INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DAIMISYL (DAIMISYL)

Composition:

Active substance: nimesulide;

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

Excipients: powdered sugar (sugar powder); corn starch; spray-dried glucose solution; polyethylene glycol (macrogol) cetostearyl ether; anhydrous citric acid; orange-flavored flavoring.

Pharmaceutical form. Granules for oral suspension.

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

Pharmacotherapeutic group. Other nonsteroidal anti-inflammatory and antirheumatic 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. AUC equals 20–35 mg*h/L. No statistically significant differences were observed between these parameters and the corresponding values after administration of a 100 mg dose of nimesulide twice daily for 7 days.

Protein binding to plasma proteins 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 excreted predominantly in 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 kinetic 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 subjects with impaired renal function did not exceed those in healthy volunteers. AUC and t1/2 beta (elimination half-life, beta-phase) values were 50% higher but remained within the kinetic range observed after nimesulide administration in healthy volunteers.

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

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 to 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) in history;
Cerebrovascular bleeding or other active bleeding or disorders associated with bleeding tendency;
Severe disorders of the blood coagulation system;
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 or breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

Other NSAIDs: Concomitant use of Daimisil and other NSAIDs, including acetylsalicylic acid administered in anti-inflammatory doses (≥ 1 g – single dose or ≥ 3 g – total daily dose), is not recommended.

Corticosteroids: Increase the risk of gastrointestinal ulceration and bleeding.

Anticoagulants: The effect of anticoagulants 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 Daimisil. Therefore, such combinations are contraindicated in patients with severe coagulation disorders. If combination cannot be avoided, blood 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 ulceration or 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 take Daimisil concomitantly with ACE inhibitors or angiotensin II antagonists. When these medicinal products are used together, the following precautions should be taken, especially in elderly patients: patients should be adequately hydrated, and their 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 the effect of furosemide on sodium excretion and to a lesser extent on potassium excretion, and reduces the response to diuretic administration.

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

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

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

In vivo studies have also investigated possible pharmacokinetic interactions with glyburide, theophylline, warfarin, digoxin, cimetidine, and antacid agents (a combination of aluminium hydroxide and magnesium hydroxide). No clinically significant interactions were observed.

Nimesulide inhibits CYP2C9. Plasma concentrations of medicinal products metabolized by this enzyme may increase when administered 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 thereby increase the toxicity of this medicinal product.

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, regardless of the possible 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 cyclooxygenase-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 effects. Rare cases have been reported in which nimesulide use was associated with serious hepatic reactions, including very rare cases with fatal outcome. Treatment must be discontinued in patients who develop symptoms of liver disorders (e.g., anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine) during treatment with Daimisil, or in patients with abnormal liver function test results. Nimesulide should not be re-administered to such patients. Liver function abnormalities have been observed 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: For all NSAIDs, gastrointestinal bleeding, ulceration, and perforation, which may be fatal, have been reported at any time during treatment, 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 be treated with 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 drugs increasing 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 in the medical history. If a patient develops gastrointestinal bleeding or ulcerative damage, nimesulide use 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 medical history.

Caution is required in patients taking concomitant medications that may increase the risk of ulcerative damage or bleeding, such as oral corticosteroids, anticoagulants (including warfarin), SSRIs, or antiplatelet agents such as acetylsalicylic acid.

If gastrointestinal ulcers or bleeding occur during treatment with Daimisil, treatment should be discontinued.

NSAIDs 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, monitoring of the clinical status of these patients is recommended.

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

Clinical trials and epidemiological data suggest that the use of certain NSAIDs (particularly 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 use.

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

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

Renal function effects. Caution should be exercised in patients with impaired renal function and cardiac disease, as nimesulide use may lead to worsening renal function. If such deterioration 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 pose the greatest risk at the beginning of treatment, with onset usually occurring within the first month of therapy. Daimisil treatment 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 nimesulide use.

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

Effects on fertility. Nimesulide use may lead to reduced fertility in women; therefore, the drug is not recommended in women planning pregnancy. In women who are unable to conceive or in whom infertility is suspected, consideration should be given to discontinuing Daimisil treatment.

Daimisil oral granules for suspension contain sugar and are therefore contraindicated in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Daimisil is contraindicated during the third trimester of pregnancy.

As with other NSAIDs, Daimisil is not recommended for women attempting to conceive.

Inhibition of prostaglandin synthesis may have adverse effects on pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of spontaneous abortion, fetal cardiac malformations, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to nearly 1.5%. The risk is considered to increase with higher doses and longer duration of treatment.

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

Rabbit studies have shown atypical reproductive toxicity, but there are no reliable human data on nimesulide use in pregnant women. Therefore, the potential risk to humans is not established. From the 20th week of pregnancy, nimesulide use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after treatment initiation and is usually reversible upon discontinuation of treatment. Additionally, there have been reports of arterial duct constriction after second-trimester treatment, most of which resolved after treatment discontinuation. Therefore, Daimisil use during the first and second trimesters of pregnancy is not recommended unless absolutely necessary.

If Daimisil 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 should be as short as possible. Monitoring for oligohydramnios and arterial duct constriction should be considered after several days of nimesulide exposure, starting from the 20th gestational week. Daimisil treatment should be discontinued if oligohydramnios or arterial duct 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 arterial duct and pulmonary hypertension);
- renal dysfunction leading to renal failure with oligohydramnios (see above);
in the mother and fetus at the end of pregnancy:
- possible prolongation of bleeding time and antiplatelet effect, which may occur even with very low doses;
- inhibition of uterine contractility, potentially leading to delayed or prolonged labor.

For these reasons, Daimisil is contraindicated during the third trimester of pregnancy (see section "Contraindications").

It is unknown whether nimesulide passes into human breast milk. Daimisil is contraindicated in breastfeeding women.

Ability to influence reaction speed when driving vehicles or operating machinery.

No studies on the effects of nimesulide on the ability to drive vehicles or operate machinery have been conducted. However, patients who experience dizziness, headache, or drowsiness after taking Daimisil should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage

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

The medication should be taken after food intake.

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

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 aged 12 years and older: dose adjustment is not required.

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

Renal Impairment

Based on 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 medicinal product Daimisil is contraindicated.

Hepatic Impairment

Daimisil 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 care. 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 NSAID overdose, symptomatic and supportive therapy should be administered. There are no specific antidotes available. There is no information regarding the effectiveness of hemodialysis; however, due to the high degree of 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, activated charcoal (60–100 g for adults) and/or an osmotic laxative may be administered within 4 hours of drug intake. Forced diuresis, urine alkalinization, hemodialysis, and hemoperfusion may be ineffective due to the high 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 (especially at high doses and with long-term 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 serious skin reactions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

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

Below is a list of adverse reactions based on controlled clinical trials and post-marketing surveillance. The frequency of adverse reactions is defined as follows: 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 isolated cases; unknown (cannot be estimated from available data).

Eye disorders:
Rare – blurred vision*; very rare – visual disturbances.

Ear and labyrinth disorders:
Very rare – vertigo.

Respiratory system disorders:
Uncommon – dyspnea*; very rare – asthma, bronchospasm.

Gastrointestinal disorders:
Common – diarrhea*, nausea*, vomiting*; uncommon – constipation*, flatulence*, gastrointestinal bleeding, gastric or duodenal ulcer and perforation; very rare – gastritis*, abdominal pain, dyspepsia, stomatitis, black stools.

Hepatobiliary disorders:
Common – increased liver enzyme levels*; very rare – hepatitis, fulminant hepatitis (including fatal cases), jaundice, cholestasis.

Renal and urinary system disorders:
Rare – dysuria*, hematuria*; very rare – urinary retention*, renal failure, oliguria, interstitial nephritis.

Metabolism and nutrition disorders:
Rare – hyperkalemia*.

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

Psychiatric disorders:
Rare – anxiety*, nervousness*, nightmares.

Cardiovascular system disorders:
Rare – tachycardia*; uncommon – arterial hypertension*; rare – hemorrhage*, blood pressure fluctuations*, flushing*.

Blood and lymphatic system disorders:
Rare – anemia*, eosinophilia*; very rare – thrombocytopenia, pancytopenia, purpura.

Immune system disorders:
Rare – hypersensitivity reactions*; very rare – anaphylaxis.

Skin and subcutaneous tissue disorders:
Uncommon – pruritus*, rash*, increased sweating*; rare – erythema*, dermatitis*; very rare – urticaria, angioneurotic edema, facial swelling, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis; unknown – fixed drug eruption (see section "Special precautions").

General disorders:
Uncommon – edema*; rare – malaise*, asthenia*; very rare – hypothermia.

* Frequency based on clinical trials

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: 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 reach and sight of children.

Packaging. 2 g per sachet. 10 sachets per pack.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.
74, Kyrylivska Street, Kyiv, 04080, Ukraine.