration its concentration is about 40% of the plasma concentration. It penetrates well into the acidic environment of the inflammation focus (40%), synovial fluid (43%). Easily penetrates through histohematic barriers.

Metabolism

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

Evolution

The elimination half-life (T_1/2) of nimesulide is about 1.56-4.95 hours, that of hydroxynimesulide 2.89-4.78 hours. Nimesulide is excreted mainly by the kidneys (about 50% of the accepted dose). Hydroxynimesulide is excreted by the kidneys (65%) and with bile (35%); it is subjected to enterohepatic recirculation.

Application in elderly patients

The pharmacokinetic profile of nimesulide in elderly persons is not altered by the use of single and repeated/repeated doses.

Application 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), C_max of nimesulide and its major metabolite were no higher than in healthy volunteers.

The AUC and T_1/2 were 50% higher but were within the AUC and T_1/2 values observed in healthy volunteers on nimesulide. Repeated administration did not result in nimesulide cumulation.

Indications

Therapy of acute pain:

Active ingredient

Composition

One packet contains:
Active ingredient: nimesulide (in terms of 100% substance) 100.0 mg;
excipients: Orange flavoring – 42.0 mg, citric acid – 30.0 mg, maltodextrin – 15.0 mg, macrogoal cetostearate – 8.0 mg, sucrose – to the weight
2000.0 mg.

How to take, the dosage

Ingestion. Oral administration in adults and children over 12 years of age (body weight over 40 kg): 100 mg 2 times a day. It is taken after a meal with enough water.

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

Patients in the elderly: No adjustment of the daily dose is required in therapy of elderly patients.

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

Patients with hepatic failure: the use of nimesulide in patients with hepatic failure is contraindicated.

Course of treatment: as prescribed by the physician. To reduce the likelihood of side effects it is recommended to take the minimum effective dose for the shortest possible time. The maximum duration of treatment with nimesulide is 15 days.

Interaction

Glucocorticosteroids increase the risk of gastrointestinal erosive ulcers or bleeding.

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

Anticoagulants. NSAIDs may increase the effect of anticoagulants, such as warfarin, or drugs with antiplatelet effects, such as acetylsalicylic acid. Because of the increased risk of bleeding, this combination is not recommended and is contraindicated in patients with severe coagulation disorders. If combination therapy still cannot be avoided, careful monitoring of blood clotting parameters is necessary.

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

Diuretics. NSAIDs may decrease the effect of diuretics. In healthy volunteers nimesulide temporarily reduces sodium excretion under the effect 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 20%) of the area under the curve “concentration – time” (AUC) and reduced 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 decrease the effect of hypotensive drugs. In patients with mild to moderate renal insufficiency (creatinine clearance 30-60 ml/min) when ACE inhibitors, angiotensin II receptor antagonists and agents inhibiting cyclooxygenase system (NSAIDs, antiaggregants) are used simultaneously, further worsening of renal function and acute renal failure may occur, which is usually reversible.

These interactions should be considered in patients taking nimesulide in combination with ACE inhibitors or angiotensin II receptor antagonists. Therefore, concomitant use of these drugs should be performed with caution, especially in elderly patients. Patients should receive adequate fluids, and renal function should be carefully monitored after concomitant use is initiated.

Mifepristone. Because of the theoretical risk of prostaglandin inhibitors altering mifepristone’s effectiveness, NSAIDs should not be used earlier than 8-12 days after mifepristone withdrawal.

There is evidence that NSAIDs decrease lithium clearance, resulting in increased plasma lithium concentrations and toxicity. When using nimesulide in patients on therapy with lithium drugs, regular monitoring of plasma lithium concentration should be performed.

The clinically significant interactions with glibenclamide, theophylline, digoxin, cimetidine and antacids (such as aluminum and magnesium hydroxide combination) were not observed.

Nimesulide inhibits the activity of CYP2C9 isoenzyme. When concomitant use of the drugs which are substrates of this enzyme with nimesulide the plasma concentration of the latter may increase.

When nimesulide is prescribed less than 24 hours before or after taking methotrexate caution is required, because in these cases the plasma level of methotrexate and, correspondingly, toxic effects may increase.

Because of its effect on renal prostaglandins, prostaglandin synthetase inhibitors such as nimesulide may increase nephrotoxicity of cyclosporines. In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid and valproic acid.

While these interactions have been identified in plasma, these effects were not observed during clinical use of the drug.

Special Instructions

Unwanted side effects can be minimized when the drug is used in the lowest effective dose with the shortest duration of use necessary to relieve pain syndrome.

There have been reports of very rare cases of serious liver reactions, including death, associated with the use of nimesulide-containing medications. In case of symptoms similar to those of liver damage (anorexia, pruritus, yellowing of the skin, nausea, vomiting, abdominal pain, darkened urine, increased “liver” transaminases activity) nimesulide use should be immediately stopped and a physician should be consulted. Repeated use of nimesulide in such patients is contraindicated. After 2 weeks of using the drug, monitoring of liver function parameters (“transaminases”) is necessary. Liver reactions, which in most cases are reversible, have been reported during the short-term use of the drug. During nimesulide use, the patient should refrain from taking other analgesics, including NSAIDs (including COX-2 selective inhibitors).

Nimesulide should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn’s disease), because 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 ulcers (ulcerative colitis, Crohn’s disease), as well as in older patients, with increasing doses of NSAIDs, so treatment should be started with the lowest possible dose. Such patients, as well as patients who require concomitant use of low doses of acetylsalicylic acid or other drugs that increase the risk of gastrointestinal complications, it is recommended to administer additional gastroprotectors (misoprostol or proton pump blockers). Patients with a history of gastrointestinal diseases, especially elderly patients, should inform the physician about new gastrointestinal symptoms (especially about symptoms that may indicate a possible gastrointestinal bleeding). Nimesulide should be administered with caution in 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). In case of gastrointestinal bleeding or gastrointestinal ulcers in patients taking nimesulide, treatment with the drug should be stopped immediately.

Given the reports of visual impairment in patients taking other NSAIDs, the use of nimesulide should be immediately discontinued and an ophthalmologic examination should be performed in case of any visual impairment.

The drug may cause fluid retention in the tissues, therefore patients with arterial hypertension, with renal and/or heart failure, coronary heart disease, peripheral artery disease and/or cerebrovascular disease, with the presence of risk factors for cardiovascular diseases (e.g.: hyperlipidemia, diabetes mellitus, in smokers) nimesulide should be used with extreme caution. In case of worsening of the condition, treatment with nimesulide should be stopped.

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

In case of signs of “cold” or acute respiratory viral infection during the use of nimesulide, the drug should be stopped.

Nimesulide may change platelet properties; therefore caution should be exercised when using the drug in subjects with hemorrhagic diathesis, but the drug does not replace the preventive action of acetylsalicylic acid in cardiovascular disease.

Elderly patients are particularly susceptible to adverse reactions to NSAIDs, including risk of gastrointestinal bleeding and life-threatening perforations, decreased renal, liver and cardiac function. Adequate clinical monitoring is needed when taking nimesulide for this patient population.

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 manifestations of skin rash, lesions of mucous membranes or other signs of allergic reactions, nimesulide should be stopped immediately.

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

The effect of nimesulide on the ability to drive vehicles and mechanisms has not been studied, but given the adverse reactions from the nervous system (dizziness, somnolence), one should refrain from driving vehicles and other mechanisms.

Synopsis

Contraindications

Side effects

The frequency of side effects is classified according to the frequency of the case: very frequently (>1/10), frequently (≥ 1/100 to < 1/10), infrequently (≥ 1/1000 to < 1/100), rarely (≥ 1/10000 to < 1/1000), very rarely (from ≥ 1/10000), frequency is unknown (frequency cannot be calculated from available data).
Blood and lymphatic system disorders: rare – anemia, eosinophilia, hemorrhages; very rare – thrombocytopenia, pancytopenia, thrombocytopenic purpura, prolongation of bleeding time.

Immune system disorders: rare – hypersensitivity reactions; very rare – anaphylactoid reactions.

Psychiatric disorders: rarely – fear, nervousness, night “nightmares” dreams.

Nervous system disorders: infrequent – dizziness; very rare – headache, somnolence, encephalopathy (Reye’s syndrome).

VIight disorders: rare – blurred vision; very rare – visual impairment.

Hearing organ disorders and labyrinth disorders: very rare – vertigo.

Chronic disorders: rare – tachycardia, palpitations.

Vascular disorders: infrequent – increase in blood pressure; rare – variability of blood pressure, “rushes” of blood to the face.

Respiratory system, chest and mediastinum disorders: infrequent – shortness of breath; very rare – exacerbation of bronchial asthma, bronchospasm.

Gastrointestinal disorders: frequently – diarrhea, nausea, vomiting; infrequently – constipation, flatulence, gastritis, gastrointestinal bleeding, stomach or duodenal ulcer and/or perforation; very rarely – abdominal pain, dyspepsia, stomatitis, tarry stool.

Liver and biliary tract disorders: often – increased activity of “liver” enzymes; very rare – hepatitis, fulminant hepatitis (including fatal outcomes), jaundice, cholestasis.

Dermatological and subcutaneous tissue disorders: infrequent – itching, 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 tract disorders: rarely – dysuria, hematuria, urinary retention; very rarely – renal failure, oliguria, interstitial nephritis, hyperkalemia.

General disorders and disorders at the site of administration: infrequent – peripheral edema; rare – malaise, asthenia; very rare – hypothermia.

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, and anaphylactoid reactions are possible.

Treatment: Symptomatic and supportive therapy. There is no specific antidote. If the symptoms of overdose occurred within 4 hours after taking the drug, it is necessary to induce vomiting, and/or ensure intake of activated charcoal (60 to 100 g for an adult) and/or osmotic laxative. Forced diuresis, hemodialysis, hemoperfusion, urine alkalinization are ineffective due to the high degree of nimesulide binding to blood plasma proteins (up to 97.5%). It is necessary to monitor the state of renal and hepatic function.

Pregnancy use

Pregnancy
. As other drugs from the class of NSAIDs that inhibit the synthesis of prostaglandins, nimesulide may adversely affect the pregnancy and/or the development of the embryo and may lead to premature closure of the arterial duct, hypertension in the pulmonary artery system of the fetus, impaired renal function, which may develop into renal failure with fetal oliguria, increased bleeding risk, reduced uterine contractility, occurrence of peripheral edema in the mother. The use of nimesulide during pregnancy is contraindicated.

Breast-feeding period
The use of nimesulide during breast-feeding is contraindicated.

Similarities