Ricksubis - instructions for use, dose, side effects, contraindications

Active substanceNonacog gammaNonacog gamma

Similar drugsTo uncover

lyophilizate in / in

Dosage form: & nbsplyophilizate for the preparation of a solution for intravenous administration

Composition:

Per 1 bottle:

Active substance:
Nonacog gamma	250 ME *	500 ME *	1000 ME *	2000 ME *	3000 ME *
Excipients:
L-cystidine			15.5 mg
Sodium chloride			17.5 mg
Calcium chloride			2.2 mg
Mannitol			100.2 mg
Sucrose			59.9 mg
Polysorbate 80			0.25 mg
Solvent:			5 ml
Water for injections

* Specific activity ranges from 200 to 390 ME per milligram of protein

Description:

Lyophilizate: powder or brittle white mass.

Solvent: clear, colorless liquid.

The reconstituted solution: transparent solution, practically free from foreign particles.

Pharmacotherapeutic group:Hemostatic agent

ATX: & nbsp

B.02.B.D.04 Coagulation factor IX

Pharmacodynamics:

The drug Ricksubis contains a recombinant coagulation factor IX (gnome). Factor IX is a single-chain glycoprotein with a molecular weight of about 68,000 Daltons. It is a vitamin K-dependent clotting factor and is synthesized in the liver. Factor IX is activated by factor XI and with the internal coagulation pathway and complex factor VIItissue factor in the external pathway. Activated factor IX in combination with activated factor VIII activates factor X. Activated factor X converts prothrombin into thrombin. Then, through thrombin, fibrinogen is converted into fibrin to form a clot.

Hemophilia B is a hereditary, sex-linked blood clotting disease with a decrease in factor IX, which leads to profuse bleeding in the joints, muscles and internal organs, both spontaneously and as a result of trauma or surgical intervention. With replacement therapy, an increase in the level of factor IX in plasma occurs, which allows temporarily replenishing the deficit of coagulability factor and stopping bleeding.

Clinical efficacy and safety

Prevention and control of bleeding in previously treated patients aged 12 years and older

The effectiveness of the Rixubis preparation was evaluated in the open part of a combined study of a 1/3 phase without a control group, in which 73 previously treated patients aged 12 to 59 years received Rixubis for the prevention and / or treatment of bleeding on demand. All patients had severe (factor IX level <1%) or moderately severe (factor IX level ≤ 2%) hemophilia B. In the preventive regimen, 59 previously treated patients received therapy, 56 of them received Rixubis for at least 3 months and were included in the assessment of the effectiveness of bleeding prevention.In addition, 14 patients received Rixubis only on demand. In patients on on-demand therapy, the annual bleeding rate was 12 or more before the study.

The average duration of therapy in the cohort of treatment on demand was 3.5 ± 1.00 months (median 3.4, range 1.2-5.1 months), and the average annual bleeding rate was 33.9 ± 17.37, while the median was 27.0 (range 12.9-73.1).

The median mean annual bleeding rate for preventive therapy with Ricksubis was 2, for spontaneous bleeding and hemarthrosis - 0. In 24 patients (42.9%), there was no bleeding.

A total of 249 hemorrhages were registered with Riccubis, of which 197 hemarthroses and 52 extra-articular hemorrhages (soft tissues, muscles, intracranial and others). Out of 249 bleedings, 163 were mild, 71 small and 15 large. Treatment was carried out individually, depending on the severity, cause and localization of bleeding.

In most cases (211 of 249, 84.7%) bleeding was stopped 1-2 infusions of the drug. Hemostatic efficacy was assessed as excellent and good with 95.4% of all bleeding.

Prevention and control of bleeding in previously treated patients under the age of 12 years

The efficacy of Rixubis was evaluated in a combined 2/3 phase study in which 23 previously treated patients aged 1.8 to 11.8 years (median age 7.10 years, 11 patients <6 years old) received Rixubis for prevention and treatment bleeding. All patients had severe (factor IX level <1%) or moderately severe (level IX IX ≤ 2%) hemophilia B. All 23 patients received a preventive treatment with Riccubis for at least 3 months and were included in the evaluation of the effectiveness of preventive therapy.

Median mean annual circulatory rate was 2.0, for spontaneous bleeding and hemarthrosis - 0. 9 patients (39.1%) had no bleeding.

A total of 26 hemorrhages were recorded, of which 23 were associated with trauma, 2 were spontaneous, and 1 was of unknown origin. A total of 19 non-articular hemorrhages developed (soft tissues, muscles, intracranial and other) and 7 hemarthroses, of which 1 was in the target joint.

Of the 26 bleedings, 15 were small, 9 moderate, and 2 large. Treatment was carried out individually, depending on the severity, cause and localization of bleeding. In most cases of bleeding (23; 88.5%) bleeding was stopped by 1-2 infusions of the drug.Hemostatic efficacy is regarded as excellent or good at 96.2% of all bleeding.

Treatment in the perioperative period

The safety and efficacy of Rixubis in the perioperative period was evaluated in a continuing prospective, open, multicentre 3-phase study without a control group in previously treated patients with severe or moderate hemophilia B. The efficacy analysis included 13 surgical interventions performed in 13 patients aged from 19 to 54 years. Of these, 10 operations were large, including 6 orthopedic and 1 dental surgery, 3 procedures, including 2 tooth extraction, were regarded as small. In patients who underwent large surgeries, the pharmacokinetic (FC) values were evaluated. The dose of the drug was determined taking into account the recovery factor of factor IX in each patient.

The recommended initial loading dose of the Rixubis preparation was to provide during the operation the maintenance of a level of activity of factor IX equal to 80-100% for large operations and 30-60% for small operations. The drug Rixubis was administered as a bolus injection. Hemostasis was achieved throughout the study.

Pharmacokinetics:

Previously treated patients aged 12 years and older

A randomized, blind, controlled cross-pharmacokinetic study of the Ricksubis preparation and a reference preparation in patients with hemophilia B aged ≥ 15 years outside bleeding was performed as part of the combined Phase 1/3 pilot study. Patients received both drugs in the form of single intravenous infusions. The mean (± SD, standard deviation) and median dose of the Ricksubis preparation in the sample for analysis according to the protocol (n = 25) were 74.69 ± 2.37 and 74.25 IU / kg, respectively, the range 71.27-79.38 IU / kg. Pharmacokinetic parameters were calculated on the basis of measuring the activity of factor IX in blood samples obtained for a period of 72 hours after each infusion.

Evaluation of pharmacokinetic parameters of the drug Ricksubis was repeated in an open study without a control group in patients who participated in the initial FC cross-over and received preventive therapy with Rixubis for 26 ± 1 weeks (mean ± SD) and who had at least 30 days of Rixubis.The dose of Rixubis in the repeated pharmacokinetic study varied within 64.48-79.18 IU / kg (n=23).

Pharmacokinetic parameters in patients for whom data were available for inclusion in the analysis (protocol analysis) are presented below in Table 1.

Table 1

Index	Ricksubis Initial cross-sectional study (N=25)	Ricksubis Reassessment (N = 23)
AUS_0-_72h (ME h / dL)^a
Average ± SD	1067,81 ± 238,42	1156,15 ± 259,44
Median (range)	1 108,35 (696,07-1571,16)	1170,26(753,85-1626,81)
Recovery rate, adjusted by FROM_m_Oh (IU / dL: IU / kg)^b
Average ± SD	0,87 ± 0,22	0,95 ± 0,25
Median (range)	0,88 (0,53-1,35)	0,93 (0,52-1,38)
Half-life (h)
Average ± SD	26,70 ± 9,55	25,36 ± 6,86
Median (range)	24,58 (15,83-52,34)	24,59 (16,24-42,20)
The maximum concentration, FROM_m_Oh (IU / dl)
Average ± SD	66,22 ± 15,80	72,75 ± 19,73
Median (range)	68,10(41,70-100,30)	72,40 (38,50-106,30)
Average circulation time (h)
Average ± SD	30,82 ± 7,26	29,88 ± 4,16
Median (range)	28,93 (22,25-47,78)	29,04 (21,32-37,52)
V_ss(dl / kg)^c
Average ± SD	2,02 ± 0,77	1,79 ± 0,45
Median (range)	1,72 (1,10-3,94)	1,74(1,12-2,72)
Clearance (dl / (kg h))
Average ± SD	0,0644 ± 0,0133	0,0602 ± 0,0146
Median (range)	0,0622 (0,0426-0,0912)	0,0576 (0,0413-0,0945)

^a - Area under the pharmacokinetic concentration-time curvefromthe moment of administration up to 72 hours after the infusion of the drug;

^b- Calculated as (C_max minus the base level of factor IX) divided by the dose; (ME / kg), where C_max- maximum factor level after administration;

^cThe volume of distribution in the equilibrium state.

The recovery rate 30 minutes after the infusion was determined in all patients in the combined study of the 1/3 phase on day 1 of the exposure and during visits at 5, 13 and 26 weeks, and at the end of the study, if this did not coincide with the visit on the 26th week. The data demonstrate that the recovery rate does not change over time (see Table 2 below):

table 2

	1st day of the exposition (N = 73)	5th week (N = 71)	13th week (N = 68)	26th week (N = 55)	At the time of completion research^b (N = 23)
Recovery rate 30 min after infusion (IU / dL: IU / kg)^a
Average ± SD	0,79 ± 0,20	0,83 ±0,21	0,85 ± 0,25	0,89 ±0,12	0,87 ± 0,20
Median (range)	0,78 (0,26-1,35)	0,79 (0,46-1,48)	0,83 (0,14-1,47)	0,88 (0,52-1,29)	0,89 (0,52-1,32)

^a - Calculated as (C_{30 min} minus the base level of factor IX), divided by the dose in IU / kg), where C_{30 min} is the measurement of factor IX 30 minutes after infusion.

^b- If it does not coincide with the visit at the 26th week.

Children (previously treated patients under the age of 12 years)

Twenty-three patients underwent baseline pharmacokinetic indices of Rixubis without bleeding as part of a combined study in children 2/3 of the phase. Patients were randomized into 2 groups, blood sampling was performed in one of two sequences in order to reduce the frequency of blood sampling. The mean (± SD) and the median dose of the Rixubis preparation in the sample for complete analysis (n= 23) were 75.50 ± 3.016 and 75.25 IU / kg, respectively, with a range of 70.0-83.6 IU / kg. Pharmacokinetic parameters were calculated on the basis of measurements of the activity of factor IX in blood samples obtained for a period of 72 hours after infusion. Pharmacokinetic parameters for all patients (sample for complete analysis) are presented below in Table 3:

Table 3

Index	<6 years (N = 11)	From 6 to 12 years (N = 12)	All (N = 23)
AUCinf (ME h/dl)^a
Average ± SD	723,7 ± 119,00	886,0 ± 133,66	808,4 ± 149,14
Median (range)	717,2 (488-947)	863,7 (730-1138)	802,9 (488-1138)
Half-life (h)
Average ± SD	27,67 ± 2,66	23,15 ± 1,58	25,31 ±3,13
Median (range)	27,28 (24,0-32.2)	22,65 (21,8-27.4)	24,48 (21,8-32,2)
Average circulation time (h)
Average ± SD	30,62 ± 3,27	25,31 ± 1,83	27,85 ± 3,73
Median (range)	30,08 (26,2-36,2)	24,74 (23,7-30,3)	26,77 (23,7-36,2)
Vss (dl / kg)^b
Average ± SD	3,22 ±0,52	2,21 ±0,32	2,7 ± 0,67
Median (range)	3,16(2,65-4,42)	2,185 (1,70-2,70)	2,69(1,70-4,42)
Clearance (dl / (kg h))
Average ± SD	0,1058 ±0,01650	0,0874 ±0,01213	0,0962 ±0,01689
Median (range)	0,1050 (0,081-0,144)	0,0863 (0,069-0,108)	0,0935 (0,069-0,144)

^a- Area under the pharmacokinetic concentration-time curve from the moment of administration to infinity;

^b The volume of distribution in the equilibrium state.

The recovery rate 30 minutes after the infusion was determined in all patients in the combined 2/3 phase study with the initial assessment of pharmacokinetic parameters (1st day of exposure) and during visits at 5, 13 and 26 weeks, and also at the end of the study , if this did not coincide with the visit at the 26th week.Data show that the recovery rate does not change over time in children of all age groups (see Table 4 below).

The recovery rate of the Riccubis preparation 30 minutes after infusion in both children's age groups is shown in Table 4:

Table 4

Recovery rate 30 min after infusion	FC (1st day of the exposition) All (N = 22)	5th week All (N = 23)	13th week All (N = 21)	26th week All (N = 21)
(IU / dL: IU / kg)^a
Average ± SD	0,67 ±0,16	0,68 ±0,12	0,71 ±0,13	0,72 ±0,15
Median (range)	0,69 (0,31-1,00)	0,66 (0,48-0,92)	0,66 (0,51-1,00)	0,734 (0,51-1,01)

^a- Calculated as (FROM_{30 min} minus the base level of factor IX), to divide per dose in IU / kg), where FROM_{30 min} is the measurement of factor IX 30 minutes after infusion. The recovery rate of Rixubis in 30 min after infusions the children <6 years of age are presented in Table 5:

Table 5

Recovery rate 30 min after infusion	FC (1st day of the exposition) All (N = 10)	5th week All (N = 11)	13th week All (N = 10)	26th week All (N = 10)
(IU / dL: IU / kg)^a
Average ± SD	0,59 ±0,13	0,63 ±0,10	0,68 ±0,12	0,65 ±0,13
Median Range)	0,59 (0,31-0,75)	0,6 (0,49-0,80)	0,66 (0,51-0,84)	0,61(0,51-0,84)

^a- is calculated as (C_{30 min} minus the base level of factor IX), divided by the dose in IU / kg), where C_{30 min} is the measurement of factor IX 30 minutes after infusion.

The recovery rate of the Rixubis drug concentration at 30 min after infusion in children aged 6 <12 years is presented in Table 6:

Table 6

Recovery rate 30 min after infusion	FC (1st day of the exposition) All (N=12)	5th week All (N = 12)	13th week All (N = 11)	26th week All (N = 11)
(IU / dL: IU / kg)^a
Average ± SD	0,73 ±0,16	0,73 ±0,13	0,73 ±0.14	0,8 ±0,14
Median (range)	0,71 (0,51-1,00)	0,70 (0,48-0,92)	0,70 (0,5-1,00)	0,78 (0,56-1,01)

^a- Calculated as (C_{30 min} minus the base level of factor IX), divided by the dose in IU / kg), where C_{30 min} is the measurement of factor IX 30 minutes after infusion.

Preclinical safety data

The drug Rixubis did not possess a thrombogenic potential at a dose of 750 IU / kg on the stasis model in rabbits (Wessler test). The drug Rixubis did not cause any undesirable clinical, respiratory or cardiovascular effects in a dose of up to 450 IU / kg in Javanica monkeys.

Studies of carcinogenicity, effects on fertility and fetal development have not been conducted. Riccubis was well tolerated in single and multiple dose toxicity studies conducted in mice, rats, and Javan macaques at doses up to 7500 IU / kg (single dose) and 750 IU / kg (repeated use).

Indications:

Treatment and prevention of bleeding in patients with hemophilia B (congenital factor IX deficiency). The drug Rixubis can be used in patients of all age groups.

Contraindications:

Hypersensitivity to the active substance or excipients.

Allergy to hamster proteins in the anamnesis.

Pregnancy and lactation:

Studies of the effect of factor IX on reproductive function in animals have not been conducted. Given that hemophilia B in women is rare, there is no evidence of the use of factor IX in pregnancy and breastfeeding. Before prescribing the Rixubis, the doctor should carefully weigh the potential risks and the expected benefits for each individual patient.

Information on the effect of the drug on fertility is absent.

Dosing and Administration:

Treatment should be under the supervision of a doctor with experience in the treatment of hemophilia.

Doses

Doses and duration of substitution therapy depend on the extent of factor IX deficiency, localization and intensity of bleeding, clinical status, age and pharmacokinetic parameters of factor IX, such as recovery rate and half-life.

During treatment, it is recommended to determine the level of factor IX to determine the dose and frequency of repeated injections.

Patients may differ in the clinical response to factor IX, achieving different pharmacokinetic parameters, in particular half-life and recovery rates.Calculation of the dose based on body weight may require appropriate adjustment for persons with reduced or increased body weight. Clear monitoring of substitution therapy is necessary, especially in cases of serious surgical interventions by determining the specific activity of factor IX.

To confirm the desired increase in the level of factor IX in the blood plasma, careful monitoring of the level of factor IX and, if necessary, correction of dosing and the frequency of repeated infusions are necessary. When a one-step method is used to determine the activity of factor IX in patient blood samples in vitro , based on activated partial thromboplastin time (APTT), the results of measurements of the activity of factor IX in plasma can be affected by the type of APTT of the reagent and the standard sample.

The quantity of introduced factor IX is expressed in the International Unit (ME) of activity established in relation to the international WHO standard for factor IX preparations currently in force.

The activity of factor IX in plasma is expressed either as a percentage (relative to normal human plasma),or in International Units (relative to the international standard for factor IX concentrates in plasma).

One International Unit (ME) of factor IX activity is equivalent to the activity of factor IX contained in 1 ml of normal human plasma.

The calculation of the required dose of factor IX is based on empirical observation that the introduction of one International UnitME) of factor IX per kilogram of body weight increases the activity of factor IX in plasma by 0.9 IU / Dl (range from 0.5 to 1.4 IU / DL) or by 0.9% of normal level for patients 12 years and older (see section "Pharmacokinetics").

The required dose for patients 12 years and older is calculated by the following formula:

Necessary dose = body weight (kg) x desired increase in factor IX level (% or IU / dL) x inverse of recovery (dl / kg)

For a recovery rate of 0.9 IU / dl per IU / kg, the dose is calculated as follows:

Necessary dose = body weight (kg) x desired increase in factor IX level (% or IU / dL) x 1.1 dl / kg

When calculating the amount of the drug administered and determining the frequency of the introduction, it is always necessary to focus on clinical effectiveness in each specific case.In the cases of bleeding mentioned below, the activity of factor IX should not fall below this level (in% or IU / dL) in the relevant period.

When calculating the doses for bleeding episodes and surgical interventions, refer to Table 7:

Table 7

Type of bleeding \ type of surgery	Necessary level of factor IX in plasma (% or IU / dL)	Frequency of administration (hours) / duration of therapy (days)
Bleeding
Beginning hemarthrosis, muscle hemorrhage or bleeding in the oral cavity	20-40	Repeat every 24 hours (minimum 1 day) until complete relief of bleeding, which is assessed by pain, or until the wound is healed
Extensive hemarthrosis, muscle hemorrhage or hematoma	30-60	Repeat infusion every 24 hours for 3-4 days or more until the pain disappears and motor activity is restored
Life threatening hemorrhages	60-100	Repeat infusion every 8-24 hours before resolving a life-threatening situation
Surgical interventions
Small surgical interventions, including tooth extraction	30-60	Every 24 hours (at least 1 day) until the wound is completely healed
Extensive surgery	80-100 (before and after surgery)	Repeat infusion every 8-24 hours before wound healing, then continue treatment for at least 7 days, maintaining factor IX activity at 30-60% (IU / dl)

Careful monitoring of substitution therapy is especially necessary in the case of extensive surgical interventions.

Prevention

For long-term prophylaxis of bleeding in patients 12 years of age and older with severe hemophilia, the usual dose is 40 to 60 ME per kg of body weight with an interval of 3 to 4 days. In some cases, depending on the individual pharmacokinetic characteristics, age, type of bleeding and physical activity of the patient, higher doses or shorter intervals of drug administration may be required.

Continuous infusion

A drug Ricksubis should not be administered by continuous infusion.

Children

The calculation of the required dose of factor IX is based on empirical observation that the introduction of one International UnitME) of factor IX per kilogram of body weight increases the activity of factor IX in the plasma by 0.7 IU / dl (range 0.31 to 1.0 IU / dl) or 0.7% of the normal level for patients under 12 years of age (cm .section "Pharmacokinetic")

The required dose for patients younger than 12 years is calculated by the following formula:

Necessary dose = body weight (kg) x desired increase in factor IX level (% or IU / dL) x inverse of recovery (dl / kg)

For a recovery rate of 0.7 IU / dl per IU / kg, the dose is calculated as follows:

Necessary dose = body weight (kg) x desired increase in factor IX level (% or IU / dL) x 1.4 dl / kg

To calculate the doses for stopping bleeding and for surgical interventions, you can follow the table for patients 12 years and older.

Prevention

The recommended dosage range for patients younger than 12 years is 40 to 80 IU / kg at intervals of 3 to 4 days. In some cases, depending on the individual pharmacokinetic characteristics, age, type of bleeding and physical activity of the patient, higher doses or shorter intervals of drug administration may be required.

Mode of application

The drug must be administered intravenously.

If the drug is administered by a person who is not a health care worker, this person must undergo the appropriate training on the administration of Rixubis.

The preparation should be administered at a speed comfortable for the patient and not exceeding 10 ml / min.

After reconstitution, the solution has a pH of 6.8 to 7.2, osmolarity> 240 mOsm / kg and is a clear solution practically free of foreign particles. The drug Rixubis should be administered intravenously after reconstitution of the lyophilisate with sterile water for injection.

To restore the drug, use only sterile water for injection and a dilution device (BAXJECT II) contained in the package.
For the introduction of the drug must use a syringe with a nozzle Luer.
Do not use the BAXJECT II device if its sterile barrier system or package is damaged or has signs of damage.

Breeding

Observe the rules of asepsis!

1. If the preparation was stored in the refrigerator until the time of dilution, bring the temperature of the Ricksubis preparation (lyophilizate and solvent) to room temperature (15 to 25 ° C).

2. Wash your hands using soap and hot water.

3. Remove the caps from the vials with lyophilizate and solvent.

4. Wipe the plugs with alcohol wipes. Place the vials on a flat, clean surface.

5. Open the packaging of the BAXJECT II device by removing the paper membrane, without touching the inner contents of the package (see Figure A). Do not remove the device from the package.

6. Turn the package over and insert a transparent plastic tip into the stopper of the vial with the solvent. Grasp the edges of the package, pull up and remove it from the device BAKSZHECT II (see Figure B). Do not remove the blue cap from the device BAKXJECT II.

7. After attaching BAXZHECT II to the solvent vial, turn the system upside down so that the solvent bottle is on top of the device. Insert a white plastic tip into the stopper of the vial with Ricksubis. Due to the vacuum, the solvent will flow into the vial with the Ricksubis preparation (see Figure B).

8. Carefully rotate the vial until the drug dissolves completely. The drug dissolves quickly (within 2 minutes). Ensure that the product has dissolved completely: otherwise, not all of the active substance will pass through the device filter.

Before use, the reconstituted solution must be visually checked for mechanical inclusions and discoloration. The reconstituted solution should be transparent and virtually free of foreign particles.

Do not use the solution if it is unclear or has a precipitate!

Application

Observe the rules of asepsis!

1. Remove the blue cap from the BAXJECT II device.

DO NOT TIGHTEN AIR IN THE SYRINGES!

Insert the syringe into the BAKSJECT II device (see figure D).

2. Turn the system over (the vial with the reconstituted drug should be on top). Type the reconstituted solution into the syringe, slowly pulling the piston (see Figure D).

3. Disconnect the syringe.

4. Connect the needle to the syringe. To introduce intravenously. The drug solution must be administered slowly, at a speed comfortable for the patient and not exceeding 10 ml per minute.

Whenever possible, it is necessary to record the name of the preparation and the serial number each time you use the Rixubis preparation (for example, in a diary) to track the drug and its series.

Within the expiration date indicated on the packaging, the Ricksubis preparation may be stored at room temperature (not above 25 ° C) for a period of more than 6 months prior to opening the vial. A new expiration date at room temperature should be recorded on the outside of the secondary (consumer) packaging. The new date of expiry of the shelf life should not exceed the original shelf life indicated on the outside of the secondary packaging.

After storage for 6 months at room temperature, the drug must be either injected to the patient, or disposed of. Subsequent storage of the drug in the refrigerator is not allowed.

To exclude the possibility of microbiological contamination, the drug should be administered immediately after the preparation of the solution. The reconstituted solution can not be stored in the refrigerator.

Side effects:

Infrequently, hypersensitivity reactions or allergic reactions (including angioedema, burning and tingling at the injection site, chills, hot flashes, generalized urticaria, headache, urticaria, lowering of blood pressure, drowsiness, hypersensitivity reactions or allergic reactions were rare in patients treated with preparations containing factor IX. (lethargy), nausea, anxiety, tachycardia, chest tightness, tingling sensation in the body, vomiting, wheezing). In some cases, these reactions progressed to severe anaphylaxis (including shock) and appeared in close temporal association with the development of inhibitors to factor IX (See also section "Special instructions and precautions").

There are reports of the development of nephrotic syndrome when trying toprograms for the induction of immune tolerance (IIT) in patients with hemophilia B with inhibitors and allergic reactions in the anamnesis.

In rare cases, the development of antibodies to hamster proteins, manifested by hypersensitivity reactions, can be observed.

Patients with hemophilia B can develop neutralizing antibodies (inhibitors) to factor IX. Clinically, the development of inhibitors manifests itself as an insufficient effect of therapy. In such cases it is recommended to consult with specialists of the hemophilia center.

There is a potential risk of developing thromboembolic episodes in response to the introduction of a factor IX drug, a risk higher for drugs with a low purity. When using preparations of factor IX with a low degree of purification, cases of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism were noted. The use of preparations of coagulation factor IX of a high degree of purification rarely leads to such side effects.

Table of unwanted reactions

In a clinical study involving 99 patients with at least one use of Rixubis, 5 undesirable drugs were reportedreactions.

The following undesirable reactions were noted when the drug was used. Their frequency was estimated based on the following criteria: very frequent (≥1 / 10), frequent (≥1 / 100; <1/10), infrequent (≥1 / 1000; <1/100), rare (≥1 / 10000 ; <1/1000) and very rare (<1/10000), the frequency is unknown (the frequency can not be estimated from the available data). Undesirable reactions are presented in Table 8 in order of decreasing importance:

Table 8

System-Organ Class of the Medical Dictionary of Regulatory Activities	Unwanted reaction	Frequency
Immune system disorders	Hypersensitivity^a	Frequency unknown
Disturbances from the nervous system	Dysgeusia	Rarely
Disturbances from musculoskeletal system and connective tissue	Pain in the extremities	Rarely

^a- explanation is presented below.

Description of some unwanted reactions

Hypersensitivity

Allergic reactions were manifested by shortness of breath, skin itching, generalized urticaria and skin rash.

Children

It is assumed that the frequency, type and severity of unwanted reactions in children should be the same as in adults.However, data for previously untreated patients are not available, since the study involved only previously treated patients.

Overdose:

The effects of doses exceeding the recommended dose for the Rixubis C preparation are not described.

Interaction:

About the cases of interaction of the drug Rixubis with other medications have not been reported.

Special instructions:

Hypersensitivity reactions

With the use of the drug Rixubis, allergic reactions of hypersensitivity were reported. The drug contains trace amounts of hamster proteins. If there are signs of hypersensitivity to patients or carers, it is recommended that the drug be discontinued immediately and consult a doctor.

Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, chest tightness, wheezing, reduction in blood pressure and anaphylaxis.

The risk of occurrence of hypersensitivity reactions is highest in previously untreated patients who are first injected with the drug of coagulation factor IX.There are published data showing the relationship between the occurrence of inhibitors to factor IX and the occurrence of allergic reactions, especially in patients at high risk of genetic mutations. Therefore, patients who develop an allergic reaction should be tested for inhibitors.

In the event of anaphylactic shock, it is necessary to conduct conventional anti-shock measures.

Development of inhibitors

When treating with drugs with coagulation factor IX (recombinant coagulation factor IX), patients should be tested for the presence of neutralizing antibodies (inhibitors) expressed in Bethezd (BY) units using appropriate biological tests.

In the literature, there are reports of the relationship between the development of inhibitors to factor IX and the occurrence of allergic reactions. Therefore, patients experiencing allergic reactions should be tested for inhibitors.

It should be noted that patients with factor IX inhibitors with repeated administration of factor IX may have an increased risk of developing anaphylaxis in subsequent injections of a factor IX preparation.

Because of the risk of allergic reactions when using factor IX concentrates, the first administration of factor IX should be performed as directed by the doctor under medical supervision to provide appropriate medical care in the event of allergic reactions.

Nephrotic syndrome

A nephrotic syndrome was reported when an attempt was made to induce immune tolerance in patients with an inhibitory form of hemophilia B.

Thromboembolism

Due to the potential risk of thromboembolic complications, patients with liver diseases, postoperative patients, newborns, or patients with risk of thrombotic events or DIC syndrome should be clinically monitored in order to identify early signs of thrombosis and consumption coagulopathy with appropriate laboratory examination. In such cases, it is necessary to correlate benefit in the use of the drug with a possible risk of developing the above complications.

Influence on the cardiovascular system

In patients with risk factors for cardiovascular disease, factor IX substitution therapy may aggravate them.

Catheter-associated complications

If a device is required for central venous access, there is a risk of developing catheter-associated complications, such as local infections, bacteremia, thrombosis at the site of the catheter.

Effect of excipients

After reconstitution, the preparation contains 0.83 mmol (19 mg) of sodium per bottle.

This should be taken into account when prescribing the drug to patients on a diet with sodium restriction.

It is strongly recommended that you write down the name and number of the series each time you use the Ricksubis drug to track the connection between the patient and the drug series.

Children

The special instructions and precautions specified in this section apply to children and adults.

Elderly age

Clinical studies of the Rixubis drug did not include persons aged 65 years or older. It is not known whether such individuals have a response to therapy compared to patients of a younger age. As for all patients, the choice of dose for elderly patients should be carried out on an individual basis.

Effect on the ability to drive transp. cf. and fur:

The drug Rixubis has no influence on the ability to drive vehicles and work with mechanisms.

Form release / dosage:

Lyophilizate for solution for intravenous administration, 250 ME, 500 ME, 1000 ME, 2000 ME and 3000 ME.

Packaging:

250 each ME, 500 ME, 1000 ME, 2000 ME or 3000 ME active substance in a bottle of clear, colorless glass of hydrolytic type I (Hebrew Farm, US Pharm.) with a capacity of 10 ml, corked with a rubber stopper with aluminum rolling and a plastic lid type snap off complete with a 5 ml solvent (water for injection) in a bottle of clear, colorless glass of hydrolytic type I (Hebrew Farm, US Pharm.), sealed with an aluminum stopper and a plastic lid type flip off.

1 vial with lyophilizate, 1 vial with a solvent and 1 device for a needleless BAKHSJECT II with a built-in filter placed in a cardboard box along with instructions for use.

In an additional cardboard box, place a butterfly needle, a disposable syringe with a volume of 10 ml, two alcohol wipes and two plasters.

Both cardboard boxes are joined by a band of transparent plastic.

Storage conditions:

Store at a temperature of 2 to 8 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life:

2 of the year.

Do not use at the end of the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004010

Date of registration:07.12.2016

Expiration Date:07.12.2021