Instructions COLLAGENASE-1000 GEL TUBE 20 G
Composition
active ingredient: nimesulide;
1 sachet of 2 g of granules contains nimesulide 100 mg;
excipients: polyethylene glycol (macrogol) cetostearyl ether, maltodextrin, anhydrous citric acid, orange flavoring, crystalline sugar.
Dosage form
Granules for oral suspension.
Main physicochemical properties: granules from light yellow to yellow.
Pharmacotherapeutic group
Non-selective non-steroidal anti-inflammatory drugs.
ATX code M01A X17.
Pharmacological properties
Pharmacodynamics.
Remisar is a nonsteroidal anti-inflammatory drug (NSAID) of the methanesulfonanilide group, which exhibits anti-inflammatory, analgesic and antipyretic effects. The therapeutic effect of the drug Remisar is due to the fact that it interacts with the arachidonic acid cascade and reduces prostaglandin biosynthesis by inhibiting cyclooxygenase (COX).
Pharmacokinetics.
Absorption. In humans, Remisar is well absorbed when taken orally. After a single dose of 100 mg of nimesulide, in adults, the maximum concentration in the blood plasma is reached after 2-3 hours and is 3-4 mg/l. The area under the concentration-time curve (AUC) is 20-35 mg h/l. No statistically significant difference was noted between these indicators and such indicators after taking 100 mg twice a day for 7 days. Up to 97.5% of nimesulide binds to plasma proteins.
Biotransformation and elimination. Nimesulide is actively metabolized in the liver with the participation of CYP2C9, an isoenzyme of cytochrome P 450. Therefore, there is a possibility of drug interactions when it is used simultaneously with drugs metabolized with the participation of CYP2C9 (see the section "Interaction with other medicinal products and other types of interactions"). The main metabolite is the parahydroxy derivative, which also has pharmacological activity. The time to detect this metabolite in the circulating blood is short (about 0.8 hours), but the reaction constant of its formation is low and significantly less than the absorption coefficient of nimesulide. Hydroxynimesulide is the only metabolite detected in blood plasma and is almost completely in bound form. The half-life is from 3.2 to 6 hours. Nimesulide is excreted from the body with urine - about 50% of the dose taken. About 29% of the dose is excreted in the feces in a metabolized form. Only 1–3% is excreted unchanged. Hydroxynimesulide is the main metabolite, which appears only as a glucuronate. The pharmacokinetic profile in elderly patients does not change with single and repeated doses.
In a short-term experimental study conducted in patients with mild to moderate renal impairment (creatinine clearance 30–80 ml/min) and healthy volunteers, the maximum plasma concentrations of nimesulide and its main metabolite in patients were not higher than those in healthy volunteers. The AUC and half-life in patients with renal impairment were 50% higher, but were always within the range of pharmacokinetic parameters observed in healthy volunteers taking nimesulide. Repeated administration did not lead to accumulation. Nimesulide is contraindicated in patients with hepatic impairment (see section "Contraindications").
Preclinical safety data.
Preclinical data obtained in standard studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential revealed no special hazard for humans. In repeated dose toxicity studies, nimesulide showed gastrointestinal, renal and hepatic toxicity. In reproductive toxicity studies, when administered to females at doses that did not cause toxicity, embryotoxic and teratogenic effects (skeletal malformations, dilatation of the cerebral ventricles) were observed in rabbits, but not in rats. In rats, increased mortality of offspring in the early postnatal period and adverse reactions regarding fertility were observed.
Indication
Treatment of acute pain, primary dysmenorrhea.
Nimesulide should only be used as a second-line drug.
The decision to prescribe nimesulide should be made based on an assessment of all risks for the individual patient.
Contraindication
- Hypersensitivity to nimesulide, other NSAIDs or to any component of the drug. History of hyperergic reactions (bronchospasm, rhinitis, urticaria) associated with the use of acetylsalicylic acid or other NSAIDs.
- History of hepatotoxic reactions to nimesulide.
- Concomitant use of other substances with potential hepatotoxicity.
- History of gastrointestinal bleeding or perforation associated with previous NSAID use.
- Gastric or duodenal ulcer in the acute phase, history of ulcer, perforation or bleeding in the digestive tract.
- History of cerebrovascular bleeding or other hemorrhages, as well as diseases accompanied by bleeding.
- Severe blood clotting disorders.
- Severe heart failure.
- Liver dysfunction.
- The patient has an elevated body temperature and/or flu-like symptoms.
- Alcoholism and drug addiction.
- Children under 12 years old.
- Third trimester of pregnancy and breastfeeding period.
Interaction with other medicinal products and other types of interactions
Pharmacodynamic interactions.
Corticosteroids. When used together with nimesulide, the risk of gastrointestinal ulceration or bleeding increases. Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). When used together with nimesulide, the risk of gastrointestinal ulceration or bleeding increases.
Anticoagulants. NSAIDs may enhance the effect of anticoagulants such as warfarin or acetylsalicylic acid. When treating nimesulide with patients taking warfarin or similar anticoagulants or acetylsalicylic acid, there is an increased risk of bleeding complications, so this combination is not recommended and is contraindicated in patients with severe coagulation disorders. If such combination therapy cannot be avoided, careful monitoring of blood coagulation parameters is necessary.
Diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists. NSAIDs may weaken the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients), the concomitant use of ACE inhibitors, angiotensin II antagonists or agents that inhibit the COX system may lead to further deterioration of renal function and the development of acute renal failure, which is usually reversible. These interactions should be considered when the patient is using Remisar concomitantly with ACE inhibitors or angiotensin II antagonists. Extreme caution should be exercised when using this combination, especially in elderly patients. Patients should be adequately hydrated and renal function should be closely monitored after initiation of the combination and periodically after discontinuation.
Other NSAIDs: The concomitant use of nimesulide-containing medicinal products with other NSAIDs, in particular acetylsalicylic acid at anti-inflammatory doses (≥ 1 g as a single dose or ≥ 3 g per day), is not recommended.
The effect of nimesulide on the pharmacokinetics of other drugs.
Furosemide. In healthy volunteers, nimesulide temporarily weakens the effect of furosemide on sodium excretion and, to a lesser extent, on potassium excretion, and also reduces the diuretic effect. Simultaneous use of nimesulide and furosemide leads to a decrease (by approximately 20%) in the area under the concentration-time curve (AUC) and a decrease in the cumulative excretion of furosemide without changes in the renal clearance of furosemide. The combined use of furosemide and the drug Remisar in patients with impaired renal or cardiac function requires caution.
Lithium: NSAIDs have been reported to reduce lithium clearance, leading to increased plasma lithium levels and lithium toxicity. When Remisar is prescribed to patients receiving lithium therapy, frequent monitoring of plasma lithium levels should be performed.
The effect of other drugs on the pharmacokinetics of nimesulide.
In vitro studies have shown that nimesulide is displaced from binding sites by tolbutamide, salicylic acid and valproic acid. Although these interactions have been identified in plasma, these effects have not been observed during clinical use of the drug and are of no clinical significance.
There is no clinically significant interaction with glibenclamide, theophylline, warfarin, digoxin, cimetidine and antacids (aluminum and magnesium hydroxide combination) in vivo. Nimesulide inhibits the activity of the CYP2C9 enzyme. When used simultaneously with the drug Remisar, drugs that are substrates of this enzyme may increase their plasma concentration.
Caution is required if nimesulide is to be administered less than 24 hours before or less than 24 hours after taking methotrexate, as it may increase the serum levels of the latter and increase its toxicity.
Due to their effect on renal prostaglandins, synthetase inhibitors, to which nimesulide belongs, may increase the nephrotoxicity of cyclosporines.
Application features
Undesirable side effects can be minimized by using the lowest effective dose for the shortest time necessary to control symptoms.
If treatment is ineffective, drug therapy should be discontinued.
The use of NSAIDs may mask fever associated with an underlying bacterial infection. Nimesulide should be discontinued if fever or flu-like symptoms occur.
While using Remisar, the patient should refrain from taking other analgesics. Concomitant use of other NSAIDs, in particular selective COX-2 inhibitors, should be avoided.
During treatment with nimesulide, it is recommended to avoid the simultaneous use of hepatotoxic drugs, as well as to refrain from drinking alcohol. There have been reports of serious liver reactions during treatment, including fatal ones, with the use of nimesulide-containing drugs. Patients who experience symptoms similar to those of liver damage, such as anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine, and patients in whom laboratory tests of liver function deviate from the norm, should discontinue use of the drug. Repeated administration of nimesulide in such patients is contraindicated. Liver damage, in most cases reversible, occurs after short-term exposure to the drug.
Effect on the gastrointestinal tract.
Gastrointestinal bleeding or ulceration/perforation (with or without warning symptoms or a history of serious gastrointestinal events), which can be fatal, has been reported with all NSAIDs. The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing NSAID doses, in patients with a history of ulcer, especially if complicated by bleeding or perforation (see section 4.3), and in the elderly. In such patients, treatment should be started at the lowest effective dose. In such patients, as well as in those taking concomitant low-dose acetylsalicylic acid or other medicinal products known to increase the risk of gastrointestinal complications, combination therapy with protective agents such as misoprostol or proton pump inhibitors should be considered.
Gastrointestinal bleeding or ulceration/perforation may occur at any time during treatment, with or without warning symptoms or a history of serious gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, nimesulide should be discontinued. Nimesulide should be used with caution in patients with a history of gastrointestinal disorders, including peptic ulcer, gastrointestinal bleeding, ulcerative colitis or Crohn's disease, as nimesulide may exacerbate them.
Patients with toxic lesions of the digestive tract, especially elderly patients, should report any unusual symptoms that occur in the digestive tract, especially bleeding. This is especially important in the initial stages of treatment. Patients taking concomitant medications that increase the risk of ulceration or bleeding, such as corticosteroids, anticoagulants, warfarin, SSRIs, antiplatelet agents (acetylsalicylic acid), should be informed about the need to exercise caution when using nimesulide.
If a patient receiving Remisar experiences bleeding or ulcers in the digestive tract, the drug should be discontinued.
Concomitant use of nimesulide with other drugs, such as oral contraceptives, anticoagulants, antiplatelet agents, may cause exacerbation of Crohn's disease and other diseases of the digestive tract.
Effects on the cardiovascular and cerebrovascular systems.
Patients with a history of hypertension and/or mild to moderate congestive heart failure, as well as patients with fluid retention and edema due to NSAID use, require appropriate monitoring and medical advice.
Clinical studies and epidemiological data suggest that some NSAIDs, especially at high doses and with prolonged use, may cause arterial thrombotic events, such as myocardial infarction and stroke. There is insufficient data to exclude a risk of such events with nimesulide.
Patients with uncontrolled hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease should be prescribed nimesulide after careful assessment. This also applies to patients with risk factors for cardiovascular disease, such as: hypertension, hyperlipidemia, diabetes mellitus, smoking.
Since nimesulide may affect platelet function, it should be administered with caution to patients with hemorrhagic diathesis. However, nimesulide does not replace acetylsalicylic acid in the prevention of cardiovascular diseases.
Effect on the kidneys.
The drug should be prescribed with caution to patients with impaired renal function or heart failure due to the possibility of worsening renal function. In case of deterioration of the patient's condition, treatment should be discontinued.
Elderly patients.
Elderly patients should be carefully monitored due to an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal, and impaired renal, hepatic or cardiac function.
There have been rare reports of severe skin reactions with NSAIDs, some of which may be fatal, such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis. If such reactions occur within the first month of treatment, the risk of their occurrence in patients with previously prescribed treatment is significantly increased. Remisar should be discontinued at the first signs of skin rash, mucosal lesions, or other allergic manifestations.
Cases of fixed drug eruption (FDE) have been reported with nimesulide. Nimesulide should not be re-administered to patients with a history of FDE associated with nimesulide.
Impact on fertility.
The use of nimesulide may impair female fertility and is not recommended for women attempting to conceive. Nimesulide is not recommended for women who have difficulty conceiving or who are undergoing investigation for infertility.
Important information about excipients.
Remisar contains sucrose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking Remisar.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Use during pregnancy or breastfeeding
Pregnancy. The use of nimesulide is contraindicated in the third trimester of pregnancy.
Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or foetal development. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformation increases from less than 1% to approximately 1.5%. The risk is thought to increase with increasing dose and duration of use.
In animals, the use of a prostaglandin synthesis inhibitor has resulted in increased pre- and post-implantation losses and increased embryo-fetal lethality. In addition, it has been reported that animals treated with a prostaglandin synthesis inhibitor during organogenesis have an increased incidence of various fetal malformations, particularly of the cardiovascular system.
From the 20th week of pregnancy, the use of Remisar may cause oligohydramnios due to fetal renal dysfunction. This condition is possible at the beginning of treatment and is usually reversible after discontinuation of treatment. In addition, there are reports of narrowing of the ductus arteriosus after treatment in the second trimester of pregnancy, which mostly disappeared after discontinuation of treatment.
Therefore, the drug Remisar should not be taken during the first two trimesters of pregnancy, except in cases where, in the opinion of the physician, the expected benefit to the patient outweighs the potential risk to the fetus. If nimesulide is used by a woman attempting to conceive, or during the first and second trimesters of pregnancy, the lowest possible dose should be used for the shortest possible time.
Antenatal monitoring for oligohydramnios and ductus arteriosus should be performed for several days after administration of Remisar, starting from the 20th week of pregnancy. If oligohydramnios or ductus arteriosus is detected, the drug should be discontinued.
In the third trimester of pregnancy, all prostaglandin synthesis inhibitors can cause the development of:
- pneumocardiac toxic lesion (with premature narrowing/closure of the ductus arteriosus and hypertension in the pulmonary artery system);
- renal dysfunction, which may progress to renal failure with the development of oligohydramnios.
In the mother and fetus at the end of pregnancy, it is possible:
- increased bleeding time, anti-aggregation effect, which can occur even when using very low doses of the drug;
- suppression of uterine contractile activity, which can lead to delayed or prolonged labor.
Breastfeeding. Since it is not known whether nimesulide passes into breast milk, its use is contraindicated during breastfeeding.
Fertility: As with other NSAIDs, nimesulide-containing medicinal products are not recommended for use in women attempting to conceive. Women who have difficulty conceiving or are undergoing investigation of infertility should discontinue nimesulide. If pregnancy is diagnosed during treatment with nimesulide, the doctor should be informed.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect of nimesulide on the ability to drive or use machines have not been conducted, but if patients experience headache, dizziness, vertigo, or drowsiness when taking nimesulide, they should refrain from driving or operating machinery.
Method of administration and doses
Dosage.
The maximum duration of the course of treatment with the drug Remisar is 15 days.
Adults: 100 mg nimesulide (1 sachet) 2 times a day after meals.
Elderly patients do not require a reduction in the daily dose.
Children aged 12 years and over. Given the pharmacokinetic profile in adults and the pharmacodynamic characteristics of nimesulide, dose adjustment is not required for children aged 12 to 18 years.
Patients with renal impairment. For patients with mild or moderate renal impairment (creatinine clearance 30–80 ml/min), no dose adjustment is required, while severe renal impairment (creatinine clearance < 30 ml/h) is a contraindication to the use of Remisar.
Patients with impaired liver function. The use of the drug Remisar is contraindicated in patients with impaired liver function.
Method of application.
Pour the contents of the sachet into a glass of still water. Stir with a spoon until a suspension with an orange scent is obtained. Drink the suspension immediately after mixing.
Children.
The drug Remisar is contraindicated in children under 12 years of age.
Overdose
Symptoms of acute NSAID overdose are usually limited to: apathy, drowsiness, nausea, vomiting, epigastric pain. These symptoms are usually reversible with supportive therapy. Gastrointestinal bleeding, hypertension, acute renal failure, respiratory depression, coma are possible, but such phenomena occur rarely. There have been reports of anaphylactoid reactions when using therapeutic doses of NSAIDs and in case of NSAID overdose. There is no specific antidote. Treatment of overdose is symptomatic and supportive. There is no data on the removal of nimesulide by hemodialysis, but if we take into account the high degree of binding of nimesulide to plasma proteins (up to 97.5%), dialysis is unlikely to be effective. In the presence of symptoms of overdose or after the use of a large dose of the drug within 4 hours after its administration, patients can be prescribed artificial vomiting and/or taking activated charcoal (60-100 g for adults), an osmotic laxative. Forced diuresis, increasing the alkalinity of the urine, hemodialysis and hemoperfusion may be ineffective due to the high degree of binding of nimesulide to blood plasma proteins. Kidney and liver function should be monitored.
Side effects
All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 - < 1/10), uncommon (≥ 1/1,000 - < 1/100), rare (≥ 1/10,000 - < 1/1,000), rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).
On the part of the organs of vision: rarely - blurred vision; rare - visual impairment.
From the side of the organs of hearing and vestibular apparatus: rare - vertigo (dizziness).
From the respiratory system, thoracic and mediastinal organs: infrequently - shortness of breath; rare - asthma, bronchospasm.
Gastrointestinal: often - diarrhea, nausea, vomiting; infrequently - constipation, flatulence, bleeding in the digestive tract, ulcer and perforation of the duodenum or stomach; rare - gastritis, abdominal pain, dyspepsia, stomatitis, black stools, bloody vomiting, ulcerative stomatitis, exacerbation of colitis and Crohn's disease.
Liver and biliary tract disorders: rare – hepatitis, fulminant hepatitis, including fatal cases, jaundice, cholestasis.
From the kidneys and urinary system: rarely - dysuria, hematuria; rare - urinary retention, renal failure, oliguria, interstitial nephritis.
From the side of metabolism: rarely - hyperkalemia.
Nervous system: infrequently - dizziness; rare - headache, drowsiness, encephalopathy (Reye's syndrome).
On the part of the psyche: rarely - a feeling of fear, nervousness, night terrors.
From the cardiovascular system: rarely - tachycardia, hemorrhage, blood pressure fluctuations, hot flashes; infrequently - arterial hypertension.
From the blood and lymphatic system: rarely - anemia, eosinophilia; rare - thrombocytopenia, pancytopenia, purpura.
On the part of the immune system: rarely - hypersensitivity reactions; rare - anaphylaxis.
Skin and subcutaneous tissue disorders: infrequently - itching, skin rash, increased sweating; rarely - erythema, dermatitis; rare - urticaria, angioedema, facial edema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis; frequency unknown - FMV (see section "Special instructions").
General disorders: infrequently - edema; rarely - malaise, asthenia; rare - hypothermia.
The most common adverse reactions observed with NSAIDs are gastrointestinal. Peptic ulcers, perforation or bleeding in the gastrointestinal tract, which are sometimes life-threatening, especially in elderly patients, may occur (see section "Special instructions"). Nausea, vomiting, diarrhea, bloating, constipation, dyspepsia, abdominal pain, melena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported after the use of nimesulide-containing products (see section "Special instructions"). Gastritis has been observed less frequently. There have been reports of edema, hypertension and heart failure in connection with NSAID treatment. Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with a frequency of rare.
Clinical and epidemiological studies suggest that some NSAIDs, especially at high doses and with prolonged use, may cause arterial thrombotic complications, such as myocardial infarction or stroke.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and/or lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua.
Expiration date
2 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
2 g of granules per sachet; 30 sachets per box.
Vacation category
According to the recipe.
Producer
PrJSC "Pharmaceutical Company "Darnitsa".
Location of the manufacturer and address of the place of its activity. Ukraine, 02093, Kyiv, Boryspilska St., 13.
Applicant
Limited Liability Company "STIF-SERVICE".
Location of the applicant. Ukraine, 61118, Kharkiv, Yuvileyny Avenue, building 57/106.
