Remesulid® rapid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REMESULIDE® RAPID (REMESULIDE RAPID)

Composition:

Active substance: nimesulide;

1 sachet contains nimesulide calculated as 100% dry substance – 100 mg;

Excipients: powdered sugar (sucrose); corn starch; spray-dried glucose syrup; polyethylene glycol (macrogol) cetyl stearyl ether; anhydrous citric acid; orange flavoring.

Pharmaceutical form. Granules for oral suspension.

Main physicochemical characteristics: granular powder of light yellow color with an orange odor.

Pharmacotherapeutic group. Other non-steroidal anti-inflammatory and anti-rheumatic drugs, nimesulide. ATC code M01AX17.

Pharmacological properties.

Pharmacodynamics.

Nimesulide belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs) with analgesic and antipyretic properties; nimesulide acts as an inhibitor of the enzyme cyclooxygenase, which is involved in the synthesis of prostaglandins.

Pharmacokinetics.

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

Plasma protein binding is 97.5%.

Nimesulide is extensively metabolized in the liver via various pathways, including the CYP2C9 isoenzyme of the cytochrome P450 system (CYP). Therefore, there is a potential for interaction with concomitantly administered drugs that are also metabolized by CYP2C9. The main metabolite is para-hydroxy derivative, which also possesses pharmacological activity. The time to appearance of this metabolite in blood is short (approximately 0.8 hours), but its rate of formation is low and significantly slower than the absorption rate of nimesulide. Hydroxynimesulide is almost completely conjugated and is the only metabolite detectable in plasma. Its elimination half-life (t½) ranges from 3.2 to 6 hours.

Nimesulide is primarily excreted via urine (approximately 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is detected only in the form of glucuronide. Approximately 29% of the administered dose is excreted in feces following biotransformation.

The pharmacokinetic profile of nimesulide in elderly patients was not altered after single or repeated dosing.

In studies involving 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 with impaired renal function did not exceed those in healthy volunteers. AUC and t½β (elimination half-life, beta phase) values were 50% higher but remained within the range of kinetic values observed in healthy volunteers receiving nimesulide.

Repeated administration of the drug did not lead to its accumulation in the body.

Nimesulide is contraindicated in patients with hepatic function impairment (see section "Contraindications").

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 overall assessment of risks for the individual patient.

Contraindications.

• Hypersensitivity to nimesulide or to any excipient of this medicinal product;
• History of hypersensitivity reactions (e.g., bronchospasm, rhinitis, urticaria, nasal polyps), including reactions to acetylsalicylic acid or other NSAIDs;
• History of hepatotoxic reactions associated with nimesulide;
• Concomitant use of other potentially hepatotoxic substances;
• Alcoholism, drug addiction;
• History of gastrointestinal bleeding or perforation related to previous NSAID therapy;
• Active or recurrent peptic ulcer/bleeding (two or more distinct episodes of confirmed ulceration or bleeding);
• Cerebrovascular hemorrhage or other active bleeding or disorders associated with bleeding tendency;
• Severe coagulation disorders;
• Severe heart failure;
• Severe renal impairment;
• Hepatic dysfunction;
• Patients with fever and/or flu-like symptoms;
• Children under 12 years of age;
• Third trimester of pregnancy and breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

Other NSAIDs: Concomitant use of Remesulide**®** Rapid and other NSAIDs, including acetylsalicylic acid taken at anti-inflammatory doses (≥ 1 g – single dose or ≥ 3 g – total daily dose), is not recommended.

Glucocorticoids: Increase the risk of gastrointestinal ulcers and bleeding.

Anticoagulants: The anticoagulant effect of agents such as warfarin may be enhanced when used concomitantly with NSAIDs.

Patients receiving warfarin or similar anticoagulants have an increased risk of bleeding when treated with Remesulide**®** Rapid. Therefore, such combinations are not recommended and are contraindicated in patients with severe coagulation disorders. If combination cannot be avoided, coagulation parameters should be closely monitored.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): Concomitant use of antiplatelet agents or SSRIs increases the risk of gastrointestinal bleeding.

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (AIIAs): NSAIDs may reduce the efficacy of diuretics and antihypertensive agents.

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 deterioration of renal function, including the possibility of acute renal failure, which is usually reversible.

This interaction should be considered in patients who must receive Remesulide**®** Rapid concomitantly with ACE inhibitors or angiotensin II antagonists. If these medicinal products are used together, the following precautions should be taken, especially in elderly patients: patients should be adequately hydrated, and renal function should be monitored from the start of combination therapy and periodically thereafter.

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

Furosemide. In healthy volunteers, nimesulide transiently reduces furosemide's effect on sodium excretion and, to a lesser extent, on potassium excretion, and also diminishes the response to diuretic administration.

Concomitant use of nimesulide and furosemide results in a reduction (by approximately 20%) in AUC and cumulative excretion of furosemide, without changes in renal clearance.

Caution should be exercised when administering nimesulide and furosemide concomitantly in patients with impaired cardiac or renal function.

Lithium. According to some reports, NSAIDs reduce lithium clearance, leading to increased plasma lithium levels and potential toxicity. If nimesulide is prescribed to patients receiving lithium therapy, lithium levels should be closely monitored.

Possible pharmacokinetic interactions with glyburide, theophylline, warfarin, digoxin, cimetidine, and antacid agents (aluminum hydroxide and magnesium hydroxide combination) have also been studied in vivo. No clinically significant interactions were observed.

Nimesulide inhibits CYP2C9. Plasma concentrations of medicinal products metabolized by this enzyme may increase when used concomitantly with nimesulide.

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

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

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

In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid, and valproic acid.

However, despite a potential effect on plasma levels, these interactions have no clinical significance.

Special precautions for use.

The risk of adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control disease symptoms.

Nimesulide must not be used concomitantly with NSAIDs, including selective COX-2 inhibitors. In addition, patients should be advised to avoid concomitant use of other analgesics.

If no positive treatment effect is observed, the drug should be discontinued.

Hepatic function

Rare cases of serious hepatic reactions, including very rare cases with fatal outcome, have been reported with the use of nimesulide. Treatment must be discontinued in patients who develop symptoms of liver dysfunction (e.g., anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine) during treatment with Remesulide**®** Rapid, or in patients with abnormal liver function test results. Nimesulide should not be re-administered to such patients. Liver function abnormalities have been reported after short-term use of nimesulide, which in most cases were reversible.

Treatment should be discontinued in patients taking nimesulide who develop fever and/or influenza-like symptoms.

Gastrointestinal effects

Gastrointestinal bleeding, ulceration, and perforation: gastrointestinal bleeding, ulceration, and perforation, which may be fatal, have been reported for all NSAIDs at any time during therapy, with or without warning symptoms, including in patients without prior gastrointestinal disorders.

The risk of gastrointestinal bleeding, ulceration, and perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. Such patients should use the lowest effective dose. Concomitant use of protective agents (e.g., misoprostol or proton pump inhibitors) should be considered for these patients, as well as for patients receiving concomitant low-dose acetylsalicylic acid or other medicinal products that increase the risk of gastrointestinal injury.

Patients with a history of gastrointestinal toxicity, particularly elderly patients, should be advised to report any unusual gastrointestinal symptoms (including gastrointestinal bleeding), especially at the beginning of treatment.

Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, with or without warning symptoms or prior gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, nimesulide should be discontinued. Nimesulide should be used with caution in patients with gastrointestinal disorders, including peptic ulcers, gastrointestinal bleeding, ulcerative colitis, or Crohn’s disease in their history.

Caution is advised in patients taking other medicinal products that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), SSRIs, or antiplatelet agents such as acetylsalicylic acid.

If gastrointestinal ulcers or bleeding occur during treatment with Remesulide**®** Rapid, treatment should be discontinued.

The medicinal product should be used with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease), as their condition may worsen.

Elderly patients

Adverse reactions occur more frequently in elderly patients taking NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal. Therefore, clinical monitoring of such patients is recommended.

Cardiovascular and cerebrovascular effects

Patients with a history of hypertension and/or mild to moderate heart failure should be monitored, as fluid retention and edema have been reported during NSAID treatment.

Clinical studies and epidemiological data suggest that the use of some NSAIDs (especially at high doses and for prolonged periods) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). There are insufficient data to exclude this risk with nimesulide.

The use of nimesulide should be carefully considered in patients with poorly controlled hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Similarly, initiation of long-term treatment in patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking) should be evaluated cautiously.

Since nimesulide may affect platelet function, it should be used with caution in patients with hemorrhagic diathesis. Remesulide**®** Rapid is not a substitute for acetylsalicylic acid in the prevention of cardiovascular diseases.

Renal function

Caution should be exercised in patients with impaired renal function or cardiac disease, as nimesulide may lead to deterioration of renal function. If such impairment occurs, treatment should be discontinued.

Skin effects

Serious skin reactions, which in some cases were fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported during NSAID treatment. These reactions are most likely to occur early in treatment, with onset typically within the first month. Treatment with Remesulide**®** Rapid should be discontinued at the first signs of skin rash, mucosal lesions, or any other symptoms of hypersensitivity.

Skin reactions

Cases of fixed drug eruption have been reported with the use of nimesulide.

Nimesulide should not be re-administered to patients with a history of fixed drug eruption associated with nimesulide (see section "Adverse reactions").

Effect on fertility

Use of nimesulide may lead to reduced fertility in women; therefore, it is not recommended for use when a woman is planning pregnancy. In women who are unable to conceive or in whom infertility is suspected, discontinuation of treatment with Remesulide**®** Rapid should be considered.

Remesulide**®** Rapid granules for oral suspension contain sugar; therefore, if intolerance to certain sugars is diagnosed, consultation with a physician is necessary before taking this medicinal product. The sugar content of the medicinal product may be harmful to teeth.

Use during pregnancy or breastfeeding.

Use of Remesulide**®** Rapid is contraindicated during the third trimester of pregnancy.

As with other NSAIDs, use of Remesulide**®** Rapid is not recommended in women attempting to conceive. Women who are unable to conceive or undergoing infertility evaluation should consider discontinuing nimesulide. If pregnancy is confirmed during nimesulide treatment, the physician should be informed.

Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of spontaneous abortion, congenital heart defects, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformation increased from less than 1% to nearly 1.5%. The risk is believed to increase with higher doses and longer duration of treatment.

Animal studies have shown that prostaglandin synthesis inhibitors cause increased pre- and post-implantation loss and embryonic/fetal mortality. In addition, increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed in animals treated with prostaglandin synthesis inhibitors during organogenesis.

Reproductive toxicity has been demonstrated in rabbits, but there are no reliable data on the use of nimesulide in pregnant women.

From the 20th week of pregnancy, use of nimesulide may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction after second-trimester treatment, most of which resolved after stopping treatment.

The potential risk to humans is not fully defined; therefore, use of the drug during the first and second trimesters of pregnancy is not recommended unless clearly necessary.

If Remesulide**®** Rapid is used in women attempting to conceive or in women during the first and second trimesters of pregnancy, the effective dose should be the lowest possible and the treatment duration the shortest possible.

Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to nimesulide for several days starting from the 20th gestational week. Treatment with Remesulide**®** Rapid should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may lead to:

• in the fetus:
  • cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
  • renal dysfunction, potentially progressing to renal failure with oligohydramnios (see above);
• in the mother and fetus at the end of pregnancy:
  • prolonged bleeding time and anti-aggregatory effect, which may occur even with very low doses;
  • inhibition of uterine contractility, potentially leading to delayed or prolonged labor.

For these reasons, Remesulide**®** Rapid is contraindicated during the third trimester of pregnancy (see section "Contraindications").

It is unknown whether nimesulide is excreted in human breast milk. Remesulide**®** Rapid is contraindicated in women who are breastfeeding.

Ability to influence reaction rate while driving or operating machinery.

Studies on nimesulide related to its possible effect on the ability to drive or operate machinery have not been conducted. However, patients who experience dizziness, headache, or somnolence after taking Remesulide**®** Rapid should refrain from driving or operating machinery.

Method of Administration and Dosage

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

The medicinal product is recommended to be taken after food intake.

The contents of the sachet should be poured into a glass, dissolved with water, and taken orally.

The maximum duration of treatment with nimesulide is 15 days.

Adults: 1 sachet of 100 mg twice daily.

Elderly patients: dose adjustment is not required.

Children from 12 years of age: dose adjustment is not required.

Children under 12 years of age: nimesulide is contraindicated in children under 12 years of age.

Renal Impairment

Considering the pharmacokinetics, dose adjustment is not required for patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). However, in cases of severe renal impairment (creatinine clearance < 30 mL/min), the medication Remesulid**®** Rapid is contraindicated.

Hepatic Impairment

The medication Remesulid**®** Rapid is contraindicated in patients with hepatic impairment.

Children

To be used in children aged 12 years and older.

Overdose

Symptoms of acute NSAID overdose are usually limited to apathy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive therapy. Gastrointestinal bleeding may occur. Additionally, arterial hypertension, acute renal failure, respiratory depression, and coma may be observed, although such events are rare. There have been reports of anaphylactoid reactions with therapeutic doses of NSAIDs, which may also occur in cases of overdose.

In the event of overdose, symptomatic and supportive treatment should be administered. There are no specific antidotes. There is no information regarding the effectiveness of hemodialysis, but considering the high plasma protein binding of nimesulide (up to 97.5%), dialysis is unlikely to be effective in overdose management. 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 functions should be monitored.

Adverse Reactions

Clinical studies and epidemiological data indicate that the use of certain NSAIDs (particularly at high doses and with prolonged use) may be associated with a moderate increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Treatment with NSAIDs has also been associated with reports of edema, arterial hypertension, and heart failure. Very rare cases of skin blistering reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported.

The most commonly observed adverse reactions are gastrointestinal. Peptic ulcers, gastrointestinal perforation, or gastrointestinal bleeding, sometimes fatal, may occur—particularly in elderly patients. Following treatment, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, black stools, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn’s disease have also been observed. Gastritis has been reported less frequently.

The following list of adverse reactions is based on data from controlled clinical trials and post-marketing surveillance with subsequent assessment of the frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare, including isolated cases (< 1/10,000); frequency not known (cannot be estimated from available data).

* Frequency is based on clinical trials.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

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

Keep out of reach and sight of children.

Packaging. 100 mg/2 g in sachets. 10 sachets per pack.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.