Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions from colorless to brownish-yellow color, transparent.
1 f. (3.5 ml)
serlaxine 3.5 mg
[PRING] sodium acetate trihydrate - 9.52 mg, water d / and - up to 3.5 ml, hydrochloric acid solution 1M - to pH 5, sodium hydroxide solution 1M - to pH 5.
3.5 ml - vials of colorless glass (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Peripheral vasodilator. Serlaxine is a recombinant molecule that is identical to the native peptide hormone relaxin-2 human. In the renal and systemic circulation, as well as in the epithelium of the kidneys, relaxin-2 binds to a specific receptor RXFP1, which is conjugated to G-protein. Linking to this receptor, relaxin-2 stimulates rapid signaling pathways leading to activation of NO synthase, as well as delayed-type signaling pathways leading to stimulation of type B endothelin receptors and expression of angiogenic growth factors and matrix metalloproteinases (gelatinases). These ways cause the relaxation of the walls of the vessels of the systemic blood flow and the vessels of the kidneys, which leads to a decrease in the OPSS and an increase in cardiac output. In addition, according to experimental studies, sulfuraxin has a beneficial effect on the processes of remodeling connective tissue, resulting in reduced hypertrophy and fibrosis of the myocardium. The cardioprotective effect of the drug is probably also mediated by the prevention of inflammation and oxidative stress.
The vasoactive properties of relaxin-2 are confirmed by studies of the adaptive capacity of the vascular bed of women during pregnancy. It is believed that a temporary increase in the concentration of relaxin-2 in blood plasma in the first trimester of pregnancy, reaching 6 mg / ml, causes a decrease in OPSS and an increase in cardiac output, which provides transport of sufficient oxygen to the fetoplacental complex.
The therapeutic use of sulfuraxine in heart failure is based on the fact that when serum -axine concentration in the blood serum reaches about 18 ng / ml, ventricular-arterial conjugation, vasorelaxation processes, blood flow and organ perfusion improve. The available data on increased production of cardiac relaxin-2 and an increase in its concentration in the bloodstream in patients with chronic heart failure indicate the presence of a natural compensatory role of relaxin-2 in heart failure.
In patients with compensated heart failure who received silveraxin at doses of 10 to 960 Ојg / kg / day in an open clinical trial, there was a tendency to improve hemodynamic parameters (in particular, to lowering the pulmonary artery wedge pressure, lower OPSS, and an increase in cardiac index) , as well as improving the renal function (lower serum creatinine, blood urea nitrogen and uric acid).
In a clinical study in patients with acute heart failure (OCH), hospitalized with dyspnea at rest or with minimal physical exertion, systolic blood pressure above 125 mm Hg. and impaired renal function of mild or moderate severity (calculated GFR - 30-75 ml / min / 1.73 m 2 ), against the background of the use of sulfuraxine, there was a statistically significant decrease in the manifestation of dyspnea, a tendency to decrease the signs and symptoms of heart failure, the frequency of worsening of the course of heart failure, the decrease in the manifestations of blood circulation disorders in small and large circles of the circulation (including pulmonary edema, wheezing in the lungs, swelling and abnormal pulsation of the cervical veins), and also ernoe reduction of hospitalization period.
Decrease in the severity of signs and symptoms of acute heart failure was accompanied by a significant decrease in the need for the use of standard OCH treatments.The total dose of diuretics for intravenous administration, used in the first 5 days after the onset of infusion of sulfuraxine, was significantly lower than in the placebo group. The proportion of patients with exacerbation of signs and / or symptoms of heart failure who, before the 5th day after the infusion, needed to increase the intensity of IV therapy of heart failure or mechanical ventilation or measures aimed at maintaining blood circulation, was significantly lower in the sullaxin group in the placebo group.
The study showed that the use of silveraxin reduces the risk of cardiovascular mortality by 37%, and the difference in the death rate due to cardiovascular causes was detected as early as the 5th day after the infusion and was observed regardless of sex or age.
PHARMACOKINETICS
Distribution
C ss in the serum were achieved 4-6 hours after the onset of IV infusion. In healthy volunteers and in patients with heart failure who received silveraxin in the form of IV infusion, the AUC and total clearance of serlaxin in the equilibrium state were approximately the same.
In healthy volunteers, V d in the equilibrium state after intravenous infusion of silveraxin was 0.267-0.339 l / kg, and in patients with acute heart failure 0.593 l / kg.
AUC and C ss of silveraxin increased in proportion to the dose. The values ​​of total clearance and V d in the equilibrium state in the dose range of 10-960 μg / kg / day remained constant.
Metabolism
Special studies of the metabolism of serlaxine have not been conducted. The main way of its metabolism, apparently, is the catabolism of peptidases and proteases in various tissues of the body, including the liver and kidneys. It is assumed that in vivo sulfuraxin breaks down to form small peptides and amino acids and is utilized in the same way as endogenous human relaxin-2.
Excretion
Serelaxin is rapidly excreted from the body. T 1/2 after completion of intravenous administration is from 7 to 15.9 hours. According to clinical studies, the plasma clearance of sulfuraxine is from 82 to 229 ml / kg / h.
Pharmacokinetics in specific patient groups
The age of the patients does not affect the pharmacokinetics of serlaxine.
The effect of liver function abnormalities on the pharmacokinetics of serlaxin was studied in patients with impaired liver function of mild, moderate and severe degree, assessed on the Child-Pugh scale (5 to 15 points), in comparison with healthy volunteers with normal liver function. Dysfunction of the liver on the pharmacokinetics of serlaxine was not affected.
No data have been obtained indicating that mild or moderate renal dysfunction affects the serlaxin clearance. Studies of silveraxin in patients with impaired renal function have not been carried out to a serious degree.
Differences in the clearance of serlaxine in men and women have not been revealed.
There were no differences in the clearance of serlaxine between the ethnic subgroups.
According to the population analysis of pharmacokinetics, the dependence of serlaxine clearance on the body mass index was not revealed.
INDICATIONS
- Acute heart failure in patients with normal or elevated blood pressure simultaneously with standard therapy of acute heart failure, incl. "looped" diuretics.
DOSING MODE
Rheazans is intended for use in hospital, only for intravenous administration.
The drug should be diluted immediately before use.
The contents of the vial are for single use only.
Before using the drug Reasans should stabilize systolic blood pressure above 125 mm Hg.
The dose of the drug Reassants should be selected based on the patient's body weight (see Table 1). The drug should be administered as a continuous IV infusion for 48 hours. The recommended dose is 30 Ојg / kg / day. Two consecutive intravenous infusions (24 hours each) should be performed at a constant rate of 10 ml / h.
Table 1. Volume of the preparation Reasans, a concentrate for the preparation of a solution for infusion, which should be diluted in 250 ml of 5% sterile dextrose (glucose) solution to prepare one 24-hour IV infusion
Weight of the patient (kg) Serelaxine (mg) Volume of the preparation Rheasant, concentrate for the preparation of a sterile solution for infusion (ml) for dilution in 250 ml of 5% dextrose (glucose)
40-59 kg 2 mg 2 ml
60-74 kg 3 mg 3 ml
75-114 kg 3.5 mg 3.5 ml
115-160 kg 5.5 mg 5.5 ml (requires 2 bottles)
Correction of dose
Regular monitoring of blood pressure during the administration of the drug Reassanz. If the level of systolic blood pressure decreases by more than 40 mm Hg. relative to the initial value, but remains at a level above 100 mm Hg. or if systolic blood pressure drops below 100 mm Hg, the following measures should be taken (see Table 2).
Table 2.
Systolic BP during infusion * Required dose adjustment
Decrease by more than 40 mm Hg. relative to the initial value, but systolic blood pressure above 100 mm Hg. Reducing the rate of IV infusion of the drug Reassanza by 50% until the end of the 48-hour infusion (i.e., a decrease in the rate of IV infusion from 10 ml / h to 5 ml / h)
Systolic blood pressure is below 100 mm Hg. Termination of infusion of the drug Reassant
* These values ​​of blood pressure should be confirmed by two measurements taken at an interval of 15 minutes.
The use of the drug in patients with impaired renal function of severe degree (GFR <30 ml / min / 1.73 m 2 ) has not been studied. The drug can be used only if the expected benefit exceeds the potential risk. In patients with impaired renal function of mild and moderate severity (GF? 30 and? 75 ml / min / 1.73 m 2 ) , dose adjustment is not required when the drug is used.
In patients with impaired liver function, dose adjustment is not required.
Changing the dosage regimen depending on sex, age or ethnicity is not required.
The safety and effectiveness of the use of the drug Reassant in children and adolescents under the age of 18 years have not been established.
Instructions for use
Preparation of the solution for infusion should be carried out in accordance with the rules of asepsis.
Reasans should not be mixed with any other medicines.
1. Use a sterile syringe to collect the required amount of concentrate to prepare the infusion solution based on the patient's body weight (see Table 3) and insert it into an infusion tank containing 250 ml of 5% sterile dextrose (glucose) solution.
Table 3. The volume of the preparation of Reasans, a concentrate for the preparation of a solution for infusion, which should be dialed using a sterile syringe
Body weight of the patient (kg) Volume of the preparation Reasans, concentrate for solution for infusion (ml), for 24-hour infusion
40-59 kg 2 ml
60-74 kg 3 ml
75-114 kg 3.5 ml
115-160 kg 5.5 ml (requires 2 bottles)
2. Mix the contents of the infusion container, gently rocking it from side to side. Do not shake the container for infusion.
3. To avoid microbiological contamination, it is necessary to start using the prepared solution no later than 4 hours after its preparation (if stored at room temperature (20-25 В° C)).
4. It is necessary to prepare an infusion system with a separate intravenous catheter (it is possible to use a multichannel catheter).
5. We recommend the use of infusion filters with pores of 0.2 Ојm.
6. The infusion system and the infusion filter should be rinsed with a prepared solution of the preparation Reassanz (15 ml) from the tank for IV infusion.
7. Initiate IV infusion of the drug should be, setting the infusion rate of 10 ml / h for 24 hours.
8. In the same way, you should prepare for use a second container for intravenous infusion shortly before the end of the first intravenous infusion.
9. Start the second 24-hour IV infusion immediately after the end of the first:
- if during the first intravenous infusion did not correct the dose of the drug, the second intravenous infusion should be started, having established the infusion rate of 10 ml / h for 24 hours;
- If the infusion rate was reduced from 10 ml / h to 5 ml / h during the first intravenous infusion, the second intravenous infusion should be started by setting the infusion rate at 5 ml / h for 24 hours.
Unused solution in vial or infusion system should be disposed after 24 hours.
Avoid exposure to direct sunlight on the prepared solution.
Dispose of unused product or waste in accordance with local regulations.
SIDE EFFECT
When using the drug, the most common adverse event was a decrease in blood pressure (3.3%).
Predominantly undesirable phenomena of mild and moderate severity were noted. In a small number of patients who received the drug Reasanz (5.4%), IV infusion of the drug was discontinued due to the development of adverse events.
Below are the undesirable phenomena noted during the use of the drug in clinical trials. Undesirable phenomena are distributed according to the frequency of occurrence. To assess the frequency, the following criteria were used (according to WHO classification): very often (? 1/10), often (? 1/100, <1/10), infrequently (? 1/1000, <1/100), rarely (? 1/10 000, <1/1000), very rarely (<1/10 000), including individual messages.
From the side of the cardiovascular system: often - a marked decrease in blood pressure.
Changes in laboratory indicators
In controlled clinical trials, there were no clinically significant changes in laboratory parameters (serum electrolytes, biochemical parameters, liver function disorders, plasma glucose concentrations) associated with the use of the drug Reasanz. In 7% of patients in the group of application of silveraxin and in 6% of patients in the placebo group hypokalemia developed, but there was no difference in serum potassium content.
When the drug was used in clinical trials, a decrease in hemoglobin, erythrocyte count and hematocrit by more than 20% at 2 weeks after initiation of treatment was noted in the group of application of the preparation Reasans in 1.5%, 1.1% and 1.6% of patients, respectively, and in the placebo group 0.6 %, 0.6% and 0.6% of patients, respectively.
Episodes for the reduction of systolic blood pressure, requiring dose adjustment
When the drug was used in clinical trials, episodes of a confirmed decrease in systolic blood pressure (more than 40 mm Hg relative to the baseline value or below 100 mm Hg) were observed in 29.4% of patients treated with Reassans, compared with 18.1 % of patients receiving placebo. Most of these adverse events occurred between 13 and 17 hours after the onset of infusion. In 84.4% of cases, these undesirable phenomena were resolved either after correction of infusion rate, or after drug discontinuation. Only 12% of such adverse events noted in the Reasanz group of patients required additional treatment: in most cases, infusion therapy was used, and in some cases cardiotonic drugs or mechanical means of supporting blood circulation were required.
CONTRAINDICATIONS
- shock of various etiologies;
- Obstruction of the outflow tract of the left ventricle (including severe aortic stenosis, hypertrophic obstructive cardiomyopathy);
- children and adolescents under 18 years of age (due to lack of data on effectiveness and safety);
- Hypersensitivity to sulfuraxine or any other components that make up the drug.
Caution should be applied to the drug simultaneously with vasodilating and / or antihypertensive agents.
In patients with severe renal dysfunction (estimated rate of glomerular filtration (rSCF) <30 ml / min / 1.73 m 2 ), application is possible only if the expected benefit exceeds the potential risk.
PREGNANCY AND LACTATION
According to the amino acid sequence and structure, serlaxine is identical to human peptide hormone relaxin-2, the concentration of which in the systemic blood flow increases significantly in pregnancy compared to its concentration during the menstrual cycle, reaches a maximum in the first trimester of pregnancy and remains elevated in the II and III trimesters of pregnancy. In addition, the hormone relaxin-2 is present in breast milk during breast-feeding.
Due to the lack of clinical data on the use of the drug Reassanza in pregnant women with acute heart failure, as well as in women during lactation, the drug can be used during pregnancy and during breastfeeding only if the intended use for the mother exceeds the potential risk to the fetus and the baby .
Fertility
Data on the effect of the drug Reassant on fertility is not available.
APPLICATION FOR FUNCTIONS OF THE LIVER
The use of the drug in patients with impaired renal function of severe degree (GFR <30 ml / min / 1.73 m 2 ) has not been studied. The drug can be used only if the expected benefit exceeds the potential risk.
In patients with impaired renal function of mild and moderate severity (GF? 30 and? 75 ml / min / 1.73 m 2) , dose adjustment is not required when the drug is used.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with impaired liver function, dose adjustment is not required.
APPLICATION FOR CHILDREN
Reasans is not recommended for use in children and adolescents under 18 years (due to lack of data on efficacy and safety).
APPLICATION IN ELDERLY PATIENTS
Do not need dose adjustment depending on age.
SPECIAL INSTRUCTIONS
Episodes of blood pressure lowering
Due to the risk of significant decrease in blood pressure during administration of the drug Reasanz should regularly monitor the blood pressure.
In clinical studies, against the background of on / in the Reasanz drug were cases of blood pressure lowering, some of which have been reported as cases of significant decrease in blood pressure. In most cases, these effects were not accompanied by clinical symptoms.
If the systolic blood pressure is reduced by more than 40 mmHg relative to the initial value, but remains above 100 mmHg, reduce speed / infusion preparation Reasanz 50%.
Discontinue treatment drug Reasanz if systolic blood pressure decreases in a patient to a level below 100 mm Hg
In accordance with clinical guidelines, caution should be exercised when applying Reasanz drug simultaneously with vasodilating and / or antihypertensive agents.
Renal function
in the absence of clinical data on the drug administration Reasanz in patients with impaired severe renal function (estimated GFR <30 mL / min / 1.73 m 2 ), the application of the drug should be considered only if the prospective advantage from treatment exceeds the potential risk.
Repeated on / in the introduction
Repeated on / in administering drug Reasanz patients with acute heart failure has not been studied.
immunogenicity
Antibodies to serelaksinu were detected only in 1 patient with severe heart failure who received a continuous serelaksin / in infusion for up to 48 hours; antibodies did not have neutralizing activity.
In clinical studies in other patient populations who have serelaksin applied as a continuous p / infusion for at least 2 weeks, serelaksinu antibodies were detected in 43% of patients. Patients with antibodies to serelaksinu the C ss serelaksina were higher than in patients without antibodies (in 1.8-3.7 times), but on the safety profile serelaksina is not reflected. According to studies in vitro antibodies did not have neutralizing activity.
Impact on the ability to drive vehicles and manage mechanisms
There are no data on the effect of the drug on the ability to drive vehicles and the performance of potentially hazardous activities that require high concentration and psychomotor speed reactions.
OVERDOSE
No cases of overdose have been reported.
Symptoms: The most likely manifestation of overdose is the excessive reduction in systolic blood pressure.
Treatment: carrying out of symptomatic and supportive treatment (fluid therapy, and in some cases - the use of cardiotonic drugs or mechanical circulatory support methods).
DRUG INTERACTION
Special studies on the interaction serelaksina with other drugs have not been undertaken.
In clinical studies serelaksina when applied simultaneously with other preparations were noted clinically significant effect on clearance serelaksina. Such drugs include digoxin, ACE inhibitors, angiotensin II receptor antagonists, beta-blockers, diuretics potassium sparing drugs (aldosterone antagonists), calcium channel blockers slow, vasodilatory drugs, cardiotonic agents neglikozidnye structure (inodilatatory).
Specific studies evaluating serelaksina effect on the pharmacokinetics of other drugs have been conducted. No data indicating serelaksina interaction with cytochrome P450 isoenzymes system, whereby the ability to enter into serelaksina drug interaction seems low.
Incompatibility
In the absence of special compatibility studies, the drug should not be confused with other drugs in a single infusion system and / or container and inserted through one I / catheter with other drugs.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be kept out of the reach of children, protected from light at a temperature of from 2 В° to 8 В° C. Do not freeze. Shelf life - 2 years.
