Affidafort-nimesulide

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AFFFIDA FORT-nimesulide (AFFIDA FORT-nimesulide)

Composition:

Active substance: nimesulide;

1 sachet of 2 g granules contains 100 mg of nimesulide;

Excipients: cetomacrogol 1000, maltodextrin, citric acid, sucrose, orange flavoring.

Pharmaceutical form. Granules for oral suspension.

Main physico-chemical characteristics: straw-yellow granules.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. ATC code M01AX17.

Pharmacological properties.

Pharmacodynamics.

Affida Fort-nimesulide is a non-steroidal anti-inflammatory agent of the methanesulfonanilide group, exhibiting anti-inflammatory, analgesic, and antipyretic effects. The therapeutic effect of the drug is due to its interaction with the arachidonic acid cascade and reduction of prostaglandin biosynthesis through cyclooxygenase inhibition.

Pharmacokinetics.

In the human body, Affida Fort-nimesulide is well absorbed after oral administration, reaching maximum plasma concentration within 2–3 hours. Approximately 97.5% of nimesulide is bound to plasma proteins. Nimesulide is actively metabolized in the liver with the involvement of CYP2C9, a cytochrome P450 isoenzyme. The main metabolite is the para-hydroxy derivative, which also possesses pharmacological activity. The elimination half-life ranges from 3.2 to 6 hours. Nimesulide is excreted from the body via urine—approximately 50% of the administered dose. About 29% of the administered dose is excreted in feces in metabolized form. Only 1–3% is excreted unchanged. The pharmacokinetic profile in elderly patients remains unchanged.

Clinical characteristics.

Indications.

Treatment of acute pain, 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.

Known hypersensitivity to nimesulide or to any component of the medicinal product. History of hypersensitivity reactions (bronchospasm, rhinitis, urticaria) associated with the use of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs). History of hepatotoxic reactions to nimesulide.

Concomitant use of other substances with potential hepatotoxicity.

Alcoholism and drug addiction.

History of gastrointestinal bleeding or perforation related to previous use of nonsteroidal anti-inflammatory agents.

Active peptic ulcer of the stomach or duodenum, history of ulcer, perforation, or gastrointestinal hemorrhage.

History of cerebrovascular hemorrhage or other bleeding disorders, as well as diseases associated with bleeding tendency.

Severe coagulation disorders.

Severe heart failure.

Severe renal impairment.

Hepatic dysfunction.

Patients with elevated body temperature 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 interactions.

Pharmacodynamic interactions.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding. Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.

Anticoagulants: NSAIDs may enhance the effect of anticoagulants such as warfarin or acetylsalicylic acid, making this combination contraindicated in patients with severe coagulation disorders. If such combination therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II antagonists.

NSAIDs may reduce the effectiveness of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients), concomitant use of ACE inhibitors, angiotensin II antagonists, or substances inhibiting the cyclooxygenase system may lead to further deterioration of renal function and development of acute renal failure, which is usually reversible. These interactions should be considered when a patient is taking Aффida fort-nimesulide together with ACE inhibitors or angiotensin II antagonists. Extreme caution is required when using such a combination, especially in elderly patients. Patients should receive adequate hydration, and renal function should be closely monitored after initiation of such combination therapy. Nimesulide temporarily reduces the sodium-excreting effect of furosemide and to a lesser extent the potassium excretion, as well as diminishes the diuretic effect. Concomitant use of furosemide and Aффida fort-nimesulide in patients with impaired renal or cardiac function requires caution.

In healthy volunteers, nimesulide rapidly reduces the sodium-excreting effect of furosemide and to a lesser extent the potassium excretion, and also reduces diuresis. Concomitant administration of nimesulide and furosemide results in a reduction (by approximately 20%) of the area under the concentration-time curve (AUC) and decreased cumulative excretion of furosemide, without changes in renal clearance of furosemide.

Pharmacokinetic interactions with other medicinal products.

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

No clinically significant interactions have been observed with glyburide, theophylline, warfarin, digoxin, cimetidine, and antacid agents (aluminum and magnesium hydroxide combination) in vivo. Nimesulide inhibits the activity of the CYP2C9 enzyme. When co-administered with drugs that are substrates of this enzyme, their plasma concentrations may increase. Caution is required if nimesulide is administered less than 24 hours before or less than 24 hours after methotrexate, as this may increase methotrexate serum levels and enhance its toxicity.

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

Effect of other drugs on nimesulide.

In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid, and valproic acid. Despite these interactions being identified in plasma, the mentioned effects have not been observed during clinical use of the drug.

Special precautions for use.

Adverse side effects can be minimized by using the lowest effective dose for the shortest duration necessary to control disease symptoms.

If treatment is ineffective (no reduction in disease symptoms), therapy with the drug should be discontinued.

During treatment with nimesulide, concomitant use of hepatotoxic drugs should be avoided, and alcohol consumption should be refrained from. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) may mask fever associated with underlying bacterial infection. In case of elevated body temperature or development of flu-like symptoms in patients receiving nimesulide, the drug should be discontinued.

There have been reports of serious hepatic reactions during treatment with APhida Fort-nimesulide, including fatal outcomes with nimesulide-containing drugs. Patients who develop symptoms suggestive of liver injury, such as anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine, or who have abnormal liver function test results, should discontinue the drug. Re-administration of nimesulide to such patients is contraindicated. During treatment, patients should refrain from using other analgesics. Concomitant use of other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Patients receiving nimesulide who develop flu-like symptoms should discontinue its use.

In elderly patients, the frequency of adverse reactions to NSAIDs is increased, particularly regarding possible gastrointestinal bleeding and perforation, which may be life-threatening.

Gastric or intestinal ulceration, bleeding, or perforation may be life-threatening, especially in patients with a history of such events during previous use of any other NSAID (regardless of time elapsed). The risk of such events increases with higher NSAID doses, particularly in patients with a history of gastrointestinal ulcers, especially if complicated by bleeding or perforation, and in elderly patients. In these patients, treatment should be initiated at the lowest possible effective dose. For these patients, as well as for those concurrently taking low-dose acetylsalicylic acid or other drugs increasing gastrointestinal complication risk, consideration should be given to combined therapy with protective agents, such as misoprostol or proton pump inhibitors.

Patients with gastrointestinal toxicity, particularly elderly patients, should report any unusual gastrointestinal symptoms, especially bleeding. This is especially important during the initial stages of treatment. Patients taking concomitant medications that may increase the risk of ulceration or bleeding, such as corticosteroids, anticoagulants, selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., acetylsalicylic acid), should be informed about the need for caution when using nimesulide.

If gastrointestinal bleeding or ulceration occurs in a patient receiving APhida Fort-nimesulide, treatment with the drug should be discontinued.

NSAIDs should be used with caution in patients with a history of Crohn’s disease or ulcerative colitis, as nimesulide may provoke exacerbations.

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

Patients with a history of arterial hypertension and/or heart failure, as well as those experiencing fluid retention and edema due to NSAID use, require appropriate monitoring and physician consultation.

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

Nimesulide should be prescribed only after careful benefit-risk assessment in patients with uncontrolled arterial hypertension, acute heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. The same approach should be applied when prescribing the drug to patients with cardiovascular risk factors, such as arterial hypertension, hyperlipidemia, diabetes mellitus, or smoking.

The drug should be used with caution in patients with impaired renal function or heart failure due to the potential for worsening renal function. If the patient's condition deteriorates, treatment should be discontinued.

Elderly patients require careful monitoring due to the increased risk of gastrointestinal bleeding and perforation, and deterioration of renal, hepatic, or cardiac function. Since nimesulide may affect platelet function, it should be used cautiously in patients with hemorrhagic diathesis. However, nimesulide does not replace acetylsalicylic acid for cardiovascular disease prevention.

Cases of fixed drug eruption have been reported with nimesulide use. Nimesulide therapy should not be resumed in patients with a history of fixed drug eruption associated with nimesulide. Rare cases of severe skin reactions have been reported with NSAID use, some of which may be life-threatening, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In most cases, the risk of such reactions significantly increases if they occur within the first month of treatment. APhida Fort-nimesulide should be discontinued at the first signs of skin rash, mucosal lesions, or other allergic manifestations.

Nimesulide may impair female fertility and is not recommended for women planning pregnancy. Nimesulide should not be prescribed to women experiencing difficulty conceiving or undergoing infertility evaluation.

APhida Fort-nimesulide contains sucrose and therefore should not be administered to patients with hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological data suggest that use of prostaglandin synthesis inhibitors during early pregnancy may increase the risk of spontaneous abortion and congenital malformations, such as cardiac 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.

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 are reports of arterial duct constriction after second-trimester treatment, most of which resolved after stopping the drug. Therefore, nimesulide should not be prescribed during the first and second trimesters unless clearly necessary. If nimesulide is used by women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment 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. APhida Fort-nimesulide use should be discontinued if oligohydramnios or arterial duct constriction is detected.

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

• Cardio-pulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• Renal dysfunction (see above);

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

• Prolonged bleeding time, antiplatelet effect (which may occur even with very low doses);
• Inhibition of uterine contractility, potentially leading to delayed or prolonged labor.

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

As an NSAID that inhibits prostaglandin synthesis, nimesulide may cause premature closure of the ductus arteriosus, pulmonary hypertension, oliguria, and oligohydramnios. The risk of bleeding, weak labor, and peripheral edema increases. Animal studies have demonstrated atypical reproductive toxicity, but reliable human data on nimesulide use in pregnancy are lacking. The potential risk to humans is not established; therefore, nimesulide should not be used during the first and second trimesters of pregnancy.

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

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

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of nimesulide on the ability to drive or operate machinery have not been conducted. However, if patients experience headache, dizziness, or drowsiness while taking nimesulide, they should refrain from driving or operating machinery.

Method of Administration and Dosage

To minimize the possibility of adverse side effects, the lowest effective dose should be used for the shortest duration necessary. It is recommended to take the medication after food intake.

Maximum duration of treatment course – 15 days.

Adults. 100 mg of nimesulide (1 single-dose packet) twice daily after meals.

Elderly patients. Dose adjustment is not required.

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

Patients with impaired renal function. For patients with mild or moderate renal impairment (creatinine clearance 30–80 mL/min), dose adjustment is not necessary. However, severe renal impairment (creatinine clearance <30 mL/min) is a contraindication for the use of Affida Fort-nimesulide.

The contents of the packet should be dissolved in a glass of water and taken orally.

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

Overdose.

Symptoms of acute overdose with nonsteroidal anti-inflammatory drugs (NSAIDs) are usually limited to: apathy, drowsiness, nausea, vomiting, epigastric pain. These symptoms are generally reversible with supportive therapy. Gastrointestinal bleeding, arterial hypertension, acute renal failure, respiratory depression, and coma are possible but occur rarely. There have been reports of anaphylactoid reactions associated 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 occur or a large dose has been ingested, within 4 hours of intake, patients may be given induced vomiting 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

The data on adverse reactions presented in the table below were obtained from clinical trials and post-marketing studies. The frequency of adverse events is classified as follows: very common (>1/10); common (>1/100, but <1/10); uncommon (>1/1000, but <1/100); rare (>1/10,000, but <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Most frequently, adverse reactions associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) involve the gastrointestinal tract. Peptic ulcers, gastrointestinal perforation, or gastrointestinal bleeding, sometimes life-threatening, may occur, particularly in elderly patients. Adverse reactions reported after using this group of drugs include nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, black stools, hematemesis, ulcerative stomatitis, and exacerbation 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 the use of NSAIDs.

Very rarely, skin reactions such as blistering, Stevens-Johnson syndrome, and toxic epidermal necrolysis may occur during NSAID therapy.

Clinical and epidemiological studies indicate that some NSAIDs, especially when used at high doses and for prolonged periods, may lead to a small increased risk of arterial thrombotic complications, such as myocardial infarction or stroke.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in a place inaccessible to children.

Packaging.

1 sachet or 3, or 6, or 30, or 999 sachets, connected in threes with perforated lines, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Fine Foods & Pharmaceuticals N.T.M. S.P.A.

Manufacturer's address.

Via Grignano, 43 - 24041 Brembate (BG), Italy.

Marketing authorization holder.

Delta Medical Promotions AG.

Address of the marketing authorization holder.

26 Oetenbachgasse, Zurich 8001, Switzerland.