Remisar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REMISAR (Remisar)

Composition:

Active substance: nimesulide;

1 sachet of 2 g granules contains nimesulide 100 mg;

Excipients: polyethylene glycol (macrogol) cetostearyl ether, maltodextrin, citric acid anhydrous, orange flavor, crystalline sugar.

Pharmaceutical form. Granules for oral suspension.

Main physicochemical properties: granules of light yellow to yellow color.

Pharmacotherapeutic group. Non-selective non-steroidal anti-inflammatory drugs.

ATC code M01AX17.

Pharmacological properties.

Pharmacodynamics.

Nimesulide is a non-steroidal anti-inflammatory agent with analgesic and antipyretic properties, acting as an inhibitor of the enzyme cyclooxygenase, which is responsible for the synthesis of prostaglandins.

Pharmacokinetics.

Absorption. Nimesulide is well absorbed after oral administration. After a single 100 mg dose of nimesulide in adults, maximum plasma concentration is reached within 2–3 hours and amounts to 3–4 mg/L. The area under the plasma concentration-time curve (AUC) ranges from 20 to 35 mg·h/L. No statistically significant differences were observed between these parameters and those after administration of 100 mg twice daily for 7 days. Approximately 97.5% of nimesulide is bound to plasma proteins.

Biotransformation and elimination. Nimesulide is actively metabolized in the liver via multiple pathways, including the cytochrome P450 isoenzyme CYP2C9. Therefore, there is a potential for drug interactions when used concomitantly with medicinal products metabolized by CYP2C9 (see section "Interaction with other medicinal products and other forms of interactions"). The main metabolite is the para-hydroxy derivative, which also possesses pharmacological activity. The time to detection of this metabolite in circulating blood is short (approximately 0.8 hours), but the rate constant of its formation is low and significantly less than the absorption coefficient of nimesulide. Hydroxynimesulide is the only metabolite detected in plasma and is almost entirely present in a conjugated form. The elimination half-life ranges from 3.2 to 6 hours. Nimesulide is primarily excreted from the body via urine (approximately 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is exclusively excreted as glucuronide. Approximately 29% of the administered dose is excreted in feces in metabolized form. The pharmacokinetic profile of nimesulide in elderly patients is not altered after single or repeated doses.

In a short-term clinical study conducted in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min) and healthy volunteers, maximum plasma concentrations of nimesulide and its main metabolite in patients were not higher than those in healthy volunteers. AUC and elimination half-life in patients with renal impairment were approximately 50% higher but remained within the range of pharmacokinetic parameters observed in healthy volunteers receiving nimesulide. Repeated administration did not lead to accumulation. Nimesulide is contraindicated in patients with hepatic impairment (see section "Contraindications").

Preclinical safety data.

Preclinical data obtained from standard pharmacological safety, repeat-dose toxicity, genotoxicity, and carcinogenicity studies revealed no special hazard for humans. In repeat-dose toxicity studies, nimesulide showed gastrointestinal, renal, and hepatic toxicity. In reproductive toxicity studies, embryotoxic and teratogenic effects (skeletal malformations, brain ventricle dilation) were observed in rabbits but not in rats when administered to females at non-toxic doses. In rats, increased postnatal mortality in offspring and adverse effects on fertility were observed.

Clinical characteristics.

Indications.

Treatment of acute pain, primary dysmenorrhea.

Nimesulide should only be used as a second-line medicinal product.

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

Contraindications.

• Known hypersensitivity to nimesulide, to any other NSAID, or to any of the excipients of the medicinal product.
• History of hypersensitivity reactions (e.g., bronchospasm, rhinitis, urticaria) associated with the use of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.
• History of hepatotoxic reactions to nimesulide.
• Concomitant use of other substances with potential hepatotoxicity.
• Alcoholism and drug dependence.
• History of gastrointestinal bleeding or perforation related to previous use of NSAIDs.
• Active peptic ulcer or history of gastrointestinal bleeding, ulcer, or perforation.
• Cerebrovascular hemorrhage or other bleeding disorders, as well as diseases associated with bleeding tendency.
• Severe coagulation disorders.
• Severe heart failure.
• Severe renal impairment.
• Severe hepatic dysfunction.
• Fever and/or flu-like symptoms.
• Children under 12 years of age.
• Third trimester of pregnancy and breastfeeding period (see section "Use during pregnancy or breastfeeding" and preclinical safety data).

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Corticosteroids. Corticosteroids may increase the risk of gastrointestinal ulceration or bleeding (see section "Special precautions for use").

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 "Special precautions for use").

Anticoagulants. NSAIDs may enhance the effect of anticoagulants such as warfarin (see section "Special precautions for use"). When treating patients receiving warfarin or similar anticoagulants or acetylsalicylic acid with nimesulide, there is an increased risk of bleeding complications; therefore, such combination is not recommended (see also section "Special precautions for use") and is contraindicated in patients with severe coagulation disorders (see also section "Contraindications"). If combined therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (AIIAs). NSAIDs may reduce the effectiveness of diuretics and other antihypertensive medicinal products. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), 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. Such interactions should be considered in patients receiving nimesulide-containing medicinal products together with ACE inhibitors or AIIAs. Therefore, such combination should be prescribed with caution, especially in elderly patients. Patients should receive adequate fluid intake. The need for monitoring renal function after initiation of concomitant therapy and periodically after its discontinuation should be evaluated.

Other nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant use of medicinal products containing nimesulide (see section "Clinical characteristics") with other NSAIDs, including acetylsalicylic acid at anti-inflammatory doses (≥ 1 g as a single dose or ≥ 3 g daily), is not recommended.

Pharmacokinetic interactions: effect of nimesulide on the pharmacokinetics of other medicinal products

Furosemide. In healthy volunteers, nimesulide transiently reduces the sodium excretion effect of furosemide and to a lesser extent potassium excretion, thereby reducing the diuretic effect. Concomitant administration of nimesulide and furosemide results in a reduction (by approximately 20%) in the area under the concentration-time curve (AUC) and cumulative excretion of furosemide, without changes in renal clearance of furosemide. Concomitant use of furosemide and nimesulide-containing medicinal products in patients with impaired renal or cardiac function requires caution (see section "Special precautions for use").

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

Pharmacokinetic interactions: effect of other medicinal products on the pharmacokinetics of nimesulide.

In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid, and valproic acid. Despite a possible effect on its plasma concentration, such interactions are not clinically significant.

Other interactions.

Possible pharmacokinetic interactions with glyburide (glibenclamide), theophylline, warfarin, digoxin, cimetidine, and antacids (specifically aluminum and magnesium hydroxide combination) in vivo. No clinically significant interactions have been observed.

Nimesulide inhibits the activity of the CYP2C9 enzyme. Plasma concentrations of medicinal products that are substrates of this enzyme may increase when used concomitantly with the medicinal product Remisar.

Caution is required when nimesulide is administered less than 24 hours before or less than 24 hours after methotrexate, as this may increase methotrexate serum levels and enhance its toxicity.

Due to its effect on renal prostaglandins, prostaglandin synthetase inhibitors such as nimesulide may increase the nephrotoxicity of cyclosporine.

Special precautions for use.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control disease symptoms (see section "Dosage and administration" and the risks related to the gastrointestinal tract and cardiovascular system below).

If treatment is ineffective, therapy with the medicinal product should be discontinued.

Concomitant use of nimesulide with NSAIDs, including selective COX-2 inhibitors, should be avoided. Patients receiving Remisar should be advised to refrain from using other analgesics.

During treatment with nimesulide, concomitant use of hepatotoxic drugs should be avoided, and alcohol consumption should be refrained from. The use of NSAIDs may mask fever associated with underlying bacterial infection.

Hepatic effects.

Serious liver-related reactions, including very rare cases with fatal outcomes, have been reported with nimesulide (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury during nimesulide treatment—such as anorexia, nausea, vomiting, abdominal pain, fatigue, or dark urine—or those with abnormal liver function test results should discontinue therapy. Re-administration of nimesulide to such patients is contraindicated. Liver injury, mostly reversible, has been reported to occur after short-term exposure to the drug.

Patients taking nimesulide who develop fever and/or flu-like symptoms should discontinue treatment.

Gastrointestinal effects.

Gastrointestinal bleeding or ulceration/perforation has been reported during treatment with all NSAIDs, sometimes fatal, and may occur at any time during treatment, regardless of the presence or absence of warning symptoms or a history of serious gastrointestinal disorders. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Therapy in these patients should be initiated at the lowest possible effective dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risk, consideration should be given to using combination therapy with protective agents such as misoprostol or proton pump inhibitors (see below and section "Interaction with other medicinal products and other forms of interaction").

Patients with a history of gastrointestinal toxicity, particularly elderly patients, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly in the early stages of treatment.

Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, regardless of the presence or absence of warning symptoms or a history of serious gastrointestinal disorders. 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 "Adverse reactions").

Patients taking concomitant medications that may increase the risk of ulceration or bleeding—such as oral corticosteroids, anticoagulants like warfarin, selective serotonin reuptake inhibitors, or antiplatelet agents like acetylsalicylic acid—should be informed of the need for caution.

If gastrointestinal bleeding or ulceration occurs in patients receiving nimesulide, treatment should be discontinued.

NSAIDs should be used cautiously in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated (see section "Adverse reactions").

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

Effects on the cardiovascular and cerebrovascular systems.

Patients with a history of mild to moderate arterial hypertension and/or congestive heart failure require appropriate monitoring and medical consultation, as fluid retention and edema have been reported with NSAID therapy.

Clinical studies and epidemiological data suggest that the use of certain NSAIDs, particularly at high doses and with prolonged treatment, may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction or stroke. There are insufficient data to exclude such a risk with nimesulide.

Nimesulide should be used only after careful benefit-risk assessment in patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. A similar assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular disease, such as hypertension, hyperlipidemia, diabetes, or smoking.

Since nimesulide may affect platelet function, it should be used with caution in patients with hemorrhagic diathesis (see also section "Contraindications"). However, nimesulide does not substitute for acetylsalicylic acid in the prevention of cardiovascular disease.

Renal effects.

Caution is required in patients with impaired renal function or heart failure, as nimesulide use may lead to worsening renal function. If the patient's condition deteriorates, treatment should be discontinued (see also section "Interaction with other medicinal products and other forms of interaction").

Elderly patients.

Elderly patients may have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, sometimes fatal (see section "Adverse reactions"), as well as impaired renal, cardiac, and hepatic function. Therefore, appropriate clinical monitoring is recommended.

Skin reactions.

Serious skin reactions have very rarely been reported with NSAIDs, some of which may be life-threatening, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see section "Adverse reactions"). These reactions appear to occur most frequently early in the course of therapy, typically within the first month of treatment. Remisar should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs 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 nimesulide-associated FDE (see section "Adverse reactions").

Effects on fertility.

Nimesulide may impair female fertility and is not recommended for women attempting to conceive. Women experiencing difficulty conceiving or undergoing infertility evaluation should consider discontinuing Remisar (see section "Use during pregnancy or breastfeeding").

Important information on excipients.

Remisar contains sucrose. Patients with known sugar intolerance should consult their physician before taking Remisar.

This medicinal product should not be used by patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Pregnancy. Nimesulide is contraindicated during the third trimester of pregnancy (see section "Contraindications").

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 miscarriage 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.

In animal studies, prostaglandin synthesis inhibitors have led to increased pre- and post-implantation loss and elevated embryonic and fetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various fetal abnormalities, particularly cardiovascular, has been reported.

Starting from the 20th week of pregnancy, use of Remisar may cause oligohydramnios due to fetal renal dysfunction. This condition may occur early in treatment and is usually reversible upon discontinuation of therapy. In addition, cases of fetal arterial duct constriction have been reported after second-trimester exposure to the drug, most of which resolved after discontinuation of treatment.

Therefore, nimesulide should not be used during the first and second trimesters of pregnancy unless absolutely necessary. If nimesulide is used in women attempting to conceive or during the first and second trimesters of pregnancy, the lowest effective dose and shortest possible duration of treatment should be used.

Fetal monitoring for oligohydramnios and arterial duct constriction should be considered following nimesulide exposure over several days, starting from the 20th gestational week. If oligohydramnios or fetal arterial duct constriction is detected, pregnant women should discontinue the medicinal product.

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

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

In the mother and fetus towards the end of pregnancy, the following may occur:

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

Breastfeeding. Since it is unknown whether nimesulide is excreted in breast milk, its use is contraindicated during breastfeeding.

Fertility. As with other NSAIDs, nimesulide-containing medicinal products are not recommended for women attempting to conceive (see section "Special precautions for use"). Women experiencing difficulty conceiving or undergoing infertility evaluation should discontinue nimesulide. If pregnancy occurs during nimesulide treatment, the physician should be informed.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of nimesulide on the ability to drive or operate machinery have not been conducted. However, patients experiencing dizziness, vertigo, or somnolence after taking nimesulide should refrain from driving or operating machinery.

Method of Administration and Dosage.

Dosage.

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

The maximum duration of treatment with Remisar is 15 days.

Adults. 100 mg of nimesulide (1 sachet) twice daily after meals.

Elderly patients. No reduction in daily dose is required.

Children aged 12 years and older. Based on the pharmacokinetic profile in adults and the pharmacodynamic characteristics of nimesulide, dose adjustment is not required for children aged 12 to 18 years.

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 for the use of Remisar.

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

Method of Administration.

The contents of the sachet should be poured into a glass of still water. Stir with a spoon until a suspension with an orange odor is formed. The suspension should be taken immediately after mixing.

Children.

Remisar 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. 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 NSAID 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 occur or a large dose has been taken, within 4 hours of ingestion, patients may be given induced emesis and/or activated charcoal (60–100 g for adults) and an osmotic laxative. Forced diuresis, urine alkalinization, hemodialysis, and hemoperfusion may be ineffective due to the high degree of plasma protein binding of nimesulide. Renal and hepatic functions should be monitored.

Adverse Reactions

The adverse reactions listed below are based on data from controlled clinical studies* (approximately 7800 patients) and post-marketing surveillance, classified according to the following frequency categories: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1,000 – < 1/100), rare (≥ 1/10,000 – < 1/1,000), very rare (< 1/10,000), including rare cases, and frequency not known (cannot be estimated from the available data).

The most common adverse reactions associated with the use of NSAIDs are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation, or bleeding, which may sometimes be life-threatening, may occur, particularly in elderly patients (see section "Special precautions for use"). With nimesulide-containing medicinal products, nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis, and Crohn's disease have been reported (see section "Special precautions for use"). Gastritis has been observed less frequently. Cases of edema, arterial hypertension, and heart failure associated with NSAID therapy have been reported. Very rare cases of bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported.

Clinical and epidemiological studies suggest that some NSAIDs, particularly at high doses and with prolonged use, may lead to a small increase in the risk of arterial thrombotic events, such as myocardial infarction or stroke (see section "Special precautions for use").

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and/or lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging. 2 g granules in sachets; 30 sachets per box.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business. 13, Boryspylske Shose, Kyiv, 02093, Ukraine.

Marketing Authorization Holder. Limited Liability Company "STIF-SERVICE".

Address of the Marketing Authorization Holder. 57/106, Yubileynyy Prospekt, Kharkiv, 61118, Ukraine.