NovoEit - instructions for use, doses, side effects, contraindications

Active substanceTurkotokog alfaTurkotokog alfa

Similar drugsTo uncover

lyophilizate in / in

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

Composition:

1 bottle with lyophilizate contains:

Component	250 ME	500 ME	1000 ME
Active substance:
Turkotokog alfa	250 ME	500 ME	1000 ME
Excipients:
L-cystidine	6.0 mg	6.0 mg	6.0 mg
Sucrose	12.0 mg	12.0 mg	12.0 mg
Polysorbate 80	0.4 mg	0.4 mg	0.4 mg
Sodium chloride	36.0 mg	36.0 mg	36.0 mg
L-methionine	0.22 mg	0.22 mg	0.22 mg
Calcium chloride dihydrate	1.0 mg	1.0 mg	1.0 mg
Hydrochloric acid	q.s. (before pH 6,9)	q.s. (before pH 6,9)	q.s. (before pH 6,9)
Sodium hydroxide	q.s. (before pH 6,9)	q.s. (before pH 6,9)	q.s. (before pH 6,9)

1 ml of solvent contains:

Component	NewEut®	NewEut®	NewEut®
	250 ME	500 ME	1000 ME
Sodium chloride	9.0 mg	9.0 mg	9.0 mg
Water for injections	up to 1.0 ml	before 1, 0 ml	up to 1.0 ml

NovoEth® contains about 62.5, 125 or 250 IU / ml of turrotokog alpha, the human recombinant factor of blood coagulation VIII.

The specific activity of NovoEth® is about 8,300 IU / mg protein. An adjuvant with a known effect:

0.31 mmol sodium (corresponding to 18 mg sodium chloride) per 1 ml reconstituted solution.

Description:

Lyophilizate is white or slightly yellowish in color. The solvent is a clear, colorless solution. The reconstituted solution for intravenous administration is a clear or slightly opalescent colorless solution.

Pharmacotherapeutic group:Hemostatic agent

ATX: & nbsp

B.02.B.D.02 Coagulation factor VIII

Pharmacodynamics:

Mechanism of action

Turoktokog alpha (human recombinant factor of blood coagulation VIII) is a purified protein consisting of 1445 amino acids, with a molecular weight of about 166 kDa (calculated with the exception of posttranslational modifications). It is produced by recombinant DNA technology in the cells of the Chinese hamster ovary (JAH). This is a preparation of the third generation coagulation factor VIII, prepared without adding any proteins of human or animal origin to the process of cell cultivation, purification and the final formulation. The turrotokog alpha molecule is a polypeptide consisting of a heavy chain having a mass of 87 kDa and a light chain having a mass of 79 kDa connected by non-covalent bonds. The heavy chain of endogenous factor VIII contains a B-domain of various lengths, which in the turrotokog-alpha structure is a truncated B-domain consisting of only 21 amino acid residues. It was shown that in the turrotokog alpha molecule, all six potential tyrosine sulfation sites are sulfated. Sulfation of tyrosine in position Tyr 1680 is important for binding the endogenous coagulation factor VIII to the von Willebrand factor. It is shown that in the turrotokog molecule, the alpha tyrosine in position Tyr 1680 is also sulfated.

Novoeit® contains a human recombinant factor of blood coagulation VIII (turrotokog), a glycoprotein whose structure is identical to the structure of the activated human coagulation factor VIII, and post-translational modifications of the turrotokog alpha are similar to modifications of a factor VIII molecule derived from blood plasma. When administered to a patient suffering from hemophilia, factor VIII binds to the endogenous von Willebrand factor circulating in the patient's blood. Complex factor VIII/ von Willebrand factor is composed of two molecules (factor VIII and von Willebrand factor) with different physiological functions.

The activated coagulation factor VIII acts as a cofactor for the activated coagulation factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin to thrombin. Then thrombin converts fibrinogen into fibrin, which leads to the formation of a fibrin clot.Hemophilia A is a sex-linked hereditary blood clotting disorder due to a decrease in the level of activity of coagulation factor VIII (VIII:C) and manifests itself in the form of profuse bleeding in the joints, muscles or internal organs, which can be either spontaneous, or the result of trauma or surgical intervention. Thanks to the substitution therapy, the level of the coagulation factor VIII in the blood plasma increases, thereby achieving a temporary correction of the factor deficiency and the tendency to bleeding.

Clinical efficacy and safety

To assess the safety and efficacy of NovoEt® to prevent and treat bleeding in patients with severe haemophilia A (factor VIII activity ≤ 1%) who had previously received treatment, 3 multicenter, open, uncontrolled clinical trials were conducted. 213 patients without inhibitors were included in the study: 150 adults and adolescents from 12 years (≥ 150 days of administration) and 63 children under 12 years of age (≥ 50 days of administration). 187 of 213 patients then went on to the extended safety study. The safety of NovoEth® therapy and its effectiveness in achieving the desired haemostatic and preventive action was demonstrated.Clinical studies of phase 3a with a total number of days of administration of more than 54,000 (342 patient years, respectively) showed no formation of inhibitors to the coagulation factor VIII. In children, bleeding due to trauma was more common, in adolescents and adults, spontaneous bleeding occurred. Basically, these were joint bleedings in the vast majority from mild to moderate severity. A general assessment of the effectiveness was performed by the patient (in case of home treatment) or by the researcher in the clinic (in the case of hospitalization) using a 4-point scale: excellent, good, medium, not effective. If the hemostatic effect of the drug was evaluated as excellent or good, treatment for bleeding was recognized as successful. In the case of choosing an "average" or "not effective" assessment, treatment was considered unsuccessful. The total number of successful cases in all studies was 85.9% (1183 cases out of 1377 evaluated for excellent and good). 148 cases (10.7%) were assessed as "medium", in 18 cases (1.3%) there was no response to NovoEt® and in 28 cases (2.0%) the response to the drug was unknown. Of the 1377 bleeding observed in 177 of

213 patients, 1244 bleeding (90.3%) were stopped after 1-2 injections of NovoEth®.

The frequency of bleeding in patients treated with NovoEt® for the prevention of bleeding was 4.06 haemorrhages per patient per year.

Two of the above studies included a surgical part for patients who during the study needed surgical intervention associated with the daily use of coagulation factor VIII for a period of at least 7 days, counting the day of the operation. A total of 14 operations were performed in 14 patients (1 adolescent and 13 adults), of which 13 cases of extensive surgery and 1 case of small surgical intervention. In all cases hemostasis was achieved, not a single case of unsuccessful treatment was not.

Pharmacokinetics:

All pharmacokinetic studies using NovoEt® were performed with patients with severe haemophilia A (factor VIII ≤ 1%) who had previously received treatment. Analysis of plasma samples was carried out by two methods: one-step Clotting method and the method of chromogenic analysis.

The pharmacokinetic parameters of a single dose of NovoEth®, determined by a single-stage clotting assay, are given in Table 1, and those determined by the chromogenic assay are shown in Table 2.

Table 1 The pharmacokinetics of a single dose of NovoEt® in patients with severe hemophilia A (FVIII ≤ 1%), a clotting analysis

Parameter	0 - <6 years	6 - <12 years	≥ 12 years
	n= 14	n= 14	n = 33
	Average value	Average value	Average value
	(Standard	(Standard	(Standard
	deviation)	deviation)	deviation)
Index	0,018(0,007)	0,020 (0,004)	0,022 (0,004)
restoration of
(IU / ml) / (IU / kg)
Area under	9,92 (4,11)	11,09 (3,74)	15,26 (5,77)
crooked (AUC)
((ME * h) / ml)
Clearance (CL) (ml / h / kg)	6,21 (3,66)	5,02 (1,68)	3,63 (1,09)
Period Half-life (t₁_/2) (h)	7,65 (1,84)	8,02 (1,89)	11,00 (4,65)
Equilibrium volume allocation of (Vss) (ml / kg)	56,68 (26,43)	46,82 (10,63)	47,40 (9,21)
The maximum concentration (C_max) (IU / ml)	1,00(0,58)	1,07 (0,35)	1,226 (0,41)
Average circulation time (h)	9,63 (2,50)	9,91 (2,57)	14,19(5,08)

Table 2 Pharmacokinetics of a single dose of NovoEt® the patients with severe hemophilia A (FVIII ≤ 1%), chromogenic analysis

Parameter	0 - <6 years	6 - <12 years	≥ 12 years
	n= 14	n = 14	n = 33
	Average value (Standard deviation)	Average value (Standard deviation)	Average value (Standard deviation)
Recovery rate (IU / ml) / (IU / kg)	0,022 (0,006)	0,025 (0,006)	0.029 (0,006)
Area under the curve (AUC) ((ME * h) / ml)	12,23 (4,36)	14,37 (3,48)	19,63 (7,73)
Clearance (CL) (ml / h / kg)	4,59(1,73)	3,70(1,00)	2,86 (0,94)
Period half-life (t₁_/₂) (h)	9,99(1,71)	9,42 (1,52)	11,22 (6,86)
The equilibrium volume of the distribution (V_ss) (ml / kg)	55,46 (23,53)	41,23 (6,00)	38,18 (10,24)
The maximum concentration (C_m_Oh) (IU / ml)	U2 (0.31)	1,25 (0,27)	1,63 (0,50)
Average circulation time (h)	12,06(1,90)	11,61 (2,32)	14,54(5,77)

Pharmacokinetic parameters in patients under 6 years of age and children from 6 to 12 years of age are comparable.There were some differences in pharmacokinetic parameters of NovoEth® in children and adults. The higher clearance and shorter half-life observed in pediatric patients compared with older patients with haemophilia A may be due in part to the large plasma volume per kilogram of body weight in children.

A multicenter, randomized, blinded, experimental study of blood plasma samples with imitation of drug administration was conducted to evaluate the activity, analysis of characteristics and variability of the parameters of NovoEt® in the blood plasma of patients with hemophilia, to which a known amount of the drug was added, in various clinical laboratories with methods and reagents, usually used in laboratories. In total, the study involved 36 laboratories; in 33 laboratories a single-stage clotting method was used, in 5 - a chromogenic analysis, and in 2 - both methods of analysis. In the laboratories participating in the study, comparable and consistent values of the target for NovoEt® were obtained.

Preclinical safety data

Preclinical data based on traditional studies of pharmacological safety and toxicity of repeated doses did not reveal any hazard to humans.

Indications:Treatment and prevention of bleeding in patients of all age groups suffering from hemophilia A (congenital insufficiency of coagulation factor VIII).

Contraindications:

Hypersensitivity to the active ingredient or any of the auxiliary substances.

Known hypersensitivity to hamster proteins.

Carefully:

Pregnancy and lactation:Research on reproductive function in animals with NovoEt® was not performed. Since hemophilia A is extremely rare in women, there is no experience with the factor of coagulation VIII during pregnancy and during breastfeeding. Therefore, NovoEt® should be used during pregnancy and during breastfeeding only if there are clear indications for its use.

Dosing and Administration:

Treatment should begin under the guidance of a physician with experience in the treatment of hemophilia.

Dosing

Dosage and duration of therapy depends on the degree of deficiency of the coagulation factor VIII, the location and severity of bleeding, and also on the clinical condition of the patient.

The number of units of coagulation factor VIII introduced is expressed in international units (ME), which are associated with the current WHO standard for factor VIII preparations. The activity of the coagulation factor VIII in the plasma is expressed either as a percentage (relative to the normal level in human plasma) or in international units (relative to the International Standard for Factor VIII in Plasma).

One ME the activity of the coagulation factor VIII is equivalent to the amount of factor VIII in 1 ml of normal human plasma.

Spontaneous bleeding and surgery

The calculation of the required dose of coagulation factor VIII is based on the empirical result, according to which 1 ME factor VIII per 1 kg of body weight increases the activity of factor VIII in plasma by 2 IU / dL. The required dose is determined using the following formula:

Necessary number of units (ME) = body weight (kg) x desired increase in factor VIII level (%) (IU / dl) x 0.5 (IU / kg per IU / dl).

The administered dose and frequency of administration should always be focused on clinical effectiveness in each specific case.

In the case of bleeding, the activity of the coagulation factor VIII should not fall below this level of plasma activity (in % from the norm or ME / dL) in the relevant period. Table 3 can be used as a guide for dosing in case of bleeding and surgical interventions:

Table 3 Guide to dosing for bleeding and surgical

interventions

Severity of bleeding / Type of surgical procedure	Required level FVIII (%) (IU / dl)	Frequency of drug administration (hours) / Duration of therapy (days)
Bleeding
Light Early stage of hemarthrosis, muscle hemorrhage or bleeding in the oral cavity	20-40	Every 12-24 hours at least 1 day before the relief of an episode of bleeding, defined as the elimination of pain, or until healing
Moderate More pronounced hemarthrosis, hemorrhage in the muscle or hematoma	30-60	Repeat injections every 12-24 hours for 3-4 days or more until pain relief and function limitation
Heavy Life threatening hemorrhages	60-100	Repeat injections every 8-24 hours before stopping bleeding
Surgical intervention
Small surgical intervention, including tooth extraction	30-60	Every 24 hours, at least 1 day, if necessary before healing
Extensive surgical intervention	80-100 (before and after surgery)	Repeat injections every 8-24 hours to satisfactory wound healing, then continue treatment for at least 7 days, ensuring maintenance of factor VIII activity from 30% to 60% (IU / dL)

Preventive treatment

For long-term prophylaxis of bleeding in patients with severe haemophilia A. Recommended doses are 20-40 ME factor VIII per kg of body weight every other day or 20-50 ME factor VIII per 1 kg of body weight 3 times a week. In some cases, especially in the treatment of younger patients, shorter intervals between drug administration or higher doses may be required.

Monitoring during treatment

During the course of treatment it is recommended to determine the level of coagulation factor VIII for correction of the administered dose and the frequency of repeated injections. In particular, in the case of extensive surgical interventions, accurate monitoring of the effectiveness of substitution therapy by means of coagulation analysis (activity of plasma factor VIII) is necessary. The response to factor VIII therapy in different patients can vary, with differences in the degree of recovery in vivo and a different half-life.

Special patient groups

Elderly patients

The experience of using the drug in patients older than 65 years is absent.

Children and teens

Patients under 12 years of age for long-term prophylaxis of bleeding are advised to administer the drug in doses of 25 to 50 ME factor VIII per 1 kg of body weight every other day or from 25 to 60 ME factor VIII per 1 kg of body weight 3 times a week. For patients older than 12 years, the recommendations for dosing are the same as for adults.

Surgical interventions

The experience of using the drug in children with extensive surgical interventions is lacking.

Patients, previously untreated

Safety and efficacy in patients who have not previously received treatment have not been established. There are no available data.

Method of administration

It is administered intravenously.

The recommended rate of NovoEt® is from 1 to 2 ml / min. Speed should be selected based on the level of comfort for the patient.

Instructions for preparing injection solutions are provided in the application.

Side effects:

Description of individual adverse reactions

Altogether, during all clinical trials with NovOyte®, there were 30 adverse reactions that occurred in 19 of 214 patients treated with NovoEt®. The most frequent undesirable reactions were reactions at the injection site and an increase in the activity of the hepatic enzymes. Of the 30 adverse reactions, 2 were reported in 1 of 31 patients under the age of 6 years, none in patients aged 6 to 18 years, and 28 in 18 of 127 adult patients.

In patients with hemophilia A, neutralizing antibodies (inhibitors) can be formed to the coagulation factor VIII, which is manifested by the lack of a clinical response to therapy. In such cases it is recommended to contact a specialized center for the treatment of hemophilia.

The list of undesirable reactions

The table below is compiled in accordance with the classification of organ systems (CSR) MedDRA (CSR and the level of the term of preferred use). Frequency of occurrence was evaluated according to the following notations: very often (≥ 1/10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1000 to <1/100), rarely (from ≥ 1/10000 to <1/1000), very rarely (<1/10000); Unknown (can not be set based on available data).

Within each frequency group, undesirable reactions are presented in descending order of severity.

Table 2 Frequency of occurrence of unwanted reactions in clinical trials

Class of organ system	Frequency occurrence *	Unwanted reaction
Disorders of the psyche	Infrequently	Insomnia
Disturbances from the nervous system	Infrequently	Headache, dizziness
Heart Disease	Infrequently	Sinus tachycardia
Vascular disorders	Infrequently	Hypertension, lymphedema
Disturbances from the liver and bile ducts	Often	Increased activity of liver enzymes **
Disturbances from the skin and subcutaneous tissues	Infrequently	Rash
Disturbances from musculoskeletal and connective tissue	Infrequently	Musculoskeletal rigidity, arthropathy, pain in the limbs, musculoskeletal pain
General disorders and	Often	Reactions at the injection site ***
violations at the site of administration	Infrequently	Fatigue, fever, peripheral edema, pyretic reaction
Instrumental data	Infrequently	Increased heart rate
Trauma, intoxication and complications of manipulation	Infrequently	Hematoma

* Calculated based on the total number of patients in all clinical trials (214).

** Increased activity of liver enzymes includes alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase and bilirubin.

*** Reactions at the injection site include erythema at the injection site, extravasation at the injection site and itching at the injection site.

Application the children

In clinical trials involving 63 children aged 0 to 12 years and 24 adolescents aged 12 to 18 years with severe haemophilia A, no difference in the safety profile of NovoEth® in children and adults was observed.

Overdose:

There are no reports of symptoms of an overdose with a recombinant coagulation factor VIII.

Interaction:

No drug studies were conducted with Novoite®.

Incompatibility

In view of the fact that no compatibility studies have been carried out, this drug should not be mixed with other medicinal products.

Special instructions:

Hypersensitivity reactions

When using protein preparations for intravenous administration, including NovoEt®, it is possible to develop allergic reactions by the type of hypersensitivity reaction.The drug contains trace amounts of hamster proteins, which in some patients can cause allergic reactions. In case of hypersensitivity symptoms, patients should be advised to immediately stop using NovoEth® and contact their doctor and / or contact an emergency medical service. Patients should be informed about early symptoms of hypersensitivity reactions, which include allergic rash, generalized urticaria, chest tightness, wheezing, lowering of blood pressure and anaphylaxis.

In case of anaphylactic shock, standard anti-shock therapy should be performed.

Formation of inhibitors

The formation of neutralizing antibodies (inhibitors) to the coagulation factor VIII is a known complication of replacement therapy in patients with hemophilia A. Inhibitors are usually immunoglobulins of class G (IgG), the action of which is directed against the procoagulant activity of factor VIII and is expressed quantitatively in Bethesda units (BY) per 1 ml of plasma on the basis of the results of modified quantitative analysis.The risk of formation of inhibitors correlates with the number of days of administration of factor VIII. the risk is highest during the first 20 days of administration. In rare cases, inhibitors may appear after the first 100 days of administration.

In general, all patients receiving blood clotting factor VIII preparations should carefully monitor the presence of inhibitors through clinical observation and laboratory tests. If the activity of the coagulation factor VIII does not reach the expected level, or if bleeding control can not be achieved by administering an adequate dose of the drug, an analysis of the presence of factor VIII inhibitors should be made. In patients with inhibitors, factor VIII therapy may not be effective, and other therapeutic options should be considered for them. These patients should be administered under the guidance of physicians experienced in the treatment of hemophilia with coagulation factor VIII inhibitors.

Every time you inject NovOut®, it is strongly recommended that you write down the name of the drug and the number of the series to maintain the connection between the patient and the drug series.

Factors, associated with ancillary substances that must be taken into account

1 ml of the prepared solution for injection contains 0.31 mmol of sodium (corresponding to 18 mg of sodium chloride). This should be taken into account for patients who adhere to a diet with controlled sodium intake.

Use in children

The listed special instructions apply to both adult patients and children.

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

NovoEt® does not affect the ability to drive vehicles and work with machinery.

Form release / dosage:Lyophilizate for the preparation of a solution for intravenous administration of 250; 500 or 1000 ME.

Packaging:

Lyophilizate for the preparation of a solution for intravenous administration of 250; 500 or 1000 ME in a bottle of glass I of hydrolytic class, sealed with a plug of chlorobutyl rubber and an aluminum cap with a polypropylene cover “Snap off”. 4 ml of solvent (sodium chloride solution 0,9%) in a pre-filled syringe of glass I of hydrolytic class with polypropylene limiter, a piston made of bromobutyl rubber and a screw cap with bromobutyl plug. Each pack of NovoEt® contains: 1 vial with lyophilizate, 1 syringe with solvent, 1 sterile adapter for vial and 1 piston rod, together with instructions for use in a cardboard pack.

Storage conditions:

Store in refrigerator (2 ° C - 8 ° C). Do not freeze.

Within the expiry date, the drug can be stored at room temperature not higher than 30 ° C for no more than 6 months. Record the start date of the storage period at room temperature on a cardboard pack. After the preparation was stored at room temperature, it should not be placed back in the refrigerator for further storage.

To protect from light store in a cardboard box.

Keep out of the reach of children.

Shelf life:

2 years.

The prepared solution retains chemical and physical stability for 24 hours at a temperature of 2 ° C to 8 ° C, and for 4 hours at room temperature not higher than 30 ° C. From the microbiological point of view, the drug should be used immediately after dilution. If the preparation has not been introduced immediately, the user is responsible for the duration and storage conditions (maximum 4 hours at a temperature not exceeding 30 ° C or not more than 24 hours at a temperature of 2 ° C to 8 ° C), except for the cases when the solution is prepared in controlled aseptic conditions, confirmed in due course.

An unused preparation that was stored at room temperature for more than 4 hours should be destroyed.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003668

Date of registration:06.06.2016

Expiration Date:06.06.2021

The owner of the registration certificate:Novo Nordisk A / SNovo Nordisk A / S Denmark

Manufacturer: & nbsp

NOVO NORDISK, A / S Denmark

Representation: & nbspNOVO NORDISK TOVNOVO NORDISK TOVDenmark

Information update date: & nbsp04.07.2016