Universal reference book for medicines
Product name: BENEFIX (BENEFIX)

Active substance: nonacog alfa

Type: Coagulation factor IX drug

Manufacturer: WAYET (Russia) manufactured by WYETH PHARMA (Spain) packaging, primary packaging Vetter Pharma-Fertigung (Germany)
Composition, form of production and packaging
Lyophilizate for the preparation of a solution for intravenous administration
as a white lyophilized mass.

1 f.

nonoc with alpha (recombinant coagulation factor IX) 1000 IU

Excipients: L-histidine 6.2 mg, glycine 78.1 mg, sucrose 40 mg, polysorbate 80 0.22 mg.

1 syringe with a solvent (sodium chloride solution 0.234%) contains: sodium chloride 11.93 mg, water for injection qs 5 ml.

bottles (1) of transparent glass (type I) complete with a syringe with 5 ml of solvent, a piston, a set for microinfusion, adapter with a filter, plaster, gauze and 2 alcoholic napkins - plastic packages (1) with a lid - cardboard packs.

Lyophilizate for the preparation of a solution for intravenous administration as a white lyophilized mass.

1 f.

nonoc with alpha (recombinant coagulation factor IX) 2000 IU

Excipients: L-histidine 6.2 mg, glycine 78.1 mg, sucrose 40 mg, polysorbate 80 0.22 mg.

1 syringe with a solvent (sodium chloride solution 0.234%) contains: sodium chloride 11.93 mg, water for injection qs 5 ml.

bottles (1) of transparent glass (type I) complete with a syringe with 5 ml of solvent, a piston, a set for microinfusion, adapter with a filter, plaster, gauze and 2 alcoholic napkins - plastic packages (1) with a lid - cardboard packs.

Lyophilizate for the preparation of a solution for intravenous administration as a white lyophilized mass.

1 f.

nonoc with alpha (recombinant coagulation factor IX) 250 IU

Excipients: L-histidine 6.2 mg, glycine 78.1 mg, sucrose 40 mg, polysorbate 80 0.22 mg.

1 syringe with a solvent (sodium chloride solution 0.234%) contains: sodium chloride 11.93 mg, water for injection qs 5 ml.

bottles (1) of transparent glass (type I) complete with a syringe with 5 ml of solvent, a piston, a set for microinfusion, adapter with a filter, plaster, gauze and 2 alcoholic napkins - plastic packages (1) with a lid - cardboard packs.

Lyophilizate for the preparation of a solution for intravenous administration as a white lyophilized mass.

1 f.

Nonocetal alpha (recombinant coagulation factor IX) 500 IU

Excipients: L-histidine 6.2 mg, glycine 78.1 mg, sucrose 40 mg, polysorbate 80 0.22 mg.

1 syringe with a solvent (sodium chloride solution 0.234%) contains: sodium chloride 11.93 mg, water for injection qs 5 ml.

bottles (1) of transparent glass (type I) complete with a syringe with 5 ml of solvent, a piston, a set for microinfusion, adapter with a filter, plaster, gauze and 2 alcoholic napkins - plastic packages (1) with a lid - cardboard packs.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2011.

PHARMACHOLOGIC EFFECT

The recombinant coagulation factor IX is a glycoprotein expressed by Chinese hamster ovary cells subjected to genetic modification.

The benefice contains the recombinant factor of blood coagulation IX (nonacar alfa).
The recombinant coagulation factor IX is a single-chain glycoprotein containing 415 amino acid residues having an approximate molecular weight of 55,000 daltons belonging to the serine protease family and being a vitamin K-dependent clotting factor.
The recombinant coagulation factor IX is a protein obtained using DNA recombination technology structurally and functionally similar to the endogenous coagulation factor IX.
The latter is activated by the factor of blood clotting VII (tissue clotting factor, taking part in the external hemocoagulation pathway), as well as the coagulation factor XIa, participating in the internal hemocoagulation pathway. Activated coagulation factor IX in combination with activated blood coagulation factor VIII leads to the activation of coagulation factor X, which in turn ensures the conversion of prothrombin to thrombin. Thrombin catalyzes the conversion of fibrinogen into fibrin and the formation of blood clotting. The activity of coagulation factor IX is absent or significantly reduced in patients with hemophilia B, which may require replacement therapy.
PHARMACOKINETICS

When benefimix was used in patients with hemophilia B and previously treated with clotting factors (baseline data), the degree of in vivo activity recovery in the range of 15% to 62% (on average 33.7 ± 10.3%) was obtained.
It has been shown that the administration of one international unit (ME) of the Beneficix drug increases the circulating coagulation factor IX activity by an average of 0.75 IU / dL (range from 0.3 IU / dl to 1.4 IU / dL).
T 1/2 of nonacoaga alfa varies from 11 to 36 hours (an average of 19.3 ± 5 hours. The degree of recovery of coagulation factor IX activity is lower by 28% when using the Beneficix drug as compared to the blood coagulation factor IX preparations. It is assumed that this difference in the degree of recovery of coagulation factor IX activity is due to their structural differences.

INDICATIONS

- Treatment and prevention of bleeding in patients with hemophilia B (congenital insufficiency of the coagulation factor IX).

DOSING MODE

The benefit is injected intravenously in a few minutes after reconstitution of the lyophilized powder with the injected water.
The speed of administration is determined by the doctor. The administration of the Beneficiks by prolonged infusion has not been studied, therefore, it should not be administered dropwise or mixed with infusion solutions or other medications. Treatment should be started under the supervision of a doctor with experience in the treatment of hemophilia.
Patients should follow the doctor's instructions related to their IV injection procedures.

Therapy with any factor of blood coagulation IX requires an individual dose selection.
Doses and duration of substitution therapy depend on the severity of the deficiency of the coagulation factor IX, localization and severity, bleeding, the general condition of the patient and the clinical effect of the therapy. The dose of the Benefiks preparation may differ from the doses of the blood coagulation factor IX preparations obtained from blood plasma.
To ensure the necessary activity of the coagulation factor IX, careful monitoring of this indicator (especially in surgical procedures) is recommended, using appropriate tests.
Calculation of the dose of the drug is carried out based on the activity of the coagulation factor IX, the pharmacokinetics parameters of the preparation, in particular, the half-life and recovery period, as well as the clinical situation.
Usually, the use of coagulation factor IX preparations more than 1 time per day is not required.

The dose of coagulation factor IX is expressed in international units (ME) corresponding to the activity of the standard coagulation factor IX WHO.
The activity of the blood coagulation factor IX in plasma is expressed either as a percentage (relative to the normal values ​​of the human blood plasma) or in international units (relative to the activity of the international standard of coagulation factor IX in plasma).
One international unit (ME) of coagulation factor IX activity corresponds to the amount of coagulation factor IX contained in 1 ml of healthy human plasma.Calculation of the dose of the Beneficix can be based on the data that the dose of coagulation factor IX corresponding to 1 IU / kg of body weight increases the level of coagulation factor IX in blood plasma by an average of 0.8 ± 0.2 IU / dl (range of variation - from 0.4 IU / dl up to 1.4 IU / dl) in adult patients (> 15 years).However, each patient should evaluate the pharmacokinetics of the drug and adjust the dose accordingly.

The required dose of the drug is calculated by the following formula:

Required quantity of ME coagulation factor IX = Body weight (kg)?
Necessary increase in the activity of coagulation factor IX (% or IU / dL)? The reciprocal of the degree of increase in the activity of the coagulation factor IX
Thus, with an average increase in coagulation factor IX activity corresponding to 0.8 IU / dl:

Required quantity of ME coagulation factor IX = Body weight (kg)?
The necessary increase in the activity of the coagulation factor IX (% or IU / dL) is 1.3 IU / kg / IU / dL
With the development of the hemorrhagic conditions listed below, the activity of the blood clotting factor IX in blood plasma should not fall below these values ​​(in% of normal or in IU / dl) for an appropriate period of time.

Severity of bleeding or type of surgical intervention Necessary activity of coagulation factor IX (% or IU / dL) Periodicity of administration (h) / duration of therapy (days)

Bleeding

Early phase of hemarthrosis, muscle hemorrhage or bleeding in the oral cavity 20-40 Repeat every 24 hours for at least 1 day, until the hemorrhagic episode is relieved, as determined by resolution of the pain syndrome or healing of the wound.

More severe hemarthrosis, muscle hemorrhage or hematoma 30-60 Repeat infusion every 24 hours for 3-4 days or more, before resolving the pain syndrome and acute impairment of function

Life-threatening hemorrhages 60-100 Repeat infusion every 8-24 hours, until life threatened

Operative intervention

Small (including extraction of the tooth) 30-60 Repeated every 24 hours, for at least 1 day, until the wound is healed

Extensive 80-100 (in the per- and postoperative period) Repeat infusion every 8-24 hours until adequate wound healing, then for the next 7 days the dose is adjusted so as to maintain the activity of factor IX in the range of 30% (ME / dl ) to 60% (IU / dl)


When performing extensive surgical interventions, careful monitoring of substitution therapy by performing blood clotting studies (in particular, the activity of coagulation factor IX in plasma) is necessary.
The response of individual patients to the coagulation factor IX therapy may vary due to the difference in the degree of in vivo activity recovery and the half-life of the drug.
The Benefiks can be used as a long-term prophylaxis for bleeding in patients with severe hemophilia B. In a clinical study, the median dose of the drug, when used as a secondary prophylaxis in patients previously treated with coagulation factors, was 40 IU / kg (range from 13 IU / kg to 78 IU / kg) with an administration interval of 3 to 4 days.
In younger patients, it may be necessary to shorten the intervals between administrations or increase the dose of the drug.
Use in children (6 to 15 years)

In children older than 15 years, the drug is administered as in adults.

Calculation of the dose of the Benefiks preparation for children aged 6 to 15 years is based on the fact that the dose of coagulation factor IX corresponding to 1 IU / kg of body weight in children increases the level of coagulation factor IX in blood plasma, on average by 0.7 ± 0.3 IU / dl (range of variation is from 0.2 IU / dl to 2.1 IU / dL).
Thus, the drug is used in children using the following scheme:
Required quantity of ME coagulation factor IX = Body weight (kg)?
The necessary increase in the activity of the coagulation factor IX (% or IU / dL) is 1.4 IU / kg / IU / dL
It was found that in 57% of children to achieve the necessary response to therapy, an increase in the dose of the drug is required because of less than expected;recovery of coagulation factor IX activity in blood plasma;
as a result, in some of them, the average dose of the drug may be> 50 IU / kg. This necessitates careful monitoring of the activity of the blood coagulation factor IX in blood plasma, as well as the calculation of pharmacokinetics parameters, in particular, the degree of activity recovery and half-life, in accordance with the clinical indications necessary for correcting the dose of the drug. If repeated administration of the drug at doses> 100 IU / kg with a prophylactic or therapeutic purpose is necessary, consideration should be given to transferring the patient to therapy with another coagulation factor drug IX.
Preparation of the solution

The preparation does not contain preservatives, therefore the reconstituted solution should be used within 3 hours after preparation.

The reconstituted solution should be stored for 3 hours after reconstitution at a temperature of no higher than 30 ° C.

When the color of the solution changes or when suspended particles appear in it, the solution must be disposed of.

The resulting solution of Benefifix contains polysorbate-80, which is known to increase the extraction rate of di- (2-ethoxyethyl) phthalate (DEHP) from polyvinyl chloride (PVC).
This must be taken into account when preparing, administering the Beneficix preparation, including storage time in a PVC container.
Unused drug residue or.
contaminated materials must be disposed of in accordance with local regulations.
Rules of drug administration

1. Give a vial of Lyophilized Powder Benefit and a solvent filled syringe to room temperature.

2. Remove the plastic hinged cap from the Benefice bottle to expose the central part of the rubber stopper.

3. Wipe the top surface of the vial cap with a swab moistened with alcohol, or use a different antiseptic solution, and allow it to dry.
After cleaning, do not touch the rubber stopper with your hands and do not touch it with any surface.
4. Open the lid from the transparent adapter package for the plastic vial.
Do not remove the adapter from the package.
5. Place the vial on a flat surface.
While holding the adapter pack, install the adapter on the bottle. Push the package firmly until the adapter snaps into place at the top of the vial with the adapter needle inserted into the vial.
6. Connect the piston rod to the syringe with the solvent, firmly pressing and turning it.

7. Break off the protective cap of the plastic tip of the syringe with the solvent in place of the perforation of the cap.
Do this by alternately bending the cap up and down until the cap breaks off at the perforation site. Do not touch the inner surface of the cap and tip of the syringe. It may be necessary to return the cap back to its original location (if the administration of the reconstituted Benefice is not carried out immediately); in this regard, the cap should be set aside, putting it with the tip down.
8. Remove the packaging from the adapter and discard it.

9. Put the bottle on a flat surface.
Connect the syringe with the solution to the bottle adapter by inserting the tip of the syringe into the hole in the adapter, simultaneously pressing and forcing the syringe clockwise until it firmly secures.
10. Slowly push on the piston rod to insert all the solvent into the bottle with the preparation Benefiks.

11. Leaving the syringe connected to the adapter, gently rotate the vial until the powder dissolves.

12. Before administration, the final solution should be visually checked for particles.
The solution should be clear and colorless.
Note: if two or more vials of Benefenix are used per administration, the contents of each vial should be restored in accordance with the above instructions.

13. After confirming that the rod of the syringe piston remains in the fully inserted position, turn the vial over.
Slowly draw the entire solution into the syringe.
In case you need to apply more than one vial of the Beneficix preparation, the syringe with the solvent should be disconnected, leaving the bottle adapter in place.Immediately after this, attach a separate Luer syringe and dial the entire solution.
To retrieve the reconstituted contents of each vial, a separate large syringe with luer tip can be used.
Do not disconnect the syringe from the vial until you are ready to attach the syringe to the next vial.

14. Disconnect the syringe from the vial adapter, gently pulling and turning the syringe counter-clockwise.
Discard the bottle with the adapter attached to it.
Note: If the solution is not intended for immediate administration, the syringe cap must be carefully installed in its place.
Do not touch the tip of the syringe and the inner surface of the cap.
Introduction (IV injection):

The benefice should be administered with an attached microinfusion set and a filled syringe with a solvent or a sterile disposable plastic syringe with a luer tip.

1. Attach the syringe to the luer end of the tube for the microinfusion set.

2. Apply the tourniquet and prepare the insertion site by wiping the skin thoroughly with an alcoholic napkin attached to the kit.

3. Insert the needle of the microinfusion tube set into the vein and remove the tourniquet.
Remove all air from the infusion set tube by pulling it back into the syringe.Dissolved product must be injected into the vein for several minutes. The doctor can change the recommendations for the speed of administration, so that the introduction becomes more convenient.
Discard all the solution was not used, empty vials and used needles and syringes in a container for disposal of medical waste.
SIDE EFFECT

To date, no account undesirable reactions which developed when using the drug Benefiks a frequency of> 1/100 to <1/10 (frequent). As a result, undesired reactions noted in the application Benefiks preparation, it has been identified as occurring infrequently (at a frequency of> 1/1000 to <1/100) or slowly (at a frequency of> 10.1 000 <1/1000). The most significant of these are anaphylaxis, cellulitis, phlebitis, and neutralizing antibodies.
Below are undesirable reactions registered in clinical trials and during postmarkstingovogo of the drug, with the distribution of organ systems and frequency of occurrence. Within each frequency category, adverse effects are presented in decreasing order of their severity. Incidence was determined based on the incidence of adverse effects based on the number of the spent infusion; The following categories are distinguished: infrequent (with a frequency of> 1/1000, but <1/100) and rare (with a frequency of> 1/10 000 and <1/1000).
From the nervous system: rare - dizziness, headache, lightheadedness, changes in taste perception; rarely - tremor, sleepiness, taste disturbance.
From the digestive system:infrequently - nausea; rarely - vomiting, diarrhea.
Systemic disorders and complications at the injection site: infrequently - abscess in the area of administration, phlebitis in the field of administration, injection site reactions (including burning and sensation of contraction), discomfort at the injection site, pain at the injection site; rarely - fever.
Immune system: infrequently - neutralizing antibodies (clotting factor inhibitors
Blood IX); rarely - hypersensitivity, allergic reactions, including anaphylaxis, laryngospasm, bronchospasm or acute respiratory distress syndrome (dyspnea), whistling cough, decrease blood pressure, angioneurotic edema, laryngeal edema, tachycardia, tightness in the chest, hives, skin rash, burning sensation in the area of the mandible and cranium, chills ( tremor), tingling, flushing, lethargy, restlessness, dry cough or sneezing, decreased visual acuity, allergic rhinitis, weakness, anaphylaxis.
The respiratory system: rarely - cough, leading to hypoxia.
Other: rarely - trembling, photosensitivity reaction.
laboratory findings:; rarely - increased activity of AST and ALT, increased bilirubin, increased
creatinine phosphokinase activity of alkaline phosphatase. It noted transient occurrence of inhibitors in low titer. Also, during the post-marketing studies marked cyanosis and decrease blood pressure.
From the urinary system
in the clinical study of the patients with antibodies to the hepatitis C virus after 12 days, after drug administration Benefiks about hemorrhagic condition, renal infarction was reported.
thrombotic state
During post-marketing applications were received of thrombosis, including life-threatening superior vena cava syndrome in infants who were in serious condition and receiving Benefiks as a continuous infusion through a central venous catheter. 6 has also been reported cases of thrombophlebitis, peripheral vein and deep vein thrombosis, most of them Benefiks administered by continuous on / in infusion, which is not registered as a method of administration of the drug.
Inadequate response and inadequate degree of reduction of activity of blood coagulation factor IX
During application of the post-marketing reports were received inadequate response and inadequate degree of reduction of activity of blood coagulation factor IX when used Benefiks preparation. With the development of any adverse reactions, which are supposed to be related to drug administration Benefiks, reduce the infusion rate or suspend it.
CONTRAINDICATIONS

- under the age of 6 years;
- intolerance to any of the formulation components, as well as an allergic reaction to proteins in hamsters anamnesis.
PREGNANCY AND LACTATION

There are limited data on the use Benefiks drug in pregnant women or during breast-feeding. In connection with this drug should be used only after assessment of the risk ratio for the fetus (or child) and benefits for the mother.
APPLICATION FOR CHILDREN

Is contraindicated in children under 6 years old.
Use in children (6 to 15 years old)
In children, the drug is administered over 15 years in adults.
Calculation of the dose at age 6 to 15 years drug Benefiks for children is based on the fact that the dose of coagulation factor IX, corresponding to 1 IU / kg body weight, increases the level of coagulation factor IX in the blood plasma of children, an average of 0.7 ± 0.3 IU / dL (range of variation - 0.2 IU / dL to 2.1 IU / dl). Thus, the drug is used in children using the following scheme:
The required amount of ME coagulation factor IX = Body weight (kg)? The required increase in the activity of blood coagulation factor IX (% or IU / dl)? 1.4 IU / kg / IU / dL
It was found that 57% of children in order to achieve the necessary response to therapy requires increasing doses of the drug due to smaller than expected; restoration activity of the blood coagulation factor IX in the blood plasma; as a result some of them mean dose of drug may be> 50 IU / kg. This necessitates the careful monitoring of the activity of coagulation factor IX in blood plasma, as well as calculate pharmacokinetic parameters, in particular, the recovery degree of activity and half-life, in accordance with clinical indications necessary for the correction of the dose. If necessary, repeated administration at doses> 100 IU / kg for prophylactic or therapeutic purposes, should consider patient transfer to other drug therapy with blood coagulation factor IX.
SPECIAL INSTRUCTIONS

Patients who have received prior therapy with blood coagulation factor IX, is sometimes marked formation of reactive neutralizing antibodies (inhibitors). As with all of the blood clotting factors IX, when applying Benefiks drug, patients should be evaluated pas presence of coagulation factor inhibitor IX.
Also, the absence of activity recovery of coagulation factor IX in plasma in accordance with the expected values or the inability to achieve control of bleeding when using the drug at appropriate dosages must perform the study for the presence of coagulation factor IX inhibitors (titer which should be measured in Bethesda units using adequate test).
In patients with high levels of inhibitory antibodies to factor the IX blood clotting, therapy, they may prove to be ineffective. In this case, you should consider the appointment of, alternative methods of treatment. Treatment of these patients should be performed by physicians experienced in the management of patients with hemophilia.
At present, in ongoing clinical trials have not accumulated a sufficient amount of patients by application Benefiks drug data from not previously treated with clotting factors.
Additional safety and efficacy studies in children who had not received prior therapy with coagulation factors and fed them, including in small amounts, are not currently completed.
In a clinical study of the drug Benefiks not included a sufficient number of patients aged 65 years and older, which does not allow to evaluate the possible differences in their response to treatment compared with those observed in younger patients. As in younger patients, in all cases requires individual dose adjustment Benefiks drug.
As with / in the introduction of any protein preparations, in applying the drug Benefiks may develop hypersensitivity reactions. Due to the nature of the production process, Benefiks drug contains trace amounts of hamster proteins, which can also develop a hypersensitivity reaction. In applying preparations of blood coagulation factor IX, including preparation Benefiks infrequently observed anaphylactic and anaphylactoid reactions. The etiology of allergic reactions to Benefiks is not defined, but the reaction can threaten the patient's life.
These allergic reactions have a close temporal relationship with the appearance of coagulation factor IX inhibitors. Therefore, patients who noted the development of allergic reactions should be evaluated for the presence of inhibitors. It should also be noted that in patients characterized by the presence of inhibitors of blood coagulation factor IX, may experience an increased risk of anaphylactic reactions with subsequent infusions coagulation factor IX. According to preliminary data, there is a relationship between the expression of the patient's main mutation (fission) gene of coagulation factor GC and increase the risk of inhibitory antibody, as well as reactions of acute hypersensitivity. Therefore, patients identified as carriers of the primary mutations (deletions) of blood coagulation factor IX,must be carefully monitored for clinical manifestations of acute hypersensitivity reactions, particularly during the initial phase of therapy.
Patients should be informed of the early clinical signs of hypersensitivity reactions, including the appearance of shortness of breath, edema, urticaria, pruritus, "tides" of blood to the face, the feeling of compression of the chest, chills, bronchospasm, laryngospasm, wheezing, decrease in blood pressure, flushing, weakness, decreased sharpness of vision and anaphylaxis. With the development of an allergic or anaphylactic reaction or anaphylactic shock,
should immediately stop the introduction of the drug and start Benefiks accordance with the applicable standards of medical therapy. With the development of severe allergic reactions, should consider the appointment of an alternative hemostatic therapy. The principles of treatment depend on the type and severity of side effects.
In view of the risk of allergic reaction, the first administration of clotting factor IX concentrates should be at the discretion of the attending physician, performed under medical supervision in institutions where there are conditions for the provision of appropriate emergency. The dose should be adjusted based on individual parameters of the patient's pharmacokinetics.
Although Benefiks preparation contains only coagulation factor IX, you must also keep in mind the risk of thrombosis and disseminated intravascular coagulation (DIC). Since the use of previously used complex concentrates of coagulation factor IX was associated with the development of thromboembolic complications administering preparations containing blood coagulation factor IX, may be potentially dangerous for patients exhibiting symptoms of fibrinolysis and for the patients with DIC syndrome.
Because of the potential risk of thromboembolic events, during the introduction of these drugs in patients with liver disease in the postoperative period, or having an increased risk of thrombosis or disseminated intravascular coagulation, is necessary to conduct surveillance for early signs of thrombotic conditions using
appropriate tests, and in their development - appropriate therapy. In each of these situations should be related to the potential benefit of drug therapy Benefiks and the risk of these complications.
There are also reports about the development of the agglutination of red blood cells in the tube or syringe during administration of the drug Benefiks. The clinical consequences of this phenomenon has not yet been determined. To reduce the likelihood of agglutination important to limit blood ingress into the system for / in infusion and exclude it from entering into the syringe. With the development of erythrocytes in agglutination system or a syringe, it is necessary to dispose of used supplies administration (system for / in infusion syringe and Benefiks drug solution) and repeat administration with a new package of the drug.
In attempts to induce immune tolerance in patients with hemophilia B, producing inhibitors of blood coagulation factor IX, and had a history of allergic reactions, there have been cases of nephrotic syndrome. The safety and efficacy of the drug Benefiks to induce immune tolerance to be determined.
Cases were reported of normalization thromboplastin time deviations. In normal thromboplastin time changes were noted.
Within this; shelf life of patients can store medication at room temperature (not above 30 ° C) for 6 months; after which the drug is not used!
Impact on the ability to drive vehicles and manage mechanisms

Studies of the effect of the drug on the ability to drive a car and work with mechanisms that require high concentration of attention, were not carried out. However, due to the possibility of dizziness, caution should be exercised in carrying out these actions.
OVERDOSE

Overdoses Benefiks preparation is not described.
DRUG INTERACTION

drug interaction studies have been performed.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

Keep out of reach of children at a temperature of from 2 ° C to 8 ° C.
Do not freeze.
Shelf life of the lyophilisate - 3 years, solvent - 3 years. Do not use beyond the expiration date.
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