Instructions Flertis solution for injection 1.5 mg/ml ampoules 20 ml No. 10
Composition
active ingredient: edaravone;
1 ml of solution contains edaravone 1.5 mg;
Excipients: sodium chloride; sodium metabisulfite (E 223); cysteine hydrochloride, monohydrate; concentrated phosphoric acid; sodium hydroxide; water for injections.
Dosage form
Solution for injection.
Main physicochemical properties: clear colorless liquid.
Pharmacotherapeutic group
Other drugs for the treatment of diseases of the central nervous system. ATC code N07XX14.
Pharmacological properties
Pharmacodynamics.
Free radicals, such as hydroxyl radicals (·OH), are one of the main factors in vascular disorders in the brain associated with ischemia. In ischemia or hemorrhage, the amount of free radicals produced increases due to an abnormal increase in the production of arachidonic acid metabolites. These free radicals cause peroxidation of unsaturated fatty acids, which are part of the lipids of cell membranes, damaging them, which leads to impaired brain function.
The etiology of the onset and progression of amyotrophic lateral sclerosis (ALS) is currently not definitively defined. However, it has been suggested that oxidative stress caused by free radicals may be an etiological factor for this pathology.
Edaravone scavenges free radicals and inhibits lipid peroxidation and thus reduces oxidative damage to brain cells (vascular endothelial cells/nerve cells).
In the acute stage of ischemic cerebral infarction, this drug protects the brain by inhibiting the onset and development (exacerbation) of ischemic cerebrovascular disorders, such as cerebral edema, ischemic stroke, neurological symptoms, slow neuronal death. In the case of amyotrophic lateral sclerosis (ALS), this drug, due to its inhibitory effect, demonstrates inhibition of the development of the disease by reducing oxidative damage to nerve cells.
Pharmacokinetics.
Plasma concentration
The pharmacokinetics of the drug were studied in five healthy male volunteers and five healthy elderly male volunteers aged 65 years 30 minutes after multiple intravenous doses of the drug (0.5 mg/kg) twice daily for 2 days.
| Pharmacokinetic parameters | Healthy male volunteers (n = 5) | Healthy elderly male volunteers (n = 5) |
| C max (ng/ml) | 888 ± 171 | 1041 ± 106 |
| t ½ α (g) | 0.27 ± 0.11 | 0.17 ± 0.03 |
| t ½ β (g) | 2.27 ± 0.80 | 1.84 ± 0.17 |
The concentration of unchanged drug in blood plasma in both groups decreased equally without any traces of accumulation.
Serum protein binding rate
The binding rate of edaravone (5 μM and 10 μM) to human serum protein and human serum albumin was 92% and 89–91%, respectively (in vitro).
Metabolism
In plasma, the major metabolites of edaravone in healthy adults and healthy elderly men are sulfate conjugates, and glucuronic acid conjugates have also been detected. In urine, glucuronides and, to a lesser extent, sulfates have been detected.
Breeding
After multiple intravenous administration of this medicinal product to healthy adult males and healthy elderly males twice daily for 2 days (0.5 mg/kg/30 min x 2 times/day), 0.7–0.9% and 71.0–79.9% of the dose were excreted in the urine as unchanged drug and as metabolites, respectively, 12 hours after administration.
Indication
Relief of neurological symptoms, manifestations of impairments in activities of daily living and functional disorders associated with acute ischemic stroke.
Slowing the progression of functional disorders in patients with amyotrophic lateral sclerosis (ALS).
Contraindication
Severe renal failure.
History of hypersensitivity to any component of the drug.
Interaction with other medicinal products and other types of interactions
When used simultaneously with antibiotics with a renal excretion type (cefazolin sodium, cefotiam hydrochloride, piperacillin sodium, etc.), there is a possibility of increased renal dysfunction - in the case of combined use, careful supervision with regular monitoring of renal function is required. The mechanism of this phenomenon is unknown. Since this drug is mainly excreted by the kidneys, the simultaneous use of antibiotics that are excreted by the kidneys may increase the burden on the kidneys.
Flertis should be dissolved in saline before administration. Mixing the drug with other intravenous solutions containing different sugars may result in decreased edaravone concentrations.
The drug should not be mixed with parenteral nutrition solutions and/or solutions containing amino acids, and should not be administered through the same infusion systems - this may lead to a decrease in edaravone concentrations.
Do not mix with anticonvulsants including diazepam, phenytoin sodium, etc. as turbidity may occur. Also do not mix with potassium canrenoate as the solution may become cloudy.
Application features
Flertis should be used under the close supervision of physicians who have sufficient knowledge of this drug and experience in its use for this disease.
Before using the medicinal product, the patient or their representative should be provided with sufficient explanations regarding adverse reactions, etc.
During therapy, worsening of acute renal failure or renal dysfunction, severe hepatic dysfunction and/or disseminated intravascular coagulation (DIC), which may be fatal, may occur. Serious cases of concomitant renal failure, hepatic failure and/or haematological disorders, etc. have been reported.
There are few cases of prescribing this medicine to patients with severe ALS (above stage 4) and patients with forced vital capacity less than 70% of theoretical normal, therefore its efficacy and safety have not been proven. Prescribing the medicine to such patients should be carefully considered, taking into account the risks and benefits.
At the beginning of treatment with the drug or immediately after its use, blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase, red blood cells and platelet analysis should be performed in order to detect early changes in these parameters, since in most cases the results of laboratory tests may deteriorate early in the drug's use. Laboratory tests should be performed regularly during the use of edaravone. If abnormal changes in test parameters and/or symptoms, such as oliguria, the drug should be discontinued immediately and appropriate measures should be taken. In addition, careful monitoring of the patient's condition should continue after the end of the injections.
Dehydrated patients with high blood urea nitrogen/creatinine ratios or other signs should be closely monitored during treatment, as fatalities have been reported in these patients.
In patients with amyotrophic lateral sclerosis (ALS), as the disease progresses, serum creatinine levels may decrease due to muscle atrophy, so instead of comparing a single serum creatinine level with a control value, the change in serum creatinine levels should be monitored to see if there is a trend toward deterioration. In addition, because ASA levels vary with body water, instead of comparing a single ASA level with a control value, the change in ASA levels should be monitored to see if there is a trend toward deterioration.
In patients with muscle atrophy, in addition to measuring serum creatinine and AST, renal function should be assessed by tests that are independent of changes in muscle mass, such as estimated glomerular filtration rate, serum cystatin C, and urinary creatinine clearance, before and during injections.
If complications such as infection occur during the injection and additional antibiotics are required, the need for continued injection of the drug should be carefully considered, and in the case of continued injections, laboratory parameters should be monitored particularly closely. In addition, even after the end of the drug administration, close observation should be maintained, with regular monitoring of laboratory test results (see section "Interaction with other medicinal products and other forms of interaction").
If renal dysfunction occurs during injection, the drug should be discontinued immediately and appropriate measures should be taken in collaboration with physicians who have sufficient knowledge and experience in the treatment of renal dysfunction.
Many fatalities have been observed in patients with infections or severe impairment of consciousness (i.e., Japanese Coma Scale score ≥ 100). Therefore, the risk/benefit ratio should be carefully evaluated in these patients.
Elderly patients require particularly careful monitoring, as many fatalities have been observed among patients in this category.
Flertis should be used with caution in the following categories of patients:
with impaired renal function and/or dehydration - due to a high risk of developing acute renal failure (acute renal failure or impaired renal function may worsen. Fatal outcomes have been reported in patients with a high blood urea nitrogen/creatinine ratio prior to use); with infection (renal failure may worsen due to deterioration of the patient's general condition); with impaired liver function (possible worsening of liver failure); with heart disease (possible worsening of the disease, as well as development of renal failure); with severe impairment of consciousness (fatalities have been reported in this category of patients); elderly patients (fatalities have been reported in this category of patients).
This medicinal product contains potassium metabisulphite (E 223), which may rarely cause hypersensitivity reactions and bronchospasm.
Use during pregnancy or breastfeeding
Pregnancy: The safety of this medicine during pregnancy has not been established. It is not recommended for use in pregnant women or women who may become pregnant.
Breastfeeding. Women should refrain from breastfeeding while using the drug. Studies in rats have shown that edaravone passes into milk.
Ability to influence reaction speed when driving vehicles or other mechanisms
The drug is intended for use in a hospital setting, therefore such data are not available.
Method of administration and doses
Relief of neurological symptoms, manifestations of impairments in activities of daily living and functional disorders associated with acute ischemic stroke.
The usual adult dose is 1 ampoule (30 mg of edaravone) diluted in 100 ml of saline, administered intravenously over 30 minutes twice daily, morning and evening.
Therapy with this drug should be started within 24 hours of the onset of symptoms, and the duration of treatment is 14 days.
Slowing the progression of functional disorders in patients with amyotrophic lateral sclerosis (ALS).
The usual dose for adults is 2 ampoules (60 mg of edaravone) diluted in 100 ml of saline, administered intravenously over 60 minutes once daily.
As a rule, the period of drug administration and the rest period in total are 28 days and are considered as one course, such courses are repeated. The first course consists of 14 days of drug administration, after which there is a 14-day break and rest, the second course and subsequent courses consist of 10 days of drug administration for 14 days, after which a rest period of 14 days begins.
Use in patients with acute ischemic stroke
It should be noted that the duration of administration is reduced according to the patient's clinical condition.
Elderly patients.
Since elderly patients generally have reduced physiological functions, if side effects occur, the drug should be discontinued and appropriate measures should be taken. It is known that elderly patients often have fatal outcomes, so monitoring should be particularly careful.
Children.
The safety of the drug for children has not been established.
There is insufficient experience in acute ischemic stroke in children; there is no clinical experience in children with ALS.
Overdose
Cases of overdose have not been described.
Side effects
From the urinary system: infrequently: acute renal failure; rarely: nephrotic syndrome.
Renal function tests should be performed regularly and patients should be closely monitored as acute renal failure or nephrotic syndrome may occur. If decreased renal function and/or symptoms such as oliguria, etc. are detected, the drug should be discontinued immediately and appropriate measures should be taken.
Skin: common: rash; uncommon: redness, swelling, itching; frequency unknown: erythema.
Hepatobiliary system: uncommon: liver function abnormalities, hepatic failure; frequency unknown: fulminant hepatitis, jaundice.
It is necessary to perform liver tests frequently and carefully monitor the condition of patients, as severe hepatitis may occur, including fulminant hepatitis, liver dysfunction or jaundice with a significant increase in the level of AST, ALT, alkaline phosphatase, gamma-glutamyltranspeptidase, LDH, blood bilirubin, etc. If pathological indicators are detected, the drug should be immediately discontinued and appropriate measures taken.
Nervous system disorders: Infrequent: insomnia, headache.
Cardiovascular system: infrequently: increased blood pressure.
Blood disorders: common: decreased red blood cell count, leukocytosis, leukopenia, decreased hematocrit, decreased hemoglobin level, thrombocytosis; rare: DIC syndrome, thrombocytopenia; frequency unknown: agranulocytosis.
Hematological studies should be performed periodically, as DIC may occur. If any abnormalities in hematological tests are detected or DIC is suspected, this medicinal product should be discontinued and appropriate therapeutic measures should be taken.
Respiratory system: frequency unknown: acute lung injury syndrome accompanied by pyrexia, cough, dyspnea, chest X-ray abnormalities.
Patients should be closely monitored for acute lung injury with fever, cough, dyspnea, and chest X-ray abnormalities. If any signs of acute lung injury are detected, the drug should be discontinued immediately and appropriate measures should be taken.
Gastrointestinal system: infrequently: nausea, vomiting.
Musculoskeletal system: frequency unknown: rhabdomyolysis.
Immune system disorders: frequency unknown: shock, anaphylaxis (urticaria, decreased blood pressure, difficulty breathing, etc.).
Patients should be carefully monitored as shock and anaphylactoid reactions (urticaria, decreased blood pressure, shortness of breath, etc.) may occur. If abnormal findings are detected, the drug should be discontinued and appropriate measures taken.
Changes in laboratory parameters: often: increased levels of ALT, AST, LDH, gamma-glutamyl transpeptidase, alkaline phosphatase, bilirubin, creatinine, uric acid in serum, glycosuria, hematuria, proteinuria, increased serum cholesterol, increased triglycerides, decreased total serum protein, increased CK (CK), decreased CK (CK), decreased serum potassium, increased serum potassium; infrequently: decreased serum cholesterol, decreased serum calcium.
Changes at the injection site: uncommon: rash, redness and swelling at the injection site.
General disorders: common: fever; uncommon: hyperthermia, feeling hot, increased blood pressure, headache.
Reporting of suspected adverse reactions
Reporting of adverse reactions after registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the link: https//aisf.dec.gov.ua/.
Expiration date
2 years.
Do not use the drug after the expiration date indicated on the package.
Incompatibility
Do not mix with other medicinal products except those mentioned in the section "Method of administration and dosage".
Storage conditions
Does not require special storage conditions.
Keep out of reach of children.
Packaging
20 ml in glass ampoules. 5 ampoules in a blister. 2 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "Farmak".
Location of the manufacturer and address of its place of business
Ukraine, 04080, Kyiv, Kyrylivska St., 74.
