Dolorsil

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

Composition:

Active substance: nimesulide;

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

Excipients: powdered sugar (sucrose); maize starch; glucose syrup, spray-dried; polyethylene glycol (macrogol) cetostearyl ether; citric acid anhydrous; orange-flavored flavoring.

Pharmaceutical form. Granules for oral suspension.

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

Pharmacotherapeutic group. Other non-steroidal 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 is 20–35 mg*h/L. No statistically significant differences were observed between these parameters and the corresponding parameters after administration of a 100 mg dose of nimesulide twice daily for 7 days.

Plasma protein binding is 97.5%.

Nimesulide is extensively metabolized in the liver via multiple 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 the urine (approximately 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide, the main metabolite, is detected only in glucuronide form. 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 with nimesulide administered to 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 t1/2 beta (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 does not lead to its accumulation in the body.

Clinical characteristics.

Indications.

Treatment of acute pain, primary dysmenorrhea.

Nimesulide should be used only 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);
• 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 and lactation period.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

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

Corticosteroids: Increase the risk of gastrointestinal ulcers and bleeding.

Anticoagulants: The effect of anticoagulants such as warfarin may be enhanced when NSAIDs are used concomitantly.

Patients receiving warfarin or similar anticoagulants have an increased risk of bleeding when treated with Dolorsil. Therefore, such combinations 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 ulceration or gastrointestinal bleeding.

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (ARBs): 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 worsening of renal function, including the possibility of acute renal failure, which is usually reversible.

This interaction should be considered in patients who are to receive Dolorsil concomitantly with ACE inhibitors or angiotensin II antagonists. Precautions should be taken when these medicinal products are used together, 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 the effect of furosemide on sodium excretion and to a lesser extent on potassium excretion, and also 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 furosemide and nimesulide are used 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 is prescribed to patients receiving lithium therapy, lithium levels should be closely monitored.

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

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 administration of methotrexate, as this may lead to increased methotrexate serum levels and, consequently, increased toxicity of this medicinal product.

Due to its effect on renal prostaglandins, prostaglandin synthase inhibitors, including 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 potential impact on plasma levels, these interactions have no clinical significance.

Special precautions for use.

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

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

If no therapeutic benefit is observed, treatment should be discontinued.

Hepatic function effects. Rarely, serious hepatic reactions, including very rare cases with fatal outcome, have been reported during nimesulide use. 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 Dolorsil, or in patients with abnormal liver function tests. Re-administration of nimesulide is not recommended in such patients. Liver function abnormalities have been reported after short-term use of nimesulide and were mostly reversible.

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

Gastrointestinal effects. Gastrointestinal bleeding, ulceration, and perforation: gastrointestinal bleeding, ulceration, and perforation have been reported with all NSAIDs and may be fatal. These events can occur at any time during treatment, with or without preceding warning symptoms, and regardless of a history of 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 medicinal products that increase the risk of gastrointestinal injury.

Patients with a history of gastrointestinal toxicity, particularly elderly patients, should be informed 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 a history of gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, nimesulide should be discontinued. Nimesulide should be used with caution in patients with a history of gastrointestinal disorders, including peptic ulcers, gastrointestinal bleeding, ulcerative colitis, or Crohn’s disease.

Caution is advised in patients receiving concomitant medications that 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 Dolorsil, treatment should be discontinued.

NSAIDs should be used with caution in patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease), as their condition may worsen.

Elderly patients: NSAIDs are associated with a higher frequency of adverse reactions in elderly patients, particularly gastrointestinal bleeding and perforation, which may be fatal. Therefore, clinical monitoring of these patients is recommended.

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

Clinical trials and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and over prolonged periods) is 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. Particular caution is also required for long-term treatment of patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking).

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

Renal function effects. Caution is advised in patients with impaired renal function or cardiac disease, as nimesulide may lead to worsening of renal function. Treatment should be discontinued if such deterioration occurs.

Skin effects. Serious skin reactions, which in some cases have been fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely during NSAID therapy. These reactions usually occur early in treatment, most often within the first month. Treatment with Dolorsil 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 attempting to conceive. For women who are unable to conceive or in whom infertility is suspected, discontinuation of Dolorsil should be considered.

Dolorsil 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.

The use of Dolorsil is contraindicated during the third trimester of pregnancy.

Dolorsil is not recommended for women attempting to conceive.

Inhibition of prostaglandin synthesis may have adverse effects on pregnancy and/or embryonic/fetal development. Epidemiological studies have shown an increased risk of miscarriage and congenital heart defects and gastroschisis after 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 demonstrated that prostaglandin synthesis inhibitors increase pre- and post-implantation losses and embryonic/fetal mortality. In addition, increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed in animals treated with a prostaglandin synthesis inhibitor during organogenesis.

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

If Dolorsil is used in women attempting to conceive or in pregnant women during the first or second trimester, the dose should be the lowest effective dose and the treatment duration as short as possible.

Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after several days of nimesulide exposure, starting from the 20th gestational week. Dolorsil should be discontinued if oligohydramnios or arterial duct constriction is detected.

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

• in the fetus:
  • cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
  • renal dysfunction leading 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 contractions, potentially leading to delayed or prolonged labor.

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

It is unknown whether nimesulide is excreted in human breast milk. Dolorsil is contraindicated in women who are breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

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

Dosage and Administration

To minimize the potential for adverse effects, 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 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

Due to the pharmacokinetic profile, dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). In cases of severe renal impairment (creatinine clearance < 30 mL/min), the medicinal product Dolorsil is contraindicated.

Hepatic impairment

The medicinal product Dolorsil is contraindicated in patients with hepatic impairment.

Children

Use 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 also occur. Additionally, arterial hypertension, acute renal failure, respiratory depression, and coma may be observed, although these are rare. Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs and 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. There is no information on the effectiveness of hemodialysis, but due to the high degree of nimesulide plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in cases of overdose. 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 ingestion. Forced diuresis, urine alkalization, hemodialysis, and hemoperfusion may be ineffective due to the high degree of nimesulide plasma protein binding. Renal and hepatic functions should be monitored.

Side effects

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 complications (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 effects are gastrointestinal reactions. Peptic ulcers, perforations, 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 or Crohn’s disease have also been observed. Gastritis has been observed less frequently.

Below is a list of adverse reactions reported during 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; not known (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 edema, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis; not known – fixed drug eruption (see section "Special precautions").

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

* Frequency determined in clinical trials

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any 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.