Nayz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NAYZ® (NISE)

Composition:

Active substance: nimesulide;

1 tablet contains 100 mg of nimesulide;

Excipients: calcium hydrogen phosphate, microcrystalline cellulose, maize starch, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, talc, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, smooth, biconvex tablets of almost white to yellow color.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic drugs.

ATC code M01AX17.

Pharmacological properties.

Pharmacodynamics.

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) of the methanesulfonanilide group, exhibiting anti-inflammatory, analgesic and antipyretic effects. The therapeutic effect of nimesulide is due to its interaction with the arachidonic acid cascade. Nimesulide selectively inhibits COX-2 (cyclooxygenase-2) and suppresses prostaglandin synthesis at the site of inflammation.

Nimesulide inhibits the release of the enzyme myeloperoxidase and also suppresses the formation of reactive oxygen species, without affecting phagocytosis and chemotaxis processes. It inhibits the production of tumor necrosis factor and other inflammatory mediators.

Pharmacokinetics.

After oral administration, nimesulide is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 2–3 hours. Approximately 97.5% of nimesulide is bound to plasma proteins.

The drug is actively metabolized in the liver with the involvement of CYP2C9, an isoenzyme of cytochrome P450. The main metabolite is hydroxynimesulide, a pharmacologically active substance. The elimination half-life ranges from 3.2 to 6 hours. Nimesulide is excreted from the body via urine—approximately 50% of the administered dose. About 29% of the administered dose is excreted in feces in metabolized form. Only 1–3% is excreted unchanged. The pharmacokinetic profile in elderly individuals is not altered.

Clinical characteristics.

Indications.

Treatment of acute pain. Treatment of primary dysmenorrhea.

Nimesulide should be used only as a second-line agent.

The decision to prescribe nimesulide should be based on an assessment of all risks for the individual patient.

Contraindications.

Hypersensitivity to nimesulide, to any other NSAID, or to any component of the medicinal product. Previous hypersensitivity reactions (bronchospasm, rhinitis, urticaria) associated with the use of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

Previous hepatotoxic reactions to nimesulide.

Concomitant use of other substances with potential hepatotoxicity.

Alcoholism and drug addiction.

Suspicion of acute surgical pathology.

History of gastrointestinal bleeding or perforation associated with previous use of nonsteroidal anti-inflammatory drugs.

Active gastric or duodenal ulcer, history of ulcer, perforation, or gastrointestinal bleeding.

History of cerebrovascular bleeding or other hemorrhages, as well as diseases associated with bleeding tendency.

Severe disorders of blood coagulation.

Severe heart failure.

Severe renal function impairment.

Hepatic function impairment.

Elevated body temperature and/or flu-like symptoms.

Patient age under 12 years.

Third trimester of pregnancy and breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding. Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal ulcers or bleeding.

Anticoagulants: NSAIDs may enhance the effect of anticoagulants such as warfarin or acetylsalicylic acid, making this combination contraindicated in patients with severe coagulation disorders. If such combination therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II 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), concomitant use of ACE inhibitors, angiotensin II antagonists, or substances that inhibit the cyclooxygenase system may lead to further deterioration of renal function and development of acute renal failure, which is usually reversible. These interactions should be considered when patients are using nimesulide in combination with ACE inhibitors or angiotensin II antagonists. Extreme caution is required when using such combinations, especially in elderly patients. Patients should receive adequate fluid intake, and renal function should be closely monitored after initiation of such combination therapy. Nimesulide temporarily reduces the sodium-excreting effect of furosemide and to a lesser extent the potassium excretion, as well as diminishes the diuretic effect. Concomitant use of furosemide and nimesulide in patients with impaired renal or cardiac function requires caution.

In healthy individuals, nimesulide rapidly reduces the sodium-excreting effect of furosemide and to a lesser extent the potassium excretion, as well as reduces diuresis. Concomitant administration of nimesulide and furosemide results in a reduction (by approximately 20%) of the area under the concentration-time curve (AUC) and decreased cumulative excretion of furosemide, without changes in renal clearance of furosemide.

Other 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 with other medicinal products.

There have been reports that NSAIDs reduce lithium clearance, leading to increased plasma lithium levels and lithium toxicity. When prescribing nimesulide to patients receiving lithium therapy, plasma lithium levels should be monitored frequently.

No clinically significant interaction has been observed with glipizide, theophylline, warfarin, digoxin, cimetidine, or antacid agents (aluminum and magnesium hydroxide combination). Nimesulide inhibits the activity of the CYP2C9 enzyme. When used concomitantly with drugs that are substrates of this enzyme, their plasma concentrations may increase.

Caution is required when nimesulide must be administered less than 24 hours before or less than 24 hours after methotrexate, as this may lead to increased methotrexate levels in blood serum and increased methotrexate toxicity.

Due to effects on renal prostaglandins, inhibitors of synthetases, including nimesulide, may increase the nephrotoxicity of cyclosporine.

Effects of other drugs on nimesulide.

Tolbutamide, salicylic acid, and valproic acid displace nimesulide from binding sites. However, despite a potential effect on plasma drug levels, these interactions are not considered clinically significant.

Special precautions for use.

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.

To minimize the risk of adverse effects, the lowest effective dose for the shortest duration of treatment should be used. If treatment is ineffective (i.e., no reduction in disease symptoms), therapy with the drug should be discontinued.

There have been reports of severe hepatic reactions, including fatal outcomes, associated with the use of nimesulide. If liver enzyme levels rise or signs of liver damage occur (e.g., anorexia, nausea, vomiting, abdominal pain, unusual fatigue, dark urine), or if liver function test results deviate from normal, the drug should be discontinued immediately. Re-administration of nimesulide to such patients is contraindicated.

During treatment with nimesulide, concomitant use of hepatotoxic drugs, analgesics, and other nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors, should be avoided. Alcohol consumption should also be avoided.

Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal. Peptic ulcer, gastrointestinal bleeding, or perforation may be life-threatening, especially in patients with a history of such events during treatment with any other NSAID (regardless of time elapsed). The risk of such events increases with higher NSAID doses in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation, and in elderly patients. In these patients, treatment should be initiated with the lowest possible effective dose. For these patients, as well as for those taking concomitant low-dose acetylsalicylic acid or other drugs that increase the risk of gastrointestinal complications, consideration should be given to using combination therapy with protective agents, such as misoprostol or proton pump inhibitors.

Patients with gastrointestinal toxicity, particularly elderly individuals, should be advised to report any unusual gastrointestinal symptoms, especially bleeding. This is particularly important during the initial stages of treatment. Patients taking concomitant medications that may increase the risk of ulceration or bleeding, such as corticosteroids, anticoagulants, selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., acetylsalicylic acid), should be informed about the need for caution when using nimesulide.

If gastrointestinal bleeding or ulceration occurs in a patient receiving nimesulide, treatment with the drug should be discontinued.

NSAIDs should be prescribed with caution in patients with a history of Crohn’s disease or ulcerative colitis, as nimesulide may exacerbate these conditions.

Concomitant use of nimesulide with other medicinal products, such as oral contraceptives, anticoagulants, and antiplatelet agents, may trigger exacerbations of Crohn’s disease and other gastrointestinal disorders.

Patients with hypertension and/or heart failure in their medical history, as well as those experiencing fluid retention and edema due to NSAID use, require appropriate monitoring and physician consultation.

Clinical studies and epidemiological data suggest that certain NSAIDs, particularly at high doses and with prolonged use, may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction and stroke. Data on the risk of such events with nimesulide are insufficient. Nimesulide should be prescribed only after careful evaluation in patients with uncontrolled hypertension, acute heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking) should also be carefully assessed before initiating treatment.

Nimesulide should be used with caution in patients with renal or cardiac insufficiency due to the potential for worsening renal function. Treatment should be discontinued if the patient's condition deteriorates. Elderly patients require close clinical monitoring due to the risk of gastrointestinal bleeding and perforation, and worsening of renal, hepatic, or cardiac function. Since nimesulide may affect platelet function, it should be used cautiously in patients with hemorrhagic diathesis. However, nimesulide does not replace acetylsalicylic acid for the prevention of cardiovascular diseases.

The use of nonsteroidal anti-inflammatory drugs may mask fever associated with underlying bacterial infection. If fever or flu-like symptoms occur in patients taking nimesulide, the drug should be discontinued.

Skin reactions

Cases of fixed drug eruption have been reported with nimesulide use. Nimesulide should not be re-administered to patients with a history of fixed drug eruption related to its use (see section "Adverse reactions").

Rare cases of severe skin reactions, some of which may be fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAID use. The risk of such reactions is particularly high if a previous reaction occurred during earlier treatment, typically within the first month of therapy. Nimesulide should be discontinued at the first signs of skin rash, mucosal lesions, or other allergic manifestations.

Nimesulide may impair female fertility and is not recommended for women attempting to conceive. Nimesulide should not be prescribed to women experiencing infertility or undergoing fertility investigations.

Use during pregnancy or breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological data suggest that use of prostaglandin synthesis inhibitors during early pregnancy may increase the risk of spontaneous abortion 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.

From the 20th week of gestation, NSAID use may cause oligohydramnios due to fetal renal dysfunction. This effect may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of fetal arterial duct constriction after NSAID treatment in the second trimester, which typically resolves after stopping treatment. Therefore, nimesulide should not be used during the first and second trimesters of pregnancy unless absolutely necessary. If use is required in women attempting to conceive or during the first or second trimester, the lowest possible dose and shortest possible duration of treatment should be selected.

Prenatal monitoring for oligohydramnios and arterial duct constriction may be advisable within several days of exposure, starting from the 20th gestational week. The drug should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may cause the following in the fetus:

• cardiopulmonary toxicity (with premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure and oliguria.

In the mother and fetus near term, the following may occur:

• prolonged bleeding time and antiplatelet effects, even with very low doses;
• inhibition of uterine contractility, potentially leading to delayed or prolonged labor.

Therefore, nimesulide is contraindicated during the third trimester of pregnancy.

As an NSAID that inhibits prostaglandin synthesis, nimesulide may cause premature closure of the ductus arteriosus, pulmonary hypertension, oliguria, and oligohydramnios. The risk of bleeding, weak labor, and peripheral edema increases. There are isolated reports of renal failure in newborns whose mothers used nimesulide near the end of pregnancy. Animal studies have demonstrated atypical reproductive toxicity of the drug, but reliable data on the use of nimesulide in pregnant women are lacking.

Since it is unknown whether nimesulide passes into breast milk, its use is contraindicated during breastfeeding.

Ability to affect driving performance or operating machinery. The effect of nimesulide on the ability to drive or operate machinery has not been studied. However, patients who experience dizziness, vertigo, or somnolence after taking nimesulide should refrain from driving or operating machinery.

Method of Administration and Dosage

To minimize the potential for adverse effects, the lowest effective dose should be used for the shortest duration necessary.

The maximum duration of treatment is 15 days.

Adults. One tablet (100 mg) twice daily – in the morning and evening.

Elderly patients. Dose adjustment is not required.

Children aged 12 years and older. Dose adjustment is not required.

Patients with renal impairment. Dose adjustment is not required in patients with mild or moderate renal impairment (creatinine clearance 30–80 mL/min). However, severe renal impairment (creatinine clearance < 30 mL/min) is a contraindication to the use of this drug.

The medication should be taken orally after meals with sufficient amount of liquid.

Adverse effects may be minimized by using the shortest duration of treatment needed to control symptoms.

Children. The medicinal product is contraindicated in children under 12 years of age.

Overdose.

Symptoms of acute overdose with nonsteroidal anti-inflammatory drugs (NSAIDs) are usually limited to: apathy, drowsiness, nausea, vomiting, epigastric pain. These symptoms are generally reversible with supportive therapy. Gastrointestinal bleeding, arterial hypertension, acute renal failure, respiratory depression, and coma may occur, although such events are rare. Anaphylactoid reactions have been reported during therapeutic use of NSAIDs as well as in cases of overdose. There is no specific antidote. Treatment of overdose is symptomatic and supportive. There are no data on the elimination of nimesulide by hemodialysis; however, considering the high degree of plasma protein binding of nimesulide (up to 97.5%), dialysis is unlikely to be effective. If symptoms of overdose are present or a large dose has been ingested, within 4 hours of intake, patients may be given: induced emesis and/or activated charcoal (60–100 g for adults) and/or an osmotic laxative. Forced diuresis, alkalinization of urine, hemodialysis, and hemoperfusion may be ineffective due to the high degree of plasma protein binding of nimesulide. Renal and hepatic function should be monitored.

Adverse Reactions

Blood system disorders: anemia, eosinophilia, thrombocytopenia, pancytopenia, purpura.

Immune system disorders: hypersensitivity reactions, anaphylaxis.

Metabolic disorders: hyperkalemia.

Psychiatric disorders: anxiety, nervousness, night terrors.

Nervous system disorders: dizziness, headache, somnolence, encephalopathy (Reye’s syndrome).

Eye disorders: blurred vision, visual disturbances.

Ear and labyrinthine disorders: vertigo (dizziness).

Cardiovascular disorders: tachycardia, hemorrhage, blood pressure lability, flushing, arterial hypertension.

Respiratory system disorders: dyspnea, asthma, bronchospasm.

Gastrointestinal disorders: diarrhea, nausea, vomiting, constipation, flatulence, gastritis, abdominal pain, dyspepsia, stomatitis, black stools, gastrointestinal bleeding, peptic ulcer and perforation of the stomach or duodenum.

Hepatobiliary disorders: hepatitis, fulminant hepatitis (including fatal cases), jaundice, cholestasis, increased liver enzyme levels.

Skin and subcutaneous tissue disorders: pruritus, skin rashes, fixed drug eruption (see section "Special precautions"), increased sweating, erythema, dermatitis, urticaria, angioneurotic edema, facial swelling, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Renal and urinary disorders: dysuria, hematuria, urinary retention, edema, renal failure, oliguria, interstitial nephritis.

General disorders: edema, malaise, asthenia, hypothermia.

Laboratory findings: elevated liver enzymes.

Adverse reactions affecting the gastrointestinal tract are most commonly observed during the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Peptic ulcers, gastrointestinal perforation, or bleeding, sometimes life-threatening, may occur, particularly in elderly patients. Reports have been received on the following adverse reactions after using this class of drugs: nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, black stools, vomiting with blood, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease, gastritis, development of edema, arterial hypertension, and heart failure. Skin reactions such as blistering, Stevens-Johnson syndrome, and toxic epidermal necrolysis have also been reported.

Clinical and epidemiological studies indicate that certain NSAIDs, especially when used at high doses and for prolonged periods, may lead to a small increase in the risk of arterial thrombotic events, such as myocardial infarction or stroke.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister pack, 2 blister packs in a cardboard box.

Prescription category. Prescription only.

Manufacturer 1.

Dr. Reddy’s Laboratories Ltd, FTO – II

Address of manufacturer and site of operation.

Survey Nos. 42R, 43, 44R, 45R, 46R, 53, 54, 83, Bachupally, Bachupally Mandal, Medchal Malkajgiri District – 500090, Telangana State, India

Manufacturer 2.

Dr. Reddy’s Laboratories Limited

Address of manufacturer and site of operation.

Unit-VI, Khol, Nalagarh Road, Baddi, Solan District, Himachal Pradesh, 173205, India

Adverse reactions or lack of efficacy with this medicinal product should be reported via the following phone numbers:

+380 44 207 51 97 or +380 50 414 39 39; or by email at: [email protected] (available 24/7).