Aponil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Aponil (APONIL)

Composition:

Active substance: nimesulide;

1 tablet contains nimesulide 100 mg;

Excipients: sodium docecyl sulfate; hydroxypropyl cellulose; lactose monohydrate; sodium starch glycolate (type A); microcrystalline cellulose; hydrogenated vegetable oil; magnesium stearate.

Pharmaceutical form. Tablets.

Main physical and chemical properties: flat, round, light-yellow tablets approximately 10.5 mm in diameter, with a break line on one side.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic drugs. ATC code M01AX17.

Pharmacological properties.

Pharmacodynamics.

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

Pharmacokinetics.

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 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 of nimesulide twice daily for 7 days. Up to 97.5% of nimesulide is bound to plasma proteins.

Nimesulide is actively metabolized in the liver via various pathways, including the cytochrome P450 isoenzyme CYP2C9. Therefore, there is a risk of drug interactions when used concomitantly with medicinal products metabolized by CYP2C9 (see section "Interaction with other medicinal products and other forms of interaction"). The main metabolite is para-hydroxy derivative, which is also pharmacologically active. The time to appearance of this metabolite in systemic circulation is short (approximately 0.8 hours), but the rate constant of its formation is low and significantly less than the absorption rate constant of nimesulide. Hydroxynimesulide is the only metabolite detected in plasma and is almost entirely present in the bound form. The elimination half-life ranges from 3.2 to 6 hours.

Nimesulide is primarily excreted in urine (about 50% of the administered dose). Only 1–3% is excreted unchanged. Hydroxynimesulide is the main metabolite found exclusively as a glucuronide conjugate. Approximately 29% of the administered dose is excreted in feces in metabolized form.

The pharmacokinetic profile of nimesulide in elderly individuals is not altered following single or repeated administration. In a short-term clinical study conducted in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min) and healthy volunteers, the 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 increased by 50%, but always 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").

Clinical characteristics.

Indications.

Treatment of acute pain. Treatment of primary dysmenorrhea.

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

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

Contraindications.

Hypersensitivity to nimesulide or to any component of the medicinal product.

History of hypersensitivity reactions (e.g., bronchospasm, rhinitis, urticaria, nasal polyps), particularly reactions to acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs).

Hepatotoxic reactions to nimesulide in medical history.

Concomitant use of other potentially hepatotoxic substances.

Alcoholism, drug addiction.

History of gastrointestinal bleeding or perforation related to previous use of nonsteroidal anti-inflammatory drugs (NSAIDs).

Peptic ulcer / bleeding in the active phase or history thereof (at least two separate episodes of confirmed ulceration or bleeding).

Cerebrovascular hemorrhage or other bleeding disorders, as well as diseases associated with bleeding tendency.

Severe disorders of blood coagulation.

Severe heart failure.

Severe renal impairment.

Hepatic dysfunction.

Fever and/or flu-like symptoms.

Children under 12 years of age.

Third trimester of pregnancy and lactation period (see section "Use during pregnancy or lactation").

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

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

Corticosteroids. Increase the risk of gastrointestinal ulcers and bleeding.

Anticoagulants. Patients receiving warfarin or similar anticoagulants have an increased risk of bleeding when treated with nimesulide. 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). Increase the risk of gastrointestinal bleeding (see section "Special precautions").

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II antagonists (A-IIA). NSAIDs may attenuate the effect of diuretics and other 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 further deterioration of renal function, including development of acute renal failure, which is usually reversible. Such interactions should be considered in patients receiving medicinal products containing nimesulide together with ACE inhibitors or angiotensin II antagonists. Extreme caution is required when using this combination, especially in elderly patients. Patients should receive adequate hydration. Monitoring of renal function after initiation of concomitant therapy and periodic monitoring after its discontinuation should be considered.

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

Furosemide. In healthy volunteers, nimesulide transiently reduces furosemide-induced sodium excretion and, to a lesser extent, potassium excretion, and decreases diuretic effect. Concomitant administration of nimesulide and furosemide results in a reduction (by approximately 20%) of 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 medicinal products containing nimesulide in patients with impaired renal or cardiac function requires caution (see section "Special precautions").

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

In vivo studies have also evaluated possible pharmacokinetic interactions with glyburide, theophylline, warfarin, digoxin, cimetidine, and antacids (combination of aluminum 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 lead to increased serum levels of methotrexate and, consequently, increased toxicity of this medicinal product.

Due to its effect on renal prostaglandins, inhibitors of prostaglandin synthase, including nimesulide, may increase the nephrotoxicity of cyclosporine.

Effect of other medicinal products on 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 its plasma concentration, such interactions are not clinically significant.

Special precautions for use.

Concomitant use of nimesulide and NSAIDs, including selective COX-2 inhibitors, should be avoided. During nimesulide therapy, patients should be advised to refrain from using other analgesics.

To minimize the risk of adverse effects, the lowest effective dose should be used for the shortest duration necessary to control symptoms (see section "Dosage and administration"). If no therapeutic effect is observed, treatment with the drug should be discontinued.

Effects on the liver. Serious hepatic reactions, rarely with fatal outcome, have been reported during nimesulide use (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury (e.g., anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine) or who have abnormal liver function test results during nimesulide treatment should discontinue therapy. Nimesulide should not be re-administered to such patients. Liver injury, mostly reversible, has been reported after short-term exposure to the drug. Patients taking nimesulide who develop fever and/or flu-like symptoms should discontinue treatment.

Effects on the gastrointestinal tract. Gastrointestinal bleeding or ulceration/perforation has been reported with all NSAIDs (with or without warning symptoms, and with or without gastrointestinal complications in history), which could be fatal and may occur at any time during treatment. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Treatment in such patients should be initiated at the lowest possible dose. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal complications risk, consideration should be given to 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 initial stages of treatment. Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, with or without warning symptoms or gastrointestinal history. If gastrointestinal bleeding or ulceration occurs, nimesulide should be discontinued.

Nimesulide should be administered with caution in patients with gastrointestinal disorders, including those with a history of peptic ulcer, gastrointestinal bleeding, ulcerative colitis, or Crohn’s disease. Patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., acetylsalicylic acid), should be informed about the need for caution (see section "Interaction with other medicinal products and other forms of interaction"). If gastrointestinal bleeding or ulceration occurs in patients receiving nimesulide, treatment should be discontinued. NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as exacerbation may occur (see section "Adverse reactions").

Elderly patients. Elderly patients have a higher incidence of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, sometimes fatal (see section "Adverse reactions"), as well as renal, cardiac, and hepatic dysfunction; therefore, appropriate clinical monitoring is recommended.

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 during NSAID therapy. Clinical trials and epidemiological data suggest that use of certain NSAIDs, especially at high doses and during long-term treatment, may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction or stroke. Data are insufficient to exclude such risk with nimesulide. Nimesulide should be prescribed to patients with uncontrolled arterial hypertension, acute heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful benefit-risk assessment. A similar assessment should be performed before initiating long-term treatment in patients with cardiovascular risk factors, such as arterial 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 cannot replace acetylsalicylic acid for cardiovascular disease prevention.

Effects on the kidneys. Use of nonsteroidal anti-inflammatory drugs may mask fever associated with underlying bacterial infection. If fever or flu-like symptoms develop in patients taking nimesulide, the drug should be discontinued.

Rare cases of severe skin reactions, some potentially fatal, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAID use. Patients are at particularly high risk of such reactions if they occurred previously during treatment, especially within the first month. Aponil should be discontinued at the first signs of skin rash, mucosal lesions, or other allergic manifestations.

Fixed drug eruptions (FDE) have been reported during nimesulide use. Nimesulide should not be re-administered to patients with a history of FDE associated with nimesulide (see section "Adverse reactions").

Nimesulide may impair female fertility and is not recommended for women who are trying to conceive. Nimesulide is not recommended for women with infertility or undergoing fertility investigations.

The product contains lactose; therefore, it should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicine.

Use during pregnancy or breastfeeding.

Pregnancy. Nimesulide is contraindicated during the third trimester of pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological data suggest that use of prostaglandin synthesis inhibitors during early pregnancy increases the risk of spontaneous abortion and congenital heart defects and gastroschisis. The absolute risk of cardiovascular malformation increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of use. In animal studies, administration of prostaglandin synthesis inhibitors resulted in increased pre- and post-implantation loss and embryonic/fetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, was observed. If nimesulide is used in women attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose and shortest duration of treatment should be prescribed.

Use of nimesulide from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This effect may occur soon after starting treatment and is usually reversible upon discontinuation of the drug. Additionally, fetal arterial duct constriction has been observed after second-trimester exposure to nimesulide, which in most cases resolves after treatment cessation. Therefore, nimesulide should not be used during the first and second trimesters unless absolutely necessary. If nimesulide is used in women attempting to conceive or during the first and second trimesters, the lowest possible dose and shortest duration of treatment should be prescribed.

Prenatal monitoring for oligohydramnios and fetal arterial duct constriction may be advisable if nimesulide is used for several days starting from the 20th gestational week. Pregnant women should discontinue nimesulide if oligohydramnios or fetal arterial duct constriction is detected.

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

• cardiopulmonary toxicity (premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure and oligohydramnios.

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

• prolonged bleeding time, anti-aggregatory effect, which may occur even with very low doses;
• inhibition of uterine contractility, which may lead to delayed or prolonged labor.

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

Breastfeeding. Since it is unknown whether nimesulide passes into breast milk, the drug is contraindicated during breastfeeding.

Fertility. Nimesulide may impair female fertility and is not recommended for women attempting to conceive. Women with infertility or undergoing fertility investigations should consider discontinuing nimesulide. If pregnancy occurs during nimesulide treatment, the physician should be informed.

Ability to influence the ability to drive and use machines.

The effect of nimesulide on the ability to drive or operate machinery has not been studied. However, patients who experience dizziness or drowsiness after taking nimesulide should refrain from driving and from tasks requiring high concentration.

Method of Administration and Dosage

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

The maximum duration of treatment is 15 days.

Adults. The recommended dose is 100 mg twice daily after meals, taken with sufficient amount of liquid.

Elderly patients. Dose adjustment is not required.

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

Patients with renal impairment. In patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), dose adjustment is not necessary. The use of the drug is contraindicated in severe renal impairment (creatinine clearance < 30 mL/min).

Patients with hepatic impairment. The use of nimesulide in patients with impaired liver function is contraindicated (see "Contraindications").

Children.

The drug is contraindicated in children under 12 years of age.

Overdose.

Symptoms of acute overdose with nonsteroidal anti-inflammatory drugs (NSAIDs) are usually limited to the following manifestations: apathy, drowsiness, nausea, vomiting, epigastric pain. These symptoms are generally reversible with supportive treatment. Gastrointestinal bleeding may occur. Less commonly, arterial hypertension, acute renal failure, respiratory depression, and coma may develop. Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs as well as in cases of overdose. There is no specific antidote. Treatment of overdose is symptomatic and supportive. There are no data on the elimination of nimesulide by hemodialysis; however, considering the high degree of plasma protein binding of nimesulide (up to 97.5%), dialysis is unlikely to be effective. If symptoms of overdose are present or a large dose has been ingested, within 4 hours of drug intake, patients may be given: induced vomiting and/or activated charcoal (60–100 g for adults), and/or administration of 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

The frequency of adverse effects was defined as follows: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10,000), including isolated cases.

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

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

Metabolic disorders:
Rare – hyperkalemia.

Psychiatric disorders:
Rare – anxiety, nervousness, night terrors.

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

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

Ear and labyrinth disorders:
Very rare – vertigo (dizziness).

Cardiovascular system disorders:
Rare – tachycardia; uncommon – arterial hypertension; rare – hemorrhage, fluctuations in blood pressure, hot flushes.

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

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

Hepatobiliary disorders:
Common – increased liver enzyme levels; very rare – hepatitis, fulminant hepatitis with fatal outcome, jaundice, cholestasis.

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

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

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

Laboratory findings:
Common – elevated liver enzymes.

The most commonly observed adverse reactions associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) involve the gastrointestinal tract. Peptic ulcers, gastrointestinal perforation or bleeding, sometimes life-threatening, may occur, particularly in elderly patients. Reported adverse reactions following use of this class of drugs include nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, black stools, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn’s disease. Gastritis has been observed less frequently. There have been reports of edema, arterial hypertension, and heart failure as reactions to NSAID use. Very rarely, skin reactions such as blistering, Stevens-Johnson syndrome, and toxic epidermal necrolysis may occur with NSAID use. Evidence suggests that certain NSAIDs, particularly at high doses and with prolonged use, may slightly increase the risk of arterial thrombotic events, such as myocardial infarction or stroke.

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

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C in the original packaging, in a place inaccessible to children.

Packaging. 10 tablets per blister pack. 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Medochemie Limited / Medochemie Limited.
2. Medochemie Limited / Medochemie Limited.

Manufacturer's address and location of business activity.

1. Konstantinoupoleos 1-10, Limassol, 3011, Cyprus /
   Konstantinoupoleos 1-10, Limassol, 3011, Cyprus.

2. Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus /
   Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus.