Nimid® [Nimesulide, tizanidine]

Pharmacological properties

Pharmacodynamic parameters. nimide forte is a combination of the muscle relaxant tizanidine and npvp nimesulide.

A nitrobenzene derivative - a representative of the methanesulfonanilide group nimesulide inhibits COX-mediated conversion of arachidonic acid into a precursor of prostaglandins, prostacyclin and thromboxane A₂. Nimesulide exhibits both analgesic and antipyretic and anti-inflammatory effects mediated by the action of COX-2, however, it has little effect on platelet function or loss of gastric cytoprotection associated with COX-1 activity. The therapeutic effect of nimesulide is the result of a complex of its effects aimed at a number of key mediators of the inflammatory process, such as prostaglandins, free radicals, proteolytic enzymes and histamine.

Tizanidine, an imidazoline derivative, is an α agonist₂-adrenergic receptors of central action. Tizanidine prevents the release of excitatory amino acids, such as glutamate and aspartate, in neurons of the spinal cord and enhances the presynaptic inhibition of motor neurons with the greatest effect in the polysynaptic spinal tract, which leads to a decrease in muscle tone, resistance to passive movements. With its use, the frequency of muscle cramps and myoclonus also decreases, the strength of active muscle contractions increases. Probably mediated by α₂-adrenergic receptors, inhibition of interneuronal activity underlies the additional antinociceptive and anticonvulsant activity of tizanidine. Affinity (to a lesser extent) for α₁β-adrenoreceptors can explain the moderate and transient effect of tizanidine on the cardiovascular system.

Pharmacokinetic parameters. Nimesulide has a rapid onset of action and has a high absorption rate when administered orally (C_max in blood plasma is achieved after 2-3 hours). Nimesulide is firmly bound to plasma proteins (up to 97.5%) and has a moderately small volume of distribution. However, it is rapidly distributed in the synovial fluid.

Nimesulide is metabolized in oxidation reactions through the liver cytochrome P450 system (mainly CYP 2C9), mainly into 4-hydroxymetabolite (4-OH-NME), which has pharmacological properties similar to the parent drug.

Elimination is progressive, T_½ is 2–5 hours for the starting preparation and 3–9 hours for its main metabolite, 4-OH-NME.

It is excreted in the form of metabolites by the kidneys (about 50% of the administered dose) and with feces (about 29%). In an unchanged state, 1-3% of the dose is excreted. Changes in pharmacokinetic parameters in elderly patients are not observed.

Tizanidine is rapidly absorbed. C_max in blood plasma is achieved 1 hour after application. Bioavailability is 20–34%, binding to plasma proteins is 30%.

T_½ - 2.5 hours, linear pharmacokinetics. The equilibrium concentration of tizanidine is achieved within 24–48 hours after administration, with repeated administration, no noticeable changes in the pharmacokinetic profile were detected.

The first passage of tizanidine is extensively metabolized in the liver by a cytochrome 450 CYP 1A2 system to inactive metabolites. 70% of the dose is excreted in the urine, 20% - with feces; about 2.7% - unchanged.

In patients with severe renal impairment, C_max in blood plasma, and the final T_½ - up to approximately 14 hours (AUC values ​​increase 6-fold).

An increase in the blood content of the drug is possible in patients with liver failure.

Indications

• Acute pain due to spasm of striated muscles; ankylosing spondylitis; vertebroalgia.

Application

Use the lowest dose necessary to control symptoms for a minimum period of time (no more than 15 days) only after a rigorous weighted analysis of risk and benefit. stop taking after the onset of analgesic effect.

Adults take 1 tablet in the morning and evening (daily dose - 2 tablets) after meals, per os, with plenty of water.

Dose adjustment is not required in elderly patients or those with impaired renal function of mild or moderate severity.

Contraindications

• Hypersensitivity to the active substance of the drug or its other components; hypersensitivity reactions (urticaria, bronchospasm, rhinitis) to acetylsalicylic acid or other NSAIDs; toxic liver damage due to the use of nimesulide; an ulcer of the stomach or duodenum (phase of exacerbation), recurring ulcers or bleeding in the digestive tract; intracerebral hemorrhage or other pathology with concomitant hemorrhage; severe coagulation system disorders; severe heart failure; severe liver or kidney failure; fever and flu-like manifestations; the assumption of acute surgical disease; combined use with fluvoxamine and ciprofloxacin;

• drug and alcohol addiction;
• childhood.

Side effects

Associated with nimesulide

• Eosinophilia, anemia, decreased platelet count (≤150⋅10⁹/ l), a decrease in the content of all the formed elements of the blood, purple;
• rash, itching, hyperhidrosis, dermatitis, erythema, Quinckes edema, swelling of the face, urticaria, blistering, Lyell, Stevens-Johnson syndrome, polymorphic erythema;
• hypersensitivity; anaphylactic reactions;
• an increase in heart rate of 90 beats / min, hemorrhages, blood pressure lability, hot flashes, hypertension, myocardial infarction, heart failure;
• swelling, weakness, malaise, decreased body temperature;
• dizziness, cephalalgia, hypersomnia, encephalopathy / Reyes syndrome;
• blurred vision disorders;
• feeling of fear, nervousness, terrifying dreams;
• dyspnea, asthma, bronchospasm;
• cholestasis, hepatitis, including fulminant, increased activity of liver enzymes;
• vomiting, nausea, diarrhea, constipation, flatulence, gastritis, stomatitis, dyspepsia, abdominal pain, melena, hemorrhage in the digestive tract, ulcer and perforation of the duodenum / stomach, hematemesis, exacerbation of Crohns disease and colitis;
• difficulty, urinary retention, hematuria, renal failure, decreased urine, interstitial nephritis;
• increased levels of potassium in the blood.

Associated with tizanidine

• Platelet count reduction (≤150110⁹/ l), petechiae or hematoma;
• anaphylactic reactions, hypersensitivity;
• hepatitis, jaundice, increased transaminase activity in blood plasma, impaired liver function;
• blurred vision, paresthesia, drowsiness, confusion and loss of consciousness, fainting, vertigo, dizziness, nervousness, agitation;
• depression, hallucinations, sleep disorders, insomnia;
• tremor, muscle weakness, cramping, muscle pain, dorsalgia;
• increased heart rate, decreased blood pressure (90/60 mm Hg), decreased heart rate (40 beats / min), lengthening of the Q – T segment;
• decreased appetite, nausea, vomiting, xerostomia, gastrointestinal disturbances and pain, stool disorders;
• flu-like condition, weakness, increased fatigue, asthenia, withdrawal syndrome;
• alopecia, itching, rashes, urticaria.

special instructions

For nimesulide

The lowest dose needed to control symptoms should be used over a minimum period of time.

If there is no effect (a decrease in the intensity of manifestations of pathology), therapy is completed.

Do not use in conjunction with hepatotoxic drugs and ethanol.

The use of NSAIDs in the infectious process of microbial etiology can mask the associated fever. Nimesulide therapy is completed if a patient has a fever or flu-like symptoms, as well as ulcers or bleeding from the digestive tract.

In case of symptoms of liver damage, drug therapy is completed without resuming. Such patients cannot be prescribed nimesulide again.

With caution, patients with ulcerative colitis or Crohns disease are used (exacerbation is possible).The development of exacerbations of Crohns disease and other gastrointestinal pathologies is also likely when combined with antiplatelet, anticoagulant agents, and oral contraceptives.

Do not use in conjunction with other painkillers and NSAIDs.

The likelihood of ulcers, hemorrhages, or perforation of the digestive tract increases in parallel with an increase in the dose of NSAIDs in patients with a history of this pathology and in elderly patients. In this group of patients, therapy should begin with the minimum dose necessary to control symptoms.

Specified patients and patients who simultaneously receive acetylsalicylic acid for cardioprophylaxis or other drugs that increase the likelihood of developing gastrointestinal complications require additional protection with proton pump inhibitors or misoprostol.

Caution is required in patients receiving corticosteroids, selective serotonin reuptake inhibitors, acetylsalicylic acid or anticoagulants, as well as in patients (primarily the elderly) with toxic damage to the digestive tract.

Monitoring of the condition of patients with heart failure and / or hypertension, patients with excessive fluid accumulation in the body, or edema associated with the use of NSAIDs is necessary.

A number of NSAIDs (mainly with prolonged use and high doses) are associated with a small likelihood of developing arterial thrombosis. Regarding nimesulide, there is little information on this subject.

Before using nimesulide, a thorough analysis of the condition of patients with risk factors for cardiovascular pathology (smoking, hypertension, elevated blood lipids, diabetes mellitus), as well as in patients with coronary heart disease, acute heart failure, uncontrolled hypertension, and pathology of the peripheral arteries and / or blood vessels of the brain is required .

In view of the likelihood of a decrease in renal function in patients with impaired or with heart failure, careful administration of the drug in this category of patients is necessary with the cessation of therapy when the condition worsens.

Due to the likelihood of bleeding and perforation of the digestive tract, impaired renal, hepatic or cardiac functions, careful monitoring of the condition of elderly patients is necessary.

It is used cautiously in patients with hemorrhagic diathesis.

It is not a substitute for acetylsalicylic acid to prevent cardiovascular disease.

The likelihood of developing Lyell and Stevens-Johnson syndrome, as well as exfoliative dermatitis, is increased in patients with the indicated reactions that occurred within a month with a previous course of therapy.

In case of allergic reactions, including rashes on the skin and damage to the mucous membrane, immediate withdrawal of the drug is required.

The use of nimesulide is not recommended in patients who are planning a pregnancy, as well as in the I and II trimester of pregnancy. In such cases, the minimum dose and duration of therapy are used.

Women who are difficult to get pregnant, or those who are being tested for infertility, are not recommended to prescribe the drug Nimid Forte.

The doctor should be notified if the patient has a pregnancy while taking nimesulide.

You should not drive vehicles or other mechanisms if taking the drug.

For tizanidine

It should not be used in conjunction with CYP 1A2 inhibitors.

A sharp withdrawal of the drug is not recommended (due to a possible increase in heart rate and blood pressure, the development of a stroke). The dose should be reduced slowly.

In severe renal impairment, one should start with 2 mg once a day with a gradual increase in the dose to small values, taking into account the tolerability and effectiveness of the treatment.

Since it is possible to develop liver dysfunction associated with tizanidine (in rare cases, at a dose of 12 mg / day), they should be monitored in patients with manifestations of liver failure. In the case of a prolonged 3-fold or more increase in the activity of AlAT or AsAT, it is necessary to complete the administration of the drug Nimid Forte.

It is possible to lower blood pressure (90 mmHg) up to loss of consciousness or cardiovascular collapse (including due to combined use with CYP 1A2 inhibitors and / or antihypertensive agents).

Caution is required with the combined use of agents that extend the Q – T interval.

Caution is required in patients with heart failure and / or CHD. At an early stage of treatment in this category of patients, regular monitoring of the ECG is necessary.

It is recommended to take with caution in elderly patients.

It should not be taken in childhood and adolescence.

A rigorous weighted analysis of the risk and benefits of taking the drug in patients with myasthenia gravis is required.

Due to the small amount of information regarding the use of tizanidine during pregnancy, the drug is not recommended for this category of patients (taking is possible if the potential benefit to the mother outweighs the possible risk to the fetus).

Interactions

Associated with nimesulide

The likelihood of developing hemorrhage or an ulcer in the digestive tract increases when used with antiplatelet drugs, selective serotonin and GCS reuptake inhibitors (the latter also increase the likelihood of developing an ulcer in the digestive tract).

The combination with acetylsalicylic acid or warfarin is not used in cases of severe coagulation. In other cases, these combinations are not recommended, but if they are inevitable, careful monitoring of the parameters of the coagulation system is necessary.

A decrease in the activity of diuretics and other antihypertensive drugs is possible. When combined with ACE inhibitors, angiotensin II antagonists in patients with impaired renal function (including the elderly or with dehydration), further deterioration of renal function and the occurrence of acute renal failure (usually reversible) are possible. A sufficient amount of fluid is required by the patient and careful monitoring of renal function.

The combined intake reduces the diuretic activity of furosemide, its effects on the excretion of sodium and potassium (to a lesser extent). Caution is required in patients with renal or hepatic insufficiency.

The combined use of lithium preparations requires monitoring of its content in blood plasma (with its increase, respectively, toxicity increases due to a decrease in clearance).

No clinically significant interactions with cimetidine and antacids, warfarin, theophylline, glibenclamide, digoxin,

The combined use of the drug with substrates of CYP 2C9 increases their content in blood plasma.

The plasma content (and toxic effects) of methotrexate may increase with the use of nimesulide within 1 day before or after taking methotrexate.

When combined with nimesulide, cyclosporin nephrotoxicity may be enhanced.

Valproic and salicylic acids, as well as tolbutamide displace bound nimesulide in vitro, but this phenomenon is not observed when using the drug in a clinical setting.

Associated with tizanidine

With combined use with CYP 1A2 inhibitors, an increase in the blood content of tizanidine is possible (and, accordingly, the development of overdose manifestations, including lengthening of the Q – T interval).

With combined use with CYP 1A2 inducers, it is possible to decrease the content of tizanidine in the blood (and, accordingly, its therapeutic effect).

Not used with ciprofloxacin and fluvoxamine, α₂-adrenomimetics.

It should not be combined with oral contraceptives, propafenone, amiodarone, mexiletine, ticlopidine, cimetidine, rofecoxib, norfloxacin, pefloxacin, enoxacin.

When combined with antihypertensive and diuretics, a decrease in blood pressure (90/60 mm Hg) and heart rate (60 beats / min) is possible. With a sharp discontinuation of the drug against the background of the use of such drugs, it is possible to increase blood pressure and heart rate, stroke in rare cases.

It is possible to reduce the concentration (and, accordingly, therapeutic effect) by 50% when combined with rifampicin. It is not recommended to be used in combination for a long period (or carefully adjust the dose if necessary).

Tobacco smoking causes a decrease in systemic exposure to tizanidine.

With the combined use of baclofen or benzodiazepine, psychotropic, narcotic, painkillers, antihistamines with tizanidine, it is possible to increase their effect, as well as hypnotic action of tizanidine.

Do not combine with the use of alcoholic beverages.

Overdose

It manifests itself as hypersomnia, lethargy, nausea, vomiting, epigastralgia, hemorrhages in the alimentary canal, ag, arthritis, acute liver failure, myosis, decreased hell (90/60 mm Hg), dizziness, respiratory depression, prolongation of the q – t interval are possible , anxiety, anaphylactoid reactions and coma.

There is no specific antidote. The treatment is symptomatic. In the 4-hour period after taking a high dose of the drug, gastric lavage and activated charcoal are taken. Hemodialysis does not have an effect. Careful monitoring of hepatic and renal functions is required.

Storage conditions

At a temperature of ≤25 ° C in the original packaging.