Nimide® forte

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIMID® FORTE (NIMID® FORTE)

Composition:

Active substances: nimesulide, tizanidine hydrochloride;

One tablet contains 100 mg of nimesulide and 2 mg of tizanidine hydrochloride calculated as tizanidine;

Inactive ingredients: microcrystalline cellulose, sodium croscarmellose, magnesium stearate, colloidal anhydrous silicon dioxide.

Dosage form. Tablets.

Main physicochemical properties: round, light-yellow tablets, smooth on one side and embossed with "NF" on the other.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01A.

Pharmacological properties.

Pharmacodynamics.

Nimide® Forte is a combination drug that includes two active ingredients: a non-steroidal anti-inflammatory drug (NSAID) from the methanesulfonanilide group – nimesulide, and a centrally-acting skeletal muscle relaxant – tizanidine.

Mechanism of action of nimesulide.

Nimesulide exerts anti-inflammatory, analgesic, and antipyretic effects. The therapeutic effect of nimesulide is due to its interaction with the arachidonic acid cascade and reduction of prostaglandin biosynthesis through inhibition of cyclooxygenase.

Mechanism of action of tizanidine.

Tizanidine is a centrally-acting myorelaxant whose primary site of action is the spinal cord. By stimulating presynaptic α-2-adrenergic receptors, it suppresses the release of amino acids that stimulate N-methyl-D-aspartate (NMDA) receptors. As a result, polysynaptic signal transmission responsible for excessive muscle tone at the level of interneuronal connections is inhibited in the spinal cord, leading to reduced muscle tone. Tizanidine is effective both in acute painful muscle spasms and in chronic spasticity of spinal and cerebral origin. It reduces resistance to passive movements, suppresses spasms and clonic seizures, and improves the strength of active muscle contractions.

Pharmacokinetics.

Nimesulide.

In humans, 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 by CYP2C9, an isoenzyme of cytochrome P450. The main metabolite is 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 – about 50% of the administered dose. Approximately 29% of the administered dose is excreted in feces in metabolized form. Only 1–3% is excreted unchanged. The pharmacokinetic profile in elderly patients is not altered.

Tizanidine.

Tizanidine is rapidly absorbed. Maximum plasma concentrations are reached approximately 1 hour after administration. The mean absolute bioavailability is 34%. Plasma protein binding is 30%. The drug undergoes rapid and extensive hepatic metabolism. Metabolites are inactive. They are primarily excreted by the kidneys (70%), with about 2.7% of tizanidine excreted unchanged.

In patients with renal impairment (creatinine clearance less than 25 mL/min), the mean maximum plasma concentration is twice that observed in healthy volunteers, and the terminal elimination half-life is prolonged to approximately 14 hours, resulting in an average six-fold increase in the area under the concentration-time curve (AUC).

Tizanidine is metabolized by the CYP1A2 isoenzyme in the liver. In patients with impaired liver function, higher plasma concentrations of the substance may occur.

Pharmacokinetic data in elderly patients are limited.

Clinical characteristics.

Indications.

Acute pain caused by skeletal muscle spasm. Ankylosing spondylitis. Vertebrogenic back pain.

Contraindications.

• Hypersensitivity to the active substances, to any other NSAID, or to any excipients of the medicinal product.

• Hypersensitivity reactions (bronchospasm, rhinitis, urticaria) associated with the use of acetylsalicylic acid or other NSAIDs in medical history.

• Active peptic ulcer, history of ulcers, gastrointestinal perforation or bleeding.

• Gastrointestinal bleeding or perforation in medical history related to previous NSAID use.

• History of cerebrovascular hemorrhage or other hemorrhagic events, as well as disorders associated with bleeding tendency.

• Hepatotoxic reactions to nimesulide in medical history; concomitant use of other substances with potential hepatotoxic effects.

• Hepatic function impairment.

• Severe coagulation disorders.

• Severe heart failure.

• Severe renal function impairment.

• Alcoholism; drug dependence.

• Elevated body temperature and/or influenza-like conditions.

• Suspected acute surgical pathology.

• Concomitant use with potent CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin.

• Pediatric age.

• Third trimester of pregnancy and breastfeeding period (see sections "Use during pregnancy or lactation").

Interaction with other medicinal products and other forms of interaction.

Interactions related to nimesulide.

Pharmacodynamic interactions.

Corticosteroids:

Increased risk of gastrointestinal ulceration or bleeding (see section "Special precautions").

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section "Special precautions").

Anticoagulants: NSAIDs may enhance the effect of anticoagulants such as warfarin (see section "Special precautions"). Treatment with nimesulide in patients taking warfarin or similar anticoagulants or acetylsalicylic acid is associated with an increased risk of hemorrhagic complications. Therefore, such combination is not recommended (see section "Special precautions"), and is contraindicated in patients with severe coagulation disorders (see section "Contraindications"). If combined therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II antagonists (AIIA): NSAIDs may attenuate the effects 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. These interactions should be considered when patients are using Nimid® Forte concomitantly with ACE inhibitors or AIIA.

Therefore, such combination should be prescribed with caution, especially in elderly patients. Patients should receive adequate fluid intake. Monitoring of renal function after initiation of concomitant therapy and periodic monitoring after its discontinuation should be considered.

Other nonsteroidal anti-inflammatory drugs (NSAIDs): concomitant use of medicinal products containing nimesulide (see section "Clinical characteristics") with other NSAIDs, including acetylsalicylic acid at anti-inflammatory doses (≥ 1 g as a single dose or ≥ 3 g per day), is not recommended.

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%) in the area under the concentration-time curve (AUC) and cumulative excretion of furosemide without changes in its renal clearance.

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 a patient receiving lithium therapy, plasma lithium levels should be closely monitored.

Pharmacokinetic interactions: effect of other medicinal products on nimesulide pharmacokinetics

In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid, and valproic acid. However, despite a possible effect on its plasma concentration, these interactions are not clinically significant.

Other interactions

Pharmacokinetic interactions with glimepiride, theophylline, warfarin, digoxin, cimetidine, and antacids (aluminum and magnesium hydroxide combination) have also been investigated in vivo. No clinically significant interactions were observed.

Nimesulide inhibits the activity of the CYP2C9 enzyme. Plasma concentrations of drugs that are substrates of this enzyme may increase when Nimid® Forte is used concomitantly. Caution is required when nimesulide is administered less than 24 hours before or less than 24 hours after methotrexate administration, as this may increase methotrexate serum levels and enhance its toxicity.

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

Interactions related to tizanidine.

CYP1A2 inhibitors: concomitant use of known CYP1A2 inhibitors may increase tizanidine plasma levels.

Elevated tizanidine plasma levels may lead to symptoms of overdose, such as QT interval prolongation.

CYP1A2 inducers: concomitant use of known CYP1A2 inducers may reduce tizanidine plasma levels. Reduced tizanidine plasma levels may lead to diminished therapeutic effect.

Potent CYP1A2 inhibitors: concomitant use of potent CYP1A2 inhibitors such as fluvoxamine or ciprofloxacin with tizanidine is contraindicated (see section "Contraindications"). Concomitant use of tizanidine with fluvoxamine increases tizanidine AUC by 33 times, while concomitant use with ciprofloxacin increases tizanidine AUC by 10 times. This may lead to clinically significant and prolonged reduction in blood pressure accompanied by somnolence, dizziness, and reduced psychomotor performance (see section "Special precautions").

Other CYP1A2 inhibitors: concomitant use of tizanidine with other CYP1A2 inhibitors such as antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, certain fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives, and ticlopidine is not recommended.

Increased tizanidine plasma levels may manifest as symptoms of overdose, including QT interval prolongation (see section "Overdose").

Antihypertensive agents (including diuretics): concomitant use with tizanidine may occasionally cause hypotension and bradycardia. In some patients receiving concomitant antihypertensive therapy, rebound hypertension and rebound tachycardia have been observed upon abrupt discontinuation of tizanidine. In individual cases, rebound hypertension may lead to stroke (see sections "Special precautions" and "Adverse reactions").

Caution should be exercised when using tizanidine concomitantly with medicinal products that prolong the QT interval.

Rifampicin: concomitant use of tizanidine with rifampicin may result in a 50% reduction in tizanidine concentration. Thus, the therapeutic effect may be reduced during rifampicin treatment, which may be clinically significant for some patients. Prolonged concomitant use should be avoided; if necessary, dosage adjustment should be performed very cautiously. Careful dose adjustment (dose increase) is required in case of planned long-term combination therapy.

Smoking: tizanidine use results in a 30% reduction in systemic exposure in men who smoke (more than 10 cigarettes per day). Long-term use of tizanidine in heavy smokers requires higher doses.

Central nervous system-acting agents (sedatives and hypnotics (benzodiazepines or baclofen), certain antihistamines, general anesthetics and analgesics, psychotropic agents, narcotics): concomitant use with tizanidine may enhance the effects of each agent and increase the sedative effect of tizanidine.

Alcohol: alcohol consumption should be avoided during treatment with the medicinal product Nimid® Forte, as the effect of tizanidine may change unpredictably and the risk of adverse reactions increases. The central nervous system depressant effect of alcohol may be enhanced by tizanidine.

α-2 adrenergic agonists (e.g., clonidine): concomitant administration of tizanidine should be avoided due to the potential additive hypotensive effect.

Special precautions for use.

Precautions related to nimesulide.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration" and the risks related to the gastrointestinal tract and cardiovascular system below).

If therapeutic efficacy is not achieved, treatment should be discontinued.

Concomitant use of nimesulide with NSAIDs, including selective COX-2 inhibitors, should be avoided. Patients receiving nimesulide should be advised to avoid using other analgesics.

During nimesulide therapy, concomitant use of hepatotoxic drugs and alcohol consumption should be avoided.

NSAIDs may mask fever associated with underlying bacterial infection.

Hepatic effects

Serious hepatic reactions, very rarely including fatal outcomes, have been reported with nimesulide (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury during nimesulide treatment, such as anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine, or who have abnormal liver function test results, should discontinue therapy. Re-administration of nimesulide is not recommended in 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.

Gastrointestinal effects

Gastrointestinal bleeding or ulceration/perforation (with or without warning symptoms or history of serious gastrointestinal events) has been reported during treatment with any NSAID, which could be fatal. 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. In such patients, treatment 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 risk, consideration should be given to combination therapy with protective agents, such as misoprostol or proton pump inhibitors (see information 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 during initial stages of treatment.

Gastrointestinal bleeding or ulceration/perforation, with or without warning symptoms or history of serious gastrointestinal events, may occur at any time during treatment. If gastrointestinal bleeding or ulceration occurs, nimesulide should be discontinued. Nimesulide should be used with caution in patients with gastrointestinal disorders, including peptic ulcer, gastrointestinal bleeding, ulcerative colitis, or Crohn's disease in medical history (see section "Adverse reactions").

Patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (including warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid, should be informed about the need for caution.

If gastrointestinal bleeding or ulceration occurs in patients receiving nimesulide, treatment should be discontinued.

NSAIDs should be prescribed with caution to patients with gastrointestinal disease (ulcerative colitis, Crohn's disease) in medical history, as exacerbation is possible (see section "Adverse reactions").

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

Cardiovascular and cerebrovascular effects

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and physician consultation, as fluid retention and edema have been reported with NSAID therapy.

Available data suggest that use of certain NSAIDs, particularly at high doses and during long-term treatment, may be associated with a small increase in the risk of arterial thrombotic events, such as myocardial infarction or stroke. Data on the risk of such events with nimesulide are insufficient.

Patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with nimesulide 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.

Renal effects

Patients with impaired renal function or heart failure should be treated with caution, as nimesulide use may lead to worsening renal function. If such deterioration occurs, treatment should be discontinued (see also section "Interaction with other medicinal products and other forms of interaction").

Elderly patients

Elderly patients may have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, in some cases fatal (see section "Adverse reactions"), as well as impaired renal, cardiac, and hepatic function; therefore, appropriate clinical monitoring is recommended.

Skin reactions

Serious, sometimes life-threatening skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported with NSAIDs (see section "Adverse reactions"). These reactions appear to occur most frequently early in the course of therapy, typically within the first month of treatment. Nimesulide should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Cases of fixed drug eruption (FDE) have been reported with nimesulide. Nimesulide should not be re-administered to patients with a history of nimesulide-related FDE (see section "Adverse reactions").

Effects on fertility

Nimesulide may impair female fertility and is not recommended for women attempting to conceive. Women experiencing difficulty conceiving or undergoing infertility evaluation should consider discontinuation of Nimid® Forte (see section "Use during pregnancy or lactation").

Precautions related to tizanidine.

Concomitant use of moderate CYP1A2 inhibitors with tizanidine is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Contraindications").

After abrupt discontinuation of tizanidine and/or concomitant use of antihypertensive drugs, rebound hypertension and tachycardia may occur in patients. In some cases, such rebound hypertension may lead to stroke. Tizanidine treatment should not be stopped abruptly but only gradually tapered (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

In patients with renal impairment (creatinine clearance < 25 mL/min), systemic exposure to tizanidine may be up to six times higher; therefore, severe renal impairment (creatinine clearance < 30 mL/min) is a contraindication for Nimid® Forte (see section "Dosage and administration").

Hepatic failure associated with tizanidine use has been reported, although it is rare in patients receiving daily doses up to 12 mg. Therefore, liver function should be monitored in patients with clinical signs suggestive of hepatic failure (such as nausea, loss of appetite, or unexplained fatigue). Treatment with Nimid® Forte should be discontinued if serum ALT or AST levels exceed three times the upper limit of normal for a prolonged period.

Hypersensitivity reactions, including anaphylaxis, angioedema, dyspnea, dermatitis, rash, urticaria, pruritus, and erythema, have been reported with tizanidine use. Close monitoring of patients is recommended during the first one or two days after the initial dose of tizanidine. If anaphylaxis or angioedema with anaphylactic shock or dyspnea occurs, Nimid® Forte should be immediately discontinued and appropriate treatment initiated. Arterial hypotension may occur during tizanidine use, as well as as a result of drug interactions with CYP1A2 inhibitors and/or antihypertensive agents (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). Severe hypotension, including loss of consciousness and circulatory collapse, has been reported.

Caution is required when using Nimid® Forte concomitantly with drugs that prolong the QT interval (e.g., cisapride, amitriptyline, azithromycin) (see section "Interaction with other medicinal products and other forms of interaction").

Caution is necessary for patients with ischemic heart disease and/or heart failure. Regular ECG monitoring should be performed at the beginning of treatment with Nimid® Forte in such patients.

Careful risk-benefit assessment is required before administering this drug to patients with myasthenia gravis.

Experience in children and adolescents is limited; therefore, use of Nimid® Forte is not recommended in this patient group.

Caution should be exercised when using this drug in elderly patients.

Special precautions related to the medicinal product Nimid® Forte.

Excipients

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or lactation

Pregnancy

Use of nimesulide

Nimesulide is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest that use of prostaglandin synthesis inhibitors during early pregnancy may increase the risk of miscarriage 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 treatment.

In animal studies, prostaglandin synthesis inhibitors caused increased pre- and post-implantation loss and increased embryonic and fetal mortality. Additionally, increased incidence of various fetal malformations, including cardiovascular defects, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

Use of nimesulide from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal ductus arteriosus constriction have been reported after intrauterine exposure to nimesulide during the second trimester, most of which resolved after discontinuation of treatment. Therefore, nimesulide should not be prescribed during the first and second trimesters of pregnancy except in cases of extreme necessity. If nimesulide is used in 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 fetal ductus arteriosus constriction should be considered after nimesulide exposure for several days starting from the 20th week of pregnancy. Nimesulide should be discontinued if oligohydramnios or fetal ductus arteriosus constriction is detected.

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

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction (see above);

In the mother near term and in the newborn, the following may occur:

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

Use of tizanidine

Women of reproductive age who are sexually active should undergo a pregnancy test before starting tizanidine treatment. Women of reproductive age should be informed that animal studies indicate tizanidine is harmful to the fetus. Sexually active women of reproductive age should use effective contraception (methods allowing pregnancy in less than 1% of cases) throughout the entire period of tizanidine treatment and for one day after discontinuation.

Data on tizanidine use in pregnant women are limited; therefore, it should not be prescribed during pregnancy except when the potential benefit to the mother outweighs the possible risk to the fetus. Tizanidine is not teratogenic in rats and rabbits but causes difficult labor, increased prenatal and postnatal mortality, and delayed fetal development in rats.

Lactation period

Use of nimesulide

It is unknown whether nimesulide passes into human breast milk. Nimesulide is contraindicated during lactation (see section "Contraindications").

Use of tizanidine

No teratogenic effects were observed in rats and rabbits treated with tizanidine. The risk to the breastfed infant should be considered. Animal studies have shown that tizanidine passes into breast milk in small amounts. Therefore, tizanidine should not be administered to breastfeeding women.

Fertility

Use of nimesulide

As with other NSAIDs, medicinal products containing nimesulide are not recommended for women attempting to conceive (see section "Special precautions for use"). Women experiencing difficulty conceiving or undergoing infertility evaluation should discontinue nimesulide.

If pregnancy is confirmed during nimesulide use, the physician should be informed.

Use of tizanidine

No impairment of fertility was observed in male and female rats treated with tizanidine at doses of 10 mg/kg/day and 3 mg/kg/day, respectively. Decreased fertility was observed in male rats receiving tizanidine at 30 mg/kg/day and in female rats receiving 10 mg/kg/day. Sedation, weight loss, and ataxia were also observed at these doses.

Women of reproductive age

Use of tizanidine

Sexually active women of reproductive age should undergo a pregnancy test before starting tizanidine treatment.

Women of reproductive age should be informed that animal studies indicate tizanidine is harmful to the fetus. Sexually active women of reproductive age should use effective contraception (methods allowing pregnancy in less than 1% of cases) throughout the entire period of tizanidine treatment and for one day after discontinuation.

Ability to affect reaction speed when driving or operating machinery

Related to nimesulide

Studies on the effect of nimesulide-containing medicinal products on the ability to drive or operate machinery have not been conducted; however, patients experiencing dizziness, vertigo, or somnolence after taking nimesulide should refrain from driving or operating machinery.

Related to tizanidine

Even when used as recommended, tizanidine may cause somnolence, dizziness, and/or arterial hypotension, thereby impairing a patient's ability to drive or operate machinery. Risks increase with concomitant alcohol consumption.

Therefore, activities requiring high concentration and rapid reaction, such as driving vehicles or operating machines and mechanisms, should be avoided.

Method of Administration and Dosage

To prevent the occurrence and reduce the severity of adverse reactions, the drug should be used for the shortest possible duration and at the lowest effective dose. The drug should be prescribed only after careful assessment of the benefit-risk ratio.

The drug should be taken orally after meals at the same time each day, with sufficient amount of liquid.

Maximum duration of treatment – 15 days.

Adults. 1 tablet twice daily – in the morning and in the evening. After achieving analgesic effect, the drug should be discontinued.

Elderly patients. Dose adjustment is not required. However, caution should be exercised when administering the drug to this patient population.

Patients with renal impairment. For patients with mild or moderate renal impairment (creatinine clearance 30–80 mL/min), dose adjustment is not required, whereas severe renal impairment (creatinine clearance < 30 mL/min) is a contraindication for the use of Nimid® Forte (see sections "Contraindications" and "Pharmacokinetics").

Patients with hepatic impairment. The use of Nimid® Forte is contraindicated in patients with hepatic dysfunction (see section "Pharmacokinetics"). Adverse reactions can be minimized by using the drug for the shortest duration necessary to control symptoms (see section "Special Instructions").

Children.

The drug is contraindicated in children.

Overdose.

Nimesulide overdose

Symptoms of acute nonsteroidal anti-inflammatory drug (NSAID) overdose are usually limited to apathy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive therapy. Gastrointestinal bleeding may occur. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma may develop. Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs and may also occur in overdose. In case of NSAID overdose, patients should receive symptomatic and supportive treatment. There are no specific antidotes. There is no information regarding the elimination of nimesulide by hemodialysis; however, considering its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. If symptoms occur or after a significant overdose within 4 hours of drug intake, vomiting may be induced and/or activated charcoal (60–100 g for adults) and/or an osmotic laxative may be administered. Forced diuresis, urine alkalinization, hemodialysis, or hemoperfusion may be ineffective due to high protein binding. Renal and hepatic functions should be monitored.

Tizanidine overdose

Symptoms: nausea, vomiting, arterial hypotension, bradycardia, QT interval prolongation, dizziness, miosis, respiratory distress, coma, restlessness, drowsiness.

Treatment: to eliminate the drug from the body, repeated administration of high doses of activated charcoal is recommended. Forced diuresis may accelerate drug elimination. Further treatment should be symptomatic.

Adverse reactions.

Adverse reactions associated with nimesulide

Blood and lymphatic system disorders: anaemia, eosinophilia, thrombocytopenia, pancytopenia, purpura.

Immune system disorders: hypersensitivity, anaphylaxis.

Metabolism and nutrition disorders: hyperkalaemia.

Psychiatric disorders: fear, nervousness, nightmares.

Nervous system disorders: dizziness, headache, somnolence, encephalopathy (Reye's syndrome), stroke.

Eye disorders: blurred vision, visual disturbances.

Ear and labyrinth disorders: vertigo (dizziness).

Cardiac disorders: tachycardia, arterial hypertension, haemorrhages, blood pressure lability, flushing, heart failure, myocardial infarction.

Respiratory, thoracic and mediastinal disorders: dyspnoea, asthma, bronchospasm.

Gastrointestinal disorders: diarrhoea, nausea, vomiting, constipation, abdominal distension, gastritis, abdominal pain, dyspepsia, stomatitis, ulcerative stomatitis, black stools (melena), gastrointestinal bleeding, peptic ulcer and perforation of stomach or duodenal ulcer, vomiting with blood, exacerbation of colitis and Crohn's disease.

Hepatobiliary disorders: hepatitis, fulminant hepatitis (including fatal cases), jaundice, cholestasis, elevated liver enzymes.

Skin and subcutaneous tissue disorders: pruritus, skin rash, increased sweating, erythema, dermatitis, urticaria, angioneurotic oedema, facial oedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, blistering, fixed drug eruption (see section "Special precautions").

Renal and urinary disorders: dysuria, haematuria, urinary retention, renal failure, oliguria, interstitial nephritis.

General disorders: oedema, malaise, asthenia, hypothermia.

Adverse reactions associated with tizanidine

Blood and lymphatic system disorders: petechiae or bruising, thrombocytopenia.

Immune system disorders: hypersensitivity reactions (including anaphylaxis, angioneurotic oedema, dyspnoea and urticaria).

Psychiatric disorders: insomnia, sleep disturbances, hallucinations, depression, confusion, anxiety.

Nervous system disorders: somnolence, dizziness, confusion, vertigo, insomnia, sleep disturbances, syncope (loss of consciousness, fainting), excitation, nervousness, paraesthesia, headache, dysarthria, stroke.

Eye disorders: blurred vision, accommodation disorders.

Cardiovascular disorders: slight decrease in blood pressure, arterial hypotension, arterial hypertension, rebound arterial hypertension and tachycardia (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"), bradycardia, palpitations, QT interval prolongation.

Gastrointestinal disorders: dry mouth, gastrointestinal pain, gastrointestinal disorders, decreased appetite, nausea, vomiting, constipation, diarrhoea.

Hepatobiliary disorders: elevated serum transaminase levels, hepatitis, hepatic failure, jaundice.

Musculoskeletal and connective tissue disorders: muscle weakness, myalgia, back pain, muscle spasms, tremor, ataxia.

Skin and subcutaneous tissue disorders: pruritus, skin rash, erythema, dermatitis, urticaria, alopecia.

General disorders: increased fatigue, asthenia, weakness, withdrawal syndrome, influenza-like illness.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report any 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 temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a blister, 1 blister in a cardboard package.

10 tablets in a blister, 1 blister in a cardboard package. 10 cardboard packages in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's address and place of business.

54 Davydovskoho Hryhoriia Street, Sumy, Sumy region, 40020, Ukraine.

INSTRUCTION

for medical use of the medicinal product

NIMID® FORTE

(NIMID® FORTE)

Composition:

Active substances: nimesulide, tizanidine hydrochloride;

One tablet contains nimesulide 100 mg, tizanidine hydrochloride equivalent to tizanidine 2 mg;

Inactive ingredients: microcrystalline cellulose, sodium croscarmellose, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: round, light-yellow tablets, smooth on one side and embossed with "NF" on the other.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01A.

Pharmacological properties.

Pharmacodynamics.

Nimide® Forte is a combination drug that includes two medicinal substances: a non-steroidal anti-inflammatory drug (NSAID) from the methanesulfonanilide group – nimesulide, and a centrally-acting skeletal muscle relaxant – tizanidine.

Mechanism of action of nimesulide.

Nimesulide exhibits anti-inflammatory, analgesic, and antipyretic effects. The therapeutic action of nimesulide is due to its interaction with the arachidonic acid cascade and reduction of prostaglandin biosynthesis through inhibition of cyclooxygenase.

Mechanism of action of tizanidine.

Tizanidine is a centrally-acting myorelaxant whose primary site of action is the spinal cord. By stimulating presynaptic α-2-adrenergic receptors, it suppresses the release of amino acids that stimulate N-methyl-D-aspartate receptors (NMDA receptors). As a result, polysynaptic signal transmission responsible for excessive muscle tone at the level of interneuronal connections is inhibited in the spinal cord, leading to reduced muscle tone. Tizanidine is effective both in acute painful muscle spasms and in chronic spasticity of spinal and cerebral origin. It reduces resistance to passive movements, suppresses spasms and clonic seizures, and improves the strength of active muscle contractions.

Pharmacokinetics.

Nimesulide.

Nimesulide is well absorbed in humans following 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 via CYP2C9, an isoenzyme of cytochrome P450. The main metabolite is 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 – about 50% of the administered dose. Approximately 29% of the administered dose is excreted in feces in metabolized form. Only 1–3% is excreted unchanged. The pharmacokinetic profile in elderly patients is not altered.

Tizanidine.

Tizanidine is rapidly absorbed. Maximum plasma concentrations are reached approximately 1 hour after administration. The mean absolute bioavailability is 34%. Plasma protein binding is 30%. The drug undergoes rapid and extensive metabolism in the liver. Metabolites are inactive. They are primarily excreted by the kidneys (70%), with about 2.7% of tizanidine excreted unchanged.

In patients with renal impairment (creatinine clearance less than 25 mL/min), the mean maximum plasma concentration is twice that observed in healthy volunteers, and the terminal elimination half-life is prolonged to approximately 14 hours, resulting in an average six-fold increase in the area under the concentration-time curve (AUC).

Tizanidine is metabolized by the CYP1A2 isoenzyme in the liver. In patients with hepatic impairment, higher plasma concentrations of the substance may occur.

Pharmacokinetic data in elderly patients are limited.

Clinical characteristics.

Indications.

Acute pain caused by skeletal muscle spasm. Bechterew's disease. Vertebroalgia.

Contraindications.

• Hypersensitivity to the active substances, to any other NSAID, or to any excipients of the medicinal product.

• Hypersensitivity reactions (bronchospasm, rhinitis, urticaria) associated with the use of acetylsalicylic acid or other NSAIDs in medical history.

• Peptic ulcer in the phase of exacerbation, history of ulcers, perforations, or gastrointestinal bleeding.

• History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.

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

• Hepatotoxic reactions to nimesulide in medical history; concomitant use of other substances with potential hepatotoxic effects.

• Liver function impairment.

• Severe coagulation disorders.

• Severe heart failure.

• Severe renal function impairment.

• Alcoholism; drug addiction.

• Elevated body temperature and/or flu-like conditions.

• Suspected acute surgical pathology.

• Concomitant use with strong CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin.

• Pediatric age.

• Third trimester of pregnancy and breastfeeding period (see sections "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Interactions related to nimesulide.

Pharmacodynamic interactions.

Corticosteroids:

increased risk of gastrointestinal ulceration or bleeding (see section "Special precautions for use").

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section "Special precautions for use").

Anticoagulants: NSAIDs may enhance the effect of anticoagulants such as warfarin (see section "Special precautions for use"). Treatment with nimesulide in patients taking warfarin or similar anticoagulants or acetylsalicylic acid is associated with an increased risk of bleeding complications. Therefore, such combination is not recommended (see section "Special precautions for use"), and contraindicated in patients with severe coagulation disorders (see section "Contraindications"). If combined therapy cannot be avoided, careful monitoring of blood coagulation parameters is required.

Diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II antagonists (AIIAs): NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with impaired renal function), concomitant use of ACE inhibitors and cyclooxygenase inhibitors may lead to further deterioration of renal function, including the development of acute renal failure, which is usually reversible. These interactions should be considered when a patient uses Nimid® Forte concomitantly with ACE inhibitors or AIIAs.

Therefore, such combination should be prescribed with caution, especially in elderly patients. Patients should receive adequate fluid intake. The need for monitoring renal function after initiation of concomitant therapy and periodic monitoring after its discontinuation should be considered.

Other non-steroidal anti-inflammatory drugs (NSAIDs): concomitant use of medicinal products containing nimesulide (see section "Clinical characteristics") with other NSAIDs, including acetylsalicylic acid at anti-inflammatory doses (≥ 1 g as a single dose or ≥ 3 g per day), is not recommended.

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

Furosemide: in healthy volunteers, nimesulide temporarily reduces furosemide-induced sodium excretion and to a lesser extent potassium excretion, and also reduces the diuretic effect. Concomitant use 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 its renal clearance.

Concomitant use of furosemide and medicinal products containing nimesulide in patients with impaired renal or cardiac function requires caution (see section "Special precautions for use").

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

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

In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid, and valproic acid. However, despite a possible effect on its plasma concentration, such interactions have no clinical significance.

Other interactions

Pharmacokinetic interactions with glimepiride, theophylline, warfarin, digoxin, cimetidine, and antacid preparations (aluminum and magnesium hydroxide combination) have also been studied in vivo. No clinically significant interactions were observed.

Nimesulide inhibits the activity of the CYP2C9 enzyme. Plasma concentrations of medicinal products that are substrates of this enzyme may increase when Nimid® Forte is used concomitantly. Caution is required when nimesulide is administered less than 24 hours before or less than 24 hours after methotrexate administration, as this may lead to increased serum levels of methotrexate and increased toxicity.

Due to the effect on renal prostaglandins, prostaglandin synthase inhibitors such as nimesulide may increase the nephrotoxicity of cyclosporines.

Interactions related to tizanidine.

CYP1A2 inhibitors: concomitant use of known CYP1A2 inhibitors may increase tizanidine plasma levels.

Elevated tizanidine plasma levels may lead to symptoms of overdose, such as QT interval prolongation.

CYP1A2 inducers: concomitant use of known CYP1A2 inducers may reduce tizanidine plasma levels. Reduced tizanidine plasma levels may lead to reduced therapeutic effect.

Strong CYP1A2 inhibitors: concomitant use of strong CYP1A2 inhibitors such as fluvoxamine or ciprofloxacin with tizanidine is contraindicated (see section "Contraindications"). Concomitant use of tizanidine with fluvoxamine increases tizanidine AUC by 33 times, while concomitant use with ciprofloxacin increases tizanidine AUC by 10 times. This may lead to clinically significant and prolonged reduction in blood pressure, accompanied by somnolence, dizziness, and reduced psychomotor performance (see section "Special precautions for use").

Other CYP1A2 inhibitors: concomitant use of tizanidine with other CYP1A2 inhibitors such as antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, certain fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives, and ticlopidine is not recommended.

Increased tizanidine plasma levels may manifest as symptoms of overdose, including QT interval prolongation (see section "Overdose").

Antihypertensive agents (including diuretics): concomitant use with tizanidine may occasionally cause arterial hypotension and bradycardia. In some patients receiving concomitant antihypertensive therapy, rebound arterial hypertension and rebound tachycardia have been observed upon abrupt discontinuation of tizanidine. In individual cases, rebound arterial hypertension may lead to stroke (see sections "Special precautions for use" and "Adverse reactions").

Caution should be exercised when using tizanidine concomitantly with medicinal products that prolong the QT interval.

Rifampicin: concomitant use of tizanidine with rifampicin may lead to a 50% reduction in tizanidine concentration. Thus, the therapeutic effect may be reduced during concomitant use of rifampicin with tizanidine, which may be clinically significant for some patients. Long-term concomitant use should be avoided, and if necessary, dosage adjustment should be made very carefully. Careful dose adjustment (increasing the dose) is required in case of planned long-term combination therapy.

Smoking. Use of tizanidine leads to a 30% reduction in its systemic exposure in men who smoke (more than 10 cigarettes per day). Long-term use of tizanidine in heavy smokers requires administration of higher doses.

Central-acting medicinal products (sedatives and hypnotics (benzodiazepines or baclofen), certain antihistamines, general anesthetics and analgesics, psychotropic agents, narcotics): concomitant use with tizanidine may enhance the effects of each drug and increase the sedative effect of tizanidine.

Alcohol: alcohol consumption should be avoided during treatment with Nimid® Forte, as the effect of tizanidine may change unpredictably and the risk of adverse reactions increases. The depressant effect of alcohol on the central nervous system may be enhanced by tizanidine.

α-2 adrenergic agonists (e.g., clonidine): concomitant administration of tizanidine should be avoided due to the potential additive hypotensive effect.

Special precautions for use.

Precautions related to nimesulide.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration" and the risks related to the gastrointestinal tract and cardiovascular system below).

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

Concomitant use of nimesulide with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided. Patients should be advised to refrain from using other analgesics during nimesulide therapy.

During treatment with nimesulide, concomitant use of hepatotoxic drugs and alcohol consumption should be avoided.

NSAIDs may mask fever associated with underlying bacterial infection.

Hepatic effects

Serious liver reactions, very rarely including fatal cases, have been reported with nimesulide (see also section "Adverse reactions"). Patients who develop symptoms suggestive of liver injury during nimesulide therapy, such as anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine, or who have abnormal liver function test results, should discontinue treatment. Re-administration of nimesulide is not recommended in 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.

Gastrointestinal effects

Gastrointestinal bleeding or ulceration/perforation, with or without preceding symptoms or history of serious gastrointestinal events, has been reported during treatment with any NSAID, and may be fatal. 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 these 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 information 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 early stages of treatment.

Gastrointestinal bleeding or ulceration/perforation, with or without preceding symptoms or history of serious gastrointestinal events, may occur at any time during treatment. If gastrointestinal bleeding or ulceration occurs, nimesulide should be discontinued. Nimesulide should be used with caution in patients with gastrointestinal disorders, including peptic ulcer, gastrointestinal bleeding, ulcerative colitis, or Crohn’s disease in history (see section "Adverse reactions").

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 such as acetylsalicylic acid, should be informed of the need for caution.

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 disease (ulcerative colitis, Crohn’s disease), as disease exacerbation may occur (see section "Adverse reactions").

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

Cardiovascular and cerebrovascular effects

Patients with a history of mild to moderate arterial hypertension and/or congestive heart failure require appropriate monitoring and physician consultation, as fluid retention and edema have been reported with NSAID therapy.

Available data suggest that use of certain NSAIDs, particularly at high doses and during long-term treatment, may be associated with a small increase in the risk of arterial thrombotic events such as myocardial infarction or stroke. Data to exclude such risk with nimesulide use are insufficient.

Patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease should be treated with nimesulide 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 mellitus, 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.

Renal effects

Patients with impaired renal function or heart failure should be treated with caution, as nimesulide use may lead to worsening of renal function. In such cases, treatment should be discontinued (see also section "Interaction with other medicinal products and other forms of interaction").

Elderly patients

In elderly patients, the frequency of adverse reactions to NSAIDs may be increased, particularly gastrointestinal bleeding and perforation, sometimes fatal (see section "Adverse reactions"), as well as impairment of renal, cardiac, and hepatic function; therefore, appropriate clinical monitoring is recommended.

Skin reactions

Very rare serious skin reactions, some of which have been fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAIDs (see section "Adverse reactions"). These reactions appear to occur most frequently early in the course of therapy, with most cases occurring within the first month of treatment. Nimesulide should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Cases of fixed drug eruption (FDE) have been reported with nimesulide. Nimesulide should not be re-administered to patients with a history of nimesulide-associated FDE (see section "Adive reactions").

Effect on fertility

Nimesulide may impair female fertility and is not recommended for women attempting to conceive. Women experiencing difficulty in becoming pregnant or undergoing infertility investigations should consider discontinuation of Nimid® Forte (see section "Use during pregnancy or lactation").

Precautions related to tizanidine.

Concomitant use of moderate CYP1A2 inhibitors with tizanidine is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Contraindications").

After abrupt discontinuation of tizanidine and/or concomitant use of antihypertensive drugs, patients may experience rebound phenomena. Under such circumstances, arterial hypertension and tachycardia may occur. In individual cases, such rebound hypertension may lead to stroke. Tizanidine treatment should not be stopped abruptly but only gradually tapered (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

In patients with renal impairment (creatinine clearance < 25 mL/min), systemic exposure to tizanidine may be up to six times higher; therefore, severe renal impairment (creatinine clearance < 30 mL/min) is a contraindication for Nimid® Forte (see section "Dosage and administration").

Hepatic failure associated with tizanidine use has been reported, although rarely in patients receiving daily doses up to 12 mg. Therefore, liver function should be monitored in patients with clinical symptoms suggestive of hepatic failure (such as nausea, loss of appetite, or unexplained fatigue). Treatment with Nimid® Forte should be discontinued if serum ALT or AST levels exceed three times the upper limit of normal for a prolonged period.

Hypersensitivity reactions, including anaphylaxis, angioedema, dyspnea, dermatitis, rash, urticaria, pruritus, and erythema, have been reported with tizanidine. Careful monitoring of patients is recommended for one or two days after the first dose of tizanidine. If anaphylaxis or angioedema with anaphylactic shock or dyspnea occurs, Nimid® Forte should be discontinued immediately and appropriate treatment initiated. Arterial hypotension may occur during tizanidine use, as well as as a result of drug interactions with CYP1A2 inhibitors and/or antihypertensive agents (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). Severe hypotension, including loss of consciousness and circulatory collapse, has been reported.

Caution is advised when using Nimid® Forte concomitantly with drugs that prolong the QT interval (e.g. cisapride, amitriptyline, azithromycin) (see section "Interaction with other medicinal products and other forms of interaction").

Caution is required in patients with ischemic heart disease and/or heart failure. Regular ECG monitoring should be performed at the beginning of treatment with Nimid® Forte in such patients.

Careful risk-benefit assessment is necessary before administering this drug to patients with myasthenia gravis.

Experience in children and adolescents is limited; therefore, the use of Nimid® Forte is not recommended in this patient population.

Caution should be exercised when using this drug in elderly patients.

Special precautions for the medicinal product Nimid® Forte.

Excipients

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or lactation.

Pregnancy

Use of nimesulide

Nimesulide is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest that use of prostaglandin synthesis inhibitors during early pregnancy may increase the risk of miscarriage 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 treatment.

In animal studies, prostaglandin synthesis inhibitors caused increased pre- and post-implantation loss and increased embryonic and fetal mortality. Furthermore, increased incidence of various fetal abnormalities, including cardiovascular defects, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

Use of nimesulide from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal arterial duct constriction after intrauterine exposure to nimesulide during the second trimester have been reported, most of which resolved after discontinuation of treatment. Therefore, nimesulide should not be prescribed during the first and second trimesters of pregnancy except in cases of extreme necessity. If nimesulide is used in 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 fetal arterial duct constriction should be considered after exposure to nimesulide for several days starting from the 20th week of pregnancy. Nimesulide should be discontinued if oligohydramnios or fetal 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 arterial duct and pulmonary hypertension);
• renal dysfunction (see above);

In the mother and the newborn at the end of pregnancy, the following may occur:

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

Use of tizanidine

Women of childbearing potential who are sexually active should undergo a pregnancy test before starting tizanidine treatment. Women of childbearing potential should be informed that animal studies indicate tizanidine may be harmful to the fetus. Sexually active women of childbearing potential should use effective contraception (methods allowing pregnancy in less than 1% of cases) throughout the entire treatment period with tizanidine and for one day after discontinuation.

Data on tizanidine use in pregnant women are limited; therefore, it should not be prescribed during pregnancy except when the potential benefit to the mother outweighs the possible risk to the fetus. Tizanidine is not teratogenic in rats and rabbits, but causes difficult labor, increased prenatal and postnatal mortality, and delayed fetal development in rats.

Lactation period.

Use of nimesulide

It is unknown whether nimesulide passes into human breast milk. Nimesulide is contraindicated during lactation (see section "Contraindications").

Use of tizanidine

No teratogenic effects were observed in rats and rabbits treated with tizanidine. The risk to the breastfed infant should be considered. Animal studies show that tizanidine passes into breast milk in small amounts. Therefore, tizanidine should not be administered to breastfeeding women.

Fertility

Use of nimesulide

Like other NSAIDs, medicinal products containing nimesulide are not recommended for women attempting to conceive (see section "Special precautions for use"). Women experiencing difficulty in becoming pregnant or undergoing infertility investigations should discontinue nimesulide.

If pregnancy is diagnosed during nimesulide treatment, the physician should be informed.

Use of tizanidine

No impairment of fertility was observed in male and female rats treated with tizanidine at doses of 10 mg/kg/day and 3 mg/kg/day, respectively. Decreased fertility was observed in male rats receiving tizanidine at 30 mg/kg/day and in female rats receiving 10 mg/kg/day. Sedation, weight loss, and ataxia were also observed at these doses.

Women of childbearing potential

Use of tizanidine

Sexually active women of childbearing potential should undergo a pregnancy test before starting tizanidine treatment.

Women of childbearing potential should be informed that animal studies indicate tizanidine may be harmful to the fetus. Sexually active women of childbearing potential should use effective contraception (methods allowing pregnancy in less than 1% of cases) throughout the entire treatment period with tizanidine and for one day after discontinuation.

Ability to affect reaction speed when driving or operating machinery.

Related to nimesulide

Studies on the effect of nimesulide-containing medicinal products on the ability to drive or operate machinery have not been conducted. However, patients who experience dizziness, vertigo, or somnolence after taking nimesulide should refrain from driving or operating machinery.

Related to tizanidine

Even when administered according to recommendations, tizanidine may cause somnolence, dizziness, and/or arterial hypotension, thereby impairing a patient's ability to drive or operate machinery. The risk increases with concomitant alcohol consumption.

Therefore, activities requiring high concentration and rapid reaction, such as driving vehicles or operating machines and mechanisms, should be avoided.

Method of Administration and Dosage

To prevent the occurrence and reduce the severity of adverse reactions, the drug should be used for the shortest possible duration and at the lowest effective dose. The drug should be prescribed only after careful assessment of the risk/benefit ratio.

The drug should be taken orally after meals at the same time each day, with sufficient fluid.

Maximum duration of treatment – 15 days.

Adults. 1 tablet twice daily – in the morning and evening. After achieving analgesic effect, the drug should be discontinued.

Elderly patients. Dose adjustment is not required. However, caution should be exercised when administering the drug to this patient group.

Patients with renal impairment. For patients with mild or moderate renal impairment (creatinine clearance 30–80 mL/min), dose adjustment is not required, whereas severe renal impairment (creatinine clearance < 30 mL/min) is a contraindication for the use of Nimide® Forte (see sections "Contraindications" and "Pharmacokinetics").

Patients with hepatic impairment. The use of Nimide® Forte is contraindicated in patients with hepatic dysfunction (see section "Pharmacokinetics"). Adverse reactions can be minimized by using the drug for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

Children.

The drug is contraindicated in children.

Overdose.

Nimesulide overdose

Symptoms of acute nonsteroidal anti-inflammatory drug (NSAID) overdose are usually limited to apathy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive therapy. Gastrointestinal bleeding may occur. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma may develop. Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs and may also occur in overdose. In case of NSAID overdose, patients should receive symptomatic and supportive treatment. There are no specific antidotes. There is no information regarding the elimination of nimesulide by hemodialysis; however, considering its high plasma protein binding (up to 97.5%), dialysis is unlikely to be effective in overdose. If symptoms occur or after significant overdose, within 4 hours of drug intake, vomiting may be induced and/or activated charcoal (60–100 g for adults) and/or an osmotic laxative may be administered. Forced diuresis, urine alkalinization, hemodialysis, or hemoperfusion may be ineffective due to high protein binding. Renal and hepatic functions should be monitored.

Tizanidine overdose

Symptoms: nausea, vomiting, arterial hypotension, bradycardia, QT interval prolongation, dizziness, miosis, respiratory distress, coma, restlessness, drowsiness.

Treatment: to enhance drug elimination, repeated administration of high doses of activated charcoal is recommended. Forced diuresis may accelerate drug elimination. Further treatment should be symptomatic.

Side effects

Side effects associated with nimesulide

Blood and lymphatic system disorders: anemia, eosinophilia, thrombocytopenia, pancytopenia, purpura.

Immune system disorders: hypersensitivity, anaphylaxis.

Metabolism and nutrition disorders: hyperkalemia.

Psychiatric disorders: fear, nervousness, nightmares.

Nervous system disorders: dizziness, headache, somnolence, encephalopathy (Reye's syndrome), stroke.

Eye disorders: blurred vision, visual disturbances.

Ear and labyrinth disorders: vertigo (dizziness).

Cardiac disorders: tachycardia, arterial hypertension, hemorrhages, blood pressure lability, flushing, heart failure, myocardial infarction.

Respiratory, thoracic and mediastinal disorders: dyspnea, asthma, bronchospasm.

Gastrointestinal disorders: diarrhea, nausea, vomiting, constipation, abdominal distension, gastritis, abdominal pain, dyspepsia, stomatitis, ulcerative stomatitis, black stools (melena), gastrointestinal bleeding, gastric or duodenal ulcer and perforation, vomiting with blood, exacerbation of colitis and Crohn's disease.

Hepatobiliary disorders: hepatitis, fulminant hepatitis (including fatal cases), jaundice, cholestasis, increased liver enzymes.

Skin and subcutaneous tissue disorders: pruritus, rash, increased sweating, erythema, dermatitis, urticaria, angioedema, facial swelling, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, blistering, fixed drug eruption (see section "Special precautions").

Renal and urinary disorders: dysuria, hematuria, urinary retention, renal failure, oliguria, interstitial nephritis.

General disorders: edema, malaise, asthenia, hypothermia.

Side effects associated with tizanidine

Blood and lymphatic system disorders: petechiae or bruising, thrombocytopenia.

Immune system disorders: hypersensitivity reactions (including anaphylaxis, angioedema, dyspnea, and urticaria).

Psychiatric disorders: insomnia, sleep disturbances, hallucinations, depression, confusion, anxiety.

Nervous system disorders: somnolence, dizziness, confusion, vertigo, insomnia, sleep disturbances, syncope (loss of consciousness, fainting), restlessness, nervousness, paresthesia, headache, dysarthria, stroke.

Eye disorders: blurred vision, accommodation disorders.

Cardiovascular disorders: slight decrease in blood pressure, arterial hypotension, arterial hypertension, rebound arterial hypertension and tachycardia (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"), bradycardia, palpitations, QT interval prolongation.

Gastrointestinal disorders: dry mouth, gastrointestinal pain, gastrointestinal disorders, decreased appetite, nausea, vomiting, constipation, diarrhea.

Hepatobiliary disorders: elevated serum transaminase levels, hepatitis, hepatic failure, jaundice.

Musculoskeletal and connective tissue disorders: muscle weakness, myalgia, back pain, muscle spasms, tremor, ataxia.

Skin and subcutaneous tissue disorders: pruritus, rash, erythema, dermatitis, urticaria, alopecia.

General disorders: increased fatigue, asthenia, weakness, withdrawal syndrome, influenza-like condition.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should 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 temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a blister, 1 blister in a cardboard box.

10 tablets in a blister, 1 blister in a cardboard box. 10 cardboard boxes in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

Kusum Healthcare Pvt Ltd.

Manufacturer's address and place of business.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.