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

Active substanceEptakog alpha (activated)Eptakog alpha (activated)

Similar drugsTo uncover

Coagil VII

lyophilizate in / in

GENERIUM, CJSC Russia

NovoSeven®

lyophilizate in / in

Novo Nordisk A / S Denmark

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

Composition:

Lyophilizate:

Component	1 mg	2 mg	5 mg
Active substance:
Eptakog alpha (rFVIIa)	1 mg (50 KED)	2 mg (100 KED)	5 mg (250 KED)
Excipients:
Sodium chloride	2.34 mg	4.68 mg	11.7 mg
Calcium chloride dihydrate	1.47 mg	2.94 mg	7.35 mg
Glycylglycine	1.32 mg	2.64 mg	6.6 mg
Polysorbate 80	0.07 mg	0.14 mg	0.35 mg
Methionine	0.5 mg	1.0 mg	2.5 mg
Sucrose	10.0 mg	20.0 mg	50.0 mg
Mannitol	25.0 mg	50.0 mg	125.0 mg

Solvent:

Component

NovoSeven®

1 mg

NovoSeven®

2 mg

NovoSeven®

5 mg

Histidine

1.705 mg

3.255 mg

8.06 mg

Water for injections

Up to 1.1 ml

Up to 2.1 ml

Up to 5.2 ml

1 KED corresponds to 1000 ME (International Units).

After dilution in 1 ml of the solution contains 1 mg of eptactagogue alpha (activated).

After dilution in 1 ml of the solution contains 10 mg of sucrose.

Description:

Lyophilizate - white lyophilizate.

Solvent - Clear or almost transparent colorless liquid.

Solution for intravenous administration - colorless almost transparent solution.

Pharmacotherapeutic group:hemostatic agent

Pharmacodynamics:

Eptakog alpha (activated) is a recombinant coagulation factor VIIa with a molecular weight equal to approximately 50,000 daltons, obtained by genetic engineering from hamster kidney cells (BHK cells).

Pharmacodynamics

The drug NovoSeven^® contains activated recombinant clotting factor VII. The mechanism of action of the drug is to bind the clotting factor VIIa with the released tissue factor. The resulting complex activates coagulation factor IX with the formation of active coagulation factor Xa and coagulation factor X with the formation of active coagulation factor Xa, which leads to the primary conversion of a small amount of prothrombin into thrombin. Thrombin activates platelets and clotting factors V and VIII in the affected area and by converting fibrinogen into fibrin provides the formation of a hemostatic plug.

In pharmacological doses, the drug NovoSeven^® directly, regardless of the tissue factor, activates the blood coagulation factor X on the surface of activated platelets localized in the injury zone. This leads to the formation of prothrombin thrombin in large quantities regardless of the tissue factor.Thus, the pharmacodynamic effect of the coagulation factor VIIa is the increased local formation of coagulation factor Ha, thrombin and fibrin.

Theoretically, the risk of systemic activation of blood coagulation in patients with diseases predisposing to the development of the syndrome of disseminated intravascular coagulation (DIC syndrome) can not be completely ruled out.

In an observational program involving patients with congenital deficiency of the blood clotting factor VII, thromboembolic events were noted in 3 of the 91 patients who underwent surgery.

Pharmacokinetics:

Healthy volunteers

Using the coagulation method of determining factor activity Coagulation VII, studied the pharmacokinetics of NovoSeven® in 35 healthy volunteers of the white and Mongoloid race in a dose-escalation study. Volunteers were divided into groups according to gender and ethnicity and NovoSeven® was administered at doses of 40, 80 and 160 μg per kg of body weight and / or placebo (three doses each).

Pharmacokinetic profiles indicate a direct proportional dose-response.

Pharmacokinetics in all groups was similar regardless of gender and ethnicity. The average equilibrium volume of distribution varied in the range from 130 to 165 ml / kg, the average clearance values were from 33.3 to 37.2 ml / h / kg, and the average half-life was from 3.9 to 6.0 hours.

Inhibitory haemophilia A and B

Using the method of quantifying the factor of blood coagulation VIIa, studied the pharmacokinetic properties of NovoSeven ® in 12 children aged 2 to 12 years and 5 adults in the absence of bleeding. In this study, proportionality of doses was also established when children received the drug in amounts of 90 and 180 μg / kg of body weight, consistent with the results of a previous study of lower doses (17.5-70 μg / kg rFVIIa). The mean values for total clearance from the children's body were approximately 1.5 times higher than in the adult group (78 versus 53 mL / h / kg), while the half-life was 2.3 hours on average in both groups. The average equilibrium volume of distribution was 196 ml / kg in children and 159 ml / kg in adult patients.It was found that the clearance value is related to age, therefore, in young patients the clearance of the drug is more than 50% higher.

Deficiency factor of blood clotting VII

The pharmacokinetics of the NovoSeven® preparation with a single dose of 15 and 30 μg per kg of body weight did not differ significantly from the dose-independent parameters: the total clearance (70.8-79.1 ml / h / kg), the equilibrium volume of distribution (280-290 ml / kg), the average residence time in plasma (3.75-3.80 hours) and the half-life (2.82-3.11 hours). The average plasma recovery rate in vivo was approximately 20%.

Glanzmann's thrombia

The pharmacokinetics of NovoSeven® in patients with Glanzman thrombastenia has not been studied, but it is assumed that it is similar to the pharmacokinetics of this drug in patients with hemophilia A and B.

Preclinical safety data

All data obtained during the preclinical safety studies program are associated with pharmacological action recombinant activated blood clotting factor VII (rFVIIa).

When combined therapy with coagulation factors rFXIII and FVIIa per ecperimentalcardiovascular model at makakakraboeda possible synergistic effect has resulted in excessive pharmacological effect (thrombosis and death) when using lower doses of drugs than when each drug therapy alone.

Indications:

NovoSeven® is used to stop bleeding, as well as prevent bleeding during surgical interventions and invasive procedures in the following groups of patients:

- In patients with hereditary hemophilia with a titer of inhibitors of coagulation factors VIII or IX> 5 BY

- In patients with hereditary hemophilia with the expected immune response to the administration of coagulation factor VIII or IX based on anamnesis

- In patients with acquired hemophilia

- In patients with congenital deficiency of the clotting factor VII

- In patients with Glanzman thrombasthenia in the presence of antibodies to glycoproteins IIb-IIIa and / or HLA (antigens of tissue compatibility) and refractory (in the present or in the past) to transfusions of platelet mass.

NovoSeven® is used to prevent bleeding in patients with hereditary hemophilia with a titer of inhibitors of blood coagulation factors VIII or IX> 5 BU or expected immune response to the administration of blood coagulation factor VIII or IX based on history.

Contraindications:

Hypersensitivity to the active component, excipients or to proteins of mice, hamsters or cows may serve as a contraindication to the appointment of NovoSeven®.

Pregnancy and lactation:

As a precaution, use of NovoSeven® during pregnancy should be avoided. Available limited data on use during pregnancy as part of the approved indications confirm the absence of influence rFVIIa on the course of pregnancy and the health of the fetus / newborn. There are no other epidemiological data at this time. Experiments on animals showed no direct or indirect harm with respect to the course of pregnancy, fetus / newborn development and childbirth (see "Preclinical safety data ").

Application in the period of breastfeeding: It is not known whether rFVIIa with breast milk. Allocation rFVIIa on animals has not been studied. The decision to continue / stop breastfeeding or continue / stop treatment with NovoSeven® should be based on the benefits of breastfeeding for the baby and the benefits of therapy with NovoSeven® for a woman.

Dosing and Administration:

Treatment should be started under the supervision of a doctor who has experience in treating hemophilia and / or the pathology of the clotting system.

Hemophilia A or B with inhibitors or with the expected immune response to the administration of coagulation factor VIII or IX

Doses

It is shown as soon as possible the introduction of NovoSeven® after the beginning of bleeding. The recommended initial dose, injected intravenously, is 90 μg per kg of body weight of the patient. After the first injection, NovoSeven® can be repeated. The duration of treatment and the interval between administrations of the drug are determined by the severity of the bleeding or by the nature of the invasive procedure / surgical intervention.

Dosage in the treatment of children

Currently available clinical experience does not allow to offer a differentiated dosing regimen for children and adults, although it is known that the clearance in children is higher. Therefore, in pediatric practice, it may be necessary to use higher doses of NovoSeven® to achieve a drug concentration in plasma similar to the plasma concentration of adult patients (see the "Pharmacokinetic properties" section).

Frequency of drug administration

Every 2-3 hours until reaching hemostasis. If there are indications for continuing treatment after stopping bleeding, the intervals between drug administration can be sequentially increased to 4, 6, 8 or 12 hours for the entire treatment period according to the indications.

Bleeding of mild and moderate severity (including outpatient treatment)

With bleeding of mild and moderate severity (articular, muscular and from mucous tissue), the most effective early administration of the drug is most effective.

The following dosing regimes are recommended:

From two to three injections in a dose of 90 mcg per kg of body weight after three hours. To maintain the effect, one additional dose of NovoSeven® can be prescribed at a rate of 90 μg per kg of body weight;
Single injection of 270 μg per kg of body weight.

The duration of outpatient treatment should not exceed 24 hours. The clinical experience of using the drug at a dose of 270 μg per kg of body weight in elderly patients is absent.

Heavy Bleeding

The recommended initial dose of the drug is 90 μg per kg of body weight and can be administered during the transport phase to a hospital where this patient is usually treated.The scheme of further therapy depends on the type and severity of the bleeding. At the beginning of the treatment, the drug is injected every two hours before the onset of clinical improvement. If there are indications for the continuation of therapy, the intervals between injections of the drug can be increased up to 3 hours within 1-2 days. Subsequently, the intervals between administration of the drug can be increased to 4, 6, 8 or 12 hours for the entire treatment period according to the indications. The duration of treatment for severe bleeding can be 2-3 weeks or more if there are clinical indications.

Prevention of bleeding

Patients with inhibitory haemophilia A or B and frequent bleeding (4 or more episodes per month) to reduce the frequency of bleeding NovoSeven® can be administered at a dose of 90 μg per kg of body weight once a day. Duration of treatment - up to three months.

Invasive procedures / surgeries

Immediately before the intervention, an initial dose of 90 μg per kg of body weight of the patient is administered. The second dose is given after 2 hours, and then the drug is administered at 2-3-hour intervals during the first 24-48 hours, depending on the intervention and the clinical condition of the patient.In large operations, treatment lasts 6-7 days with 2-4 hour intervals between administration of the drug at the recommended dose. During treatment for the next 2 weeks, the intervals between drug administration can be increased to 6-8 hours. The total duration of the drug after a large operation can be 2-3 weeks until the wound is healed.

Acquired hemophilia

The dose and interval between doses (including outpatient treatment)

It is shown as soon as possible the introduction of NovoSeven® after the beginning of bleeding. The recommended initial dose administered intravenously is 90 μg per kg of body weight of the patient. After the first injection, NovoSeven® can be repeated as needed. The duration of treatment and the interval between drug administration are determined by the severity of the bleeding or by the nature of the invasive procedure / surgical intervention. When the initial dose is administered, the interval should be 2-3 hours. After achieving hemostasis, the intervals between drug administration for the entire treatment period can be increased to 4, 6, 8 or 12 hours.

Deficiency factor of blood clotting VII

Doses, the range of doses and the interval between administrations

The recommended dose for stopping bleeding and preventing bleeding during surgical interventions or invasive procedures is 15-30 μg per kg of body weight. The drug is injected every 4-6 hours until reaching hemostasis. The dose and frequency of administration are specified on an individual basis.

Glanzmann's thrombia

The dose, the range of doses and the interval between administrations

The recommended dose for monitoring bleeding and preventing bleeding during surgical interventions or invasive procedures is 90 μg (80-120 μg) per kg of body weight. The drug is administered every 2 hours (1.5-2.5 hours). At least three doses are required to ensure persistent hemostasis. An intravenous bolus route of administration is recommended, as the effectiveness of the drug may decrease with drop administration. In patients with thrombastenia Glanzmann without refractoriness, the drug of choice is platelet mass.

Introduction

Prepare the solution, as described in the manual for use, injected slowly for 2-5 minutes.

Monitoring during treatment - laboratory tests

Therapy with NovoSeven® does not require laboratory testing. Doses of the drug are determined depending on the severity of bleeding and the clinical effect.

It was shown that after administration rFVIIa prothrombin time (PV) and activated partial thromboplastin time (APTT) are reduced, however, correlations between PV and APTT and clinical efficacy rFVIIa it was not revealed.

Side effects:

The list of adverse reactions, both serious and non-serious, is presented in the table.

All of the adverse reactions presented below, based on data from clinical trials, are grouped according to the frequency of development according to the classification MedDRA and organ systems. Within each group, the frequency of development of adverse reactions are listed in descending order of their severity.

The incidence of adverse reactions is defined as: infrequently (> 1/1000 to <1/100) and rarely (> 1/10000 to <1/1000). The incidence of adverse reactions observed only during post-marketing use (and not in clinical trials) is listed as "unknown."

Violations of the blood and lymphatic system	Rarely: Disseminated intravascular coagulation and a concomitant change in laboratory parameters (an increase in the D-dimer content and a decrease in the level of activity of antithrombin III (see section "Specific guidance")) Coagulopathy.
Immune system disorders	Rarely: Hypersensitivity (see the sections "Contraindications" and "Special instructions"). Unknown: Anaphylactic reactions.
Disturbances from the nervous system	Rarely: Headache
Vascular disorders	Rarely: Cases of arterial thromboembolism (myocardial infarction, cerebral infarction, cerebral ischemia, cerebral artery occlusion, cerebrovascular complications, renal artery thrombosis, peripheral vascular ischemia, peripheral arterial thrombosis and intestinal ischemia), Angina pectoris. Infrequently: Cases of thromboembolism (deep vein thrombosis, vein thrombosis at the injection site, pulmonary thromboembolism, cases of thromboembolism of the liver, including portal vein thrombosis, renal vein thrombosis, thrombophlebitis, surface vein thrombophlebitis and intestinal ischemia). Unknown: Intra-cardiac thrombus.
Disturbances of the gastrointestinal tract	Rarely: Nausea.
Disturbances from the skin and subcutaneous tissues	Infrequently: The appearance of skin rashes (including allergic dermatitis and erythematous rash), Itching and urticaria rash. Unknown: Redness of the skin, Angioedema.
General disorders and disorders at the site of administration	Infrequently: Reduction of therapeutic effect , Fever. Rarely:* Reactions at the site of administration, including pain at the site of administration.
Research	Rarely: Increase in the content of degradation products of fibrin, Increased activity of alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and prothrombin concentration

* Cases of insufficient effectiveness (decrease in therapeutic effect) are described. It is necessary that the dosage regimen of NovoSeven® meets the recommended therapy regimens described in the "Method of administration and dose" section.

Thromboembolism can lead to cardiac arrest.

Patients with acquired hemophilia

Clinical studies involving 61 patients (total 100 episodes of the drug) showed that some adverse reactions occur more frequently (1% of the number of episodes): cases of arterial thromboembolism (occlusion of the cerebral arteries,cerebrovascular pathology), cases of venous thromboembolism (pulmonary thromboembolism, deep vein thrombosis), angina pectoris, nausea, fever, erythematous rash and an increase in the content of fibrin degradation products in laboratory studies.

Formation of inhibitory antibodies

In post-marketing applications and in clinical trials, there was no evidence of the formation of inhibitory antibodies to NovoSeven® or the factor of blood coagulation VII in patients with haemophilia A or B. In the post-marketing surveillance program, cases of the formation of inhibitory antibodies to the drug NovoSeven® in patients with congenital deficiency of the clotting factor VII.

In clinical trials in patients with a deficiency of the coagulation factor VII, the formation of antibodies to the drug NovoSeven^® or the factor of blood coagulation VII was the only observed adverse reaction (frequency of development: often (from ≥ 1/100 to <1/10)).

In some cases, the inhibitory effect of antibodies in vitro. The formation of antibodies may be facilitated by the risk factors present in these patients,such as previous therapy with human plasma and / or plasma blood coagulation factor VII, severe mutation of the blood coagulation factor VII gene or an overdose of NovoSeven®.

In patients with a deficiency of the blood clotting factor VII receiving therapy with NovoSeven®, the development of antibodies to the coagulation factor VII should be monitored, see section "Specific guidance".

Thromboembolic complications

When using NovoSeven^® in patients whose diseases are not included in the approved indications, cases of development of arterial thromboembolism were noted frequently (from ≥ 1/100 to <1/10). A higher risk of developing cases of arterial thromboembolism (see "Vascular disorders" in the table above) (5.3% in the group of patients receiving therapy with the test drug, compared with 2.8% in the placebo group) was detected in a meta-analysis of data collectively obtained from placebo-controlled clinical trials using the drug for the treatment of diseases outside of approved indications , which were carried out in different clinical groups of patients who had different characteristics of the disease and, accordingly, a different risk profile.The use of NovoSeven® outside the approved indications is not recommended, since the safety and efficacy of such an application have not been established.

Overdose:

In the course of clinical trials, the dose-limiting toxicity of NovoSeven® was not studied. Several cases of overdose have been reported in patients with hemophilia. The only complication associated with overdose was a slight transient increase in blood pressure in a 16-year-old patient who received 24 mg of rFVIIa instead of 5.5 mg.

No cases of overdose have been reported in patients with acquired hemophilia or Glanzmann's thrombastenia.

In patients with a deficiency of the clotting factor VII, for which the recommended dose rFVIIa is 15-30 mcg / kg, one case of overdose was associated with a thrombotic complication (thrombosis of the vessels of the occipital region of the brain) in an elderly patient (over 80 years old) of a male who received the drug at a dose exceeding the recommended dose by 10-20 times.

There has also been reported an overdose-related development of antibodies to NovoSeven® and FVII in one patient with a deficiency of the clotting factor VII.

Do not exceed recommended doses, since there is no information about the associated additional risk.

Interaction:

Data on the risk of possible interaction between NovoSeven® and coagulation factor concentrates are not available.

Do not use concentrates at the same time prothrombin complex (activated or non-activated) and NovoSeven®.

According to available data, antifibrinolytics reduce intraoperative hemorrhage in patients with hemophilia, especially in orthopedic operations and operations on tissues with high fibrinolytic activity, for example, in the oral cavity. The combined use of antifibrinolytic drugs and NovoSeven® is limited.

Based on the results of preclinical research (see subsection "Preclinical safety data"), combined therapy with preparations of coagulation factors rFVIIa and rFXIII Not recommended. Clinical data on the interaction of clotting factors rFVIIa and rFXIII are absent.

Special instructions:

In pathological conditions, accompanied by elevated release of tissue factor, the use of NovoSeven® may be associated with a potential risk of thrombotic complications or disseminated intravascular coagulation (DVS) syndrome.

Such conditions include severe atherosclerosis, crushed wounds, septicemia and DIC syndrome.

Patients with an increased risk of developing thrombotic complications or disseminated intravascular coagulation (DIC) syndrome, patients with a history of coronary heart disease and liver disease, as well as patients in the postoperative period and newborns, NovoSeven® should be administered with caution.

In each case, the potential benefit of using NovoSeven® for the treatment of patients with these conditions should be carefully weighed against the risk of developing the described complications. Such patients need careful monitoring.

Because the recombinant coagulation factor VIIa - NovoSeven® preparation - can contain trace amounts of murine IgG, bovine IgG and other residual proteins of the culture (whey proteins of hamsters and cows), in patients,receiving this drug, there is a very small possibility of developing an increased sensitivity to these proteins. In these cases, intravenous use of antihistamines should be considered in accordance with the accepted algorithms for the treatment of such conditions and the indications contained in the instructions for the use of the antihistamine drug used.

At the onset of allergic or anaphylactic reactions, the drug should be discontinued immediately. In the case of anaphylactic shock, standard therapy is used to relieve its symptoms. It is necessary to warn patients about early symptoms of allergic reactions. They should be aware that with the development of these symptoms they should immediately stop treatment with this medication and consult their doctor.

In severe bleeding, the drug should be used in hospitals specializing in the treatment of hemophilia with inhibitors of blood coagulation factors VIII or IX, and, if this is not possible, in close collaboration with a doctor specializing in the treatment of hemophilia.

If the bleeding does not manage to stop the patient, his hospitalization is mandatory.

Patients or caregivers should, at the earliest opportunity, notify the attending physician or hospital about each case of NovoSeven^® at home.

In patients with a deficiency of the blood clotting factor VII, prothrombin time and the activity of the blood coagulation factor VII should be monitored before and after administration of the NovoSeven® preparation. If the activity of the coagulation factor VIIa does not reach the expected value, or the bleeding continues, despite the use of the drug at recommended doses, it is possible to assume the formation of antibodies. In this case, an antibody test should be performed.

There have been reports of cases of thrombosis with NovoSeven^® during surgical interventions in patients with a deficiency of the blood clotting factor VII, but data on the risk of thrombosis in patients with a deficiency of the coagulation factor VII against the background of treatment with NovoSeven® are absent.

Patients with rare hereditary problems associated with intolerance to fructose and insufficiency of absorption of glucose, galactose and sucrose isomaltose, this medication should not be taken.

The effectiveness and safety of NovoSeven® for the prevention of bleeding

The effectiveness and safety of preventive use of NovoSeven® was confirmed in a double-blind, uncontrolled study (study F7HAEM-1505) in one group of patients. Patients with frequent episodes of bleeding in the anamnesis (> 4 bleedings per month) were included in the study. During the first three months of standard treatment, patients were observed to establish the frequency of bleeding. Over the next three months, they injected NovoSeven® daily. The administration of a dose of 90 μg per kg of body weight once a day resulted in a 45% reduction in bleeding frequency. The average bleeding rate decreased from 5.4 per month during the initial follow-up period to 2.8 per month during the period of preventive treatment (p <0.001). During the next three months of observation without treatment, the average bleeding rate (3.9 per month) was 27% lower (p <0.01) than in the initial period.

The safety and effectiveness of preventive use for periods longer than three months have not been established.

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

Studies of the impact on the ability to drive vehicles and mechanisms have not been carried out.

Form release / dosage:Lyophilizate for the preparation of a solution for intravenous administration, 1 mg (50 KED), 2 mg (100 KED) or 5 mg (250 KED).

Packaging:

In a vial of colorless glass of hydrolytic class I, sealed with a plug of chlorobutyl rubber and an aluminum cap with a polypropylene cover "Snap-off".

1.1 ml, 2.1 ml or 5.2 ml of solvent (for dosages of 1 mg, 2 mg and 5 mg, respectively) in a bottle of colorless glass of hydrolytic class I, sealed with a plug of chlorobutyl rubber and an aluminum cap with a polypropylene cover "Snap-off".

1 vial with lyophilizate and 1 vial with solvent together with instructions for use in a cardboard bundle.

Storage conditions:

Store below 25 ° C. Do not freeze to avoid damaging the solvent bottle. Protect from light.

Keep out of the reach of children.

Shelf life:

3 years.

The prepared solution retains its physical and chemical properties for 6 hours at a temperature of 25 ° C and 24 hours at a temperature of 5 ° C.

From the microbiological point of view, the drug should be used immediately after preparation.In the event that the preparation has not been introduced immediately, the user is responsible for the duration and storage conditions (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.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N012454 / 01

Date of registration:07.12.2010

Expiration Date:Unlimited

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: & nbsp04.12.2016

Illustrated instructions

Instructions

NovoSeven® (NovoSeven®)