FEIBA NF 500 U

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

________

April 19, 2015

___

םש

רישכת

תילגנאב

רפסמו

םושירה

_

FEIBA NF 500 U, 1000 U

Powder for Solution for Injection

Reg No: 500 U: 026 14 25389 00; 1000U: 0261525390 00

_

םש

לעב

םושירה

Teva Medical (Marketing) Ltd., Haorgim St 8, Ashdod 77100

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Indication

FEIBA NF is indicated for the control of

bleeding episodes in haemophilia A patients

with Factor VIII inhibitors and also in

patients

with

acquired

Factor

VIII

inhibitors.

Control of bleeding episodes in haemophilia A

patients with Factor VIII inhibitors and also in

patients with acquired Factor VIII inhibitors.

Control of bleeding in hemophilia B patients with

inhibitors,

other

specific

treatment

available.

contraindications

Posology, dosage &

administration

Surgery

50-100 U/kg bw should be given at

intervals of up to 6 hours, a maximum

daily dose of 200 U/kg bw should not

be exceeded.

Surgery

In surgical interventions, an initial dose of 100 U/kg body

weight may be administered preoperatively, and a further

dose of 50 – 100 U/kg body weight may be administered after

6 – 12 hours. As a postoperative maintenance dose, 50 – 100

U/kg body weight may be administered at 6 – 12-hour

intervals; dosage, dosage intervals and duration of the peri-

and postoperative therapy are guided by the surgical

intervention, the patient’s general condition and the clinical

efficacy in each individual case. (The maximum daily dose of

200 U/kg body weight must not be exceeded!)

Surgery

50-100 U/kg bw should be given at intervals of up to 6

hours, a maximum daily dose of 200 U/kg bw should not

be exceeded.

Use of FEIBA NF in special patient groups

See Section 5.1 for information in relation to hemophilia B

patients with factor IX inhibitor.

In combination with factor VIII concentrate, NF was also

used for long term therapy to achieve complete and

permanent elimination of the factor VIII inhibitor.

Special Warnings and

Special Precautions

for Use

Risk

of

Thrombotic

and

Thromboembolic Events

Thrombotic and thromboembolic events,

including

disseminated

intravascular

coagulation

(DIC),

venous

thrombosis,

pulmonary

embolism,

myocardial

infarction, and stroke, have occurred in the

Hypersensitivity Reactions

FEIBA NF can precipitate allergic-type hypersensitivity

reactions

that

have

included,

urticaria,

angioedema,

gastrointestinal

manifestations,

bronchospasm,

hypotension; these reactions can be severe and can be

systemic (e.g., anaphylaxis with urticaria and angioedema,

course of treatment with FEIBA NF.

The risk of thrombotic and thromboembolic

events may be increased with high doses of

FEIBA NF. Some of these events occurred

with doses above 200 U/kg/day or in

patients

with

other

risk

factors

thromboembolic

events.

possible

presence of such risk factors should always

be considered in patients with congenital

and acquired hemophilia.

A single dose of 100 U/kg body weight and

a daily dose of 200 U/kg body weight

should not be exceeded unless the severity

of bleeding warrants and justifies the use of

higher doses. Patients receiving more than

100 U/kg body weight must be monitored

for the development of DIC and/or acute

coronary ischemia. When used to stop

bleeding, the product should be given only

for as long as absolutely necessary to

achieve the therapeutic goal.

In the following situations FEIBA NF

should only be used when no reaction to

treatment

with

other

appropriate

coagulation factor concentrates is to be

expected- such as in case of a high inhibitor

titre and a life-threatening haemorrhage or

risk of bleeding e.g. posttraumatic or

postoperative.

Disseminated

Intravascular

Coagulation (DIC):

Liver damage

Due to the delayed clearance of

activated

coagulation

factors,

patients

with

impaired

liver

function are at increased risk of

developing DIC.

Coronary

heart

disease,

acute

thrombosis and/or embolism.

Allergic-Type Hypersensitivity Reactions

As with any intravenously administered

plasma

products,

allergic

type

hypersensitivity

reactions

occur.

Patients should be informed of the early

signs of hypersensitivity reactions including

hives, generalised urticaria, tightness of the

chest, wheezing, drop in blood pressure and

anaphylactic shock. If these symptoms

occur,

patients

should

advised

discontinue the treatment and to contact

their

physician

immediately.

Shock

treated according to the rules of modern

shock therapy.

When considering re-exposure to FEIBA

patients

with

suspected

hypersensitivity to the product or any of its

components, the expected benefit and the

risk of re-exposure must be carefully

weighed, taking into account the known or

suspected

type

patient’s

hypersensitivity (allergic or non-allergic),

including

potential

remedial

and/or

bronchospasm,

circulatory

shock).

Other

infusion

reactions, such as chills, pyrexia, and hypertension have also

been reported.

Patients

should

informed

early

signs

hypersensitivity reactions, for example erythema, skin rash,

generalized

urticaria,

pruritus,

breathing

difficulties/dyspnoea,

tightness

chest,

general

indisposition, dizziness and drop in blood pressure up to

allergic shock.

At the first sign or symptom of an infusion/hypersensitivity

reaction, FEIBA NF administration should be stopped and

medical care initiated as appropriate.

When considering re-exposure to FEIBA NF in patients with

suspected hypersensitivity to the product or any of its

components, the expected benefit and the risk of re-exposure

must be carefully weighed, taking into account the known or

suspected type of the patient’s hypersensitivity (allergic or

non-allergic),

including

potential

remedial

and/or

preventative therapy or alternative therapeutic agents.

Thromboembolic Events

Thromboembolic

events,

including

disseminated

intravascular

coagulation

(DIC),

venous

thrombosis,

pulmonary embolism, myocardial infarction, and stroke, have

occurred in the course of treatment with FEIBA NF. Some of

these events occurred with doses above 200 U/kg/day or in

patients with other risk factors (including DIC, advanced

atherosclerotic disease, crush injury or septicemia) for

thromboembolic

events.

Concomitant

treatment

with

recombinant Factor Vlla may increase the risk of developing

a thromboembolic event.

The possible presence of such risk factors should always be

considered

patients

with

congenital

acquired

hemophilia.

FEIBA NF should be used with particular caution and only if

there are no therapeutic alternatives in patients with an

increased risk of thromboembolic complications.

These

include, but are not limited to, patients with a history of

coronary heart disease, liver disease, DIC, arterial or venous

thrombosis, post-operative immobilization, elderly patients

and neonates.

If signs or symptoms of thrombotic and thromboembolic

events are observed, the infusion should be stopped

immediately and appropriate diagnostic and therapeutic

measures initiated.

A single dose of 100 U/kg body weight and a daily dose of

200 U/kg body weight should not be exceeded unless the

severity of bleeding warrants and justifies the use of higher

doses. When used to stop bleeding, the product should be

given only for as long as absolutely necessary to achieve the

therapeutic goal.

Therapy monitoring

Individual doses of 100 U/kg body weight and daily doses of

200 U/kg body weight must not be exceeded.

Patients

receiving more than 100 U/kg body weight must be

monitored for the development of DIC and/or acute coronary

ischemia.. High doses of FEIBA NF should be administered

only as long as strictly necessary – in order to stop a

hemorrhage.

If clinically significant changes in blood pressure or pulse

rate, respiratory distress, coughing or chest pain occur, the

infusion is to be discontinued immediately and appropriate

diagnostic and therapeutic measures are to be initiated.

Significant laboratory parameters for DIC are a drop in

fibrinogen, a drop of the thrombocyte count and/or the

preventative

therapy

alternative

therapeutic agents.

In patients with a history of hypersensitivity

reactions

plasma

derivatives

prophylactic

administration

antihistamines may be indicated.

Appropriate

vaccination

should

be

considered in patients with an inhibitor

against a coagulation factor.

As

the

quantity

of

sodium

in

the

maximum daily dose may exceed 200 mg,

special

care

should

be

taken

with

individuals on a low sodium diet.

Monitoring of Therapy

Individual doses of 100 U/kg body weight

and daily doses of 200 U/kg body weight

must not be exceeded. Patients who receive

an individual dose of 100 U/kg body weight

are to be monitored carefully, particularly

with regard to the development of a DIC or

the occurrence of symptoms of acute

coronary ischaemia. High doses of FEIBA

NFshould be administered only as long as

strictly necessary to stop a haemorrhage.

If clinically significant changes in blood

pressure or pulse rate, respiratory distress,

coughing or chest pain occur, the infusion is

discontinued

immediately

appropriate

diagnostic

therapeutic

measures are to be initiated. Laboratory

parameters indicative at DIC are decreased

fibrinogen values, decreased platelet count

and/or the presence of fibrin/fibrinogen

degradation products (FDP).

Other

parameters

include

significantly

prolonged

thrombin

time,

prothrombin time, or aPTT.

If coagulation parameters are suspicious of

DIC, a physician experienced in coagulation

therapies should be consulted.

There is insufficient data in children under 6

years of age to recommend the use of

FEIBA NF. However, inhibitor formation is

common

occurrence

haemophilic

children undergoing factor VIII replacement

therapy. Case studies have shown the

successful use of FEIBA NF in the young

age group.

FEIBA NF 500 U and FEIBA NF 1000 U

contain approx. 80 mg sodium (calculated)

per vial. This has to be attended for patients

on low sodium diet.

Acquired haemophilia

Patients with inhibitor haemophilia or with

acquired inhibitors to coagulation factors,

who are treated with FEIBA NF, may have

increased bleeding tendency as well as

increased risk of thrombosis at the same

time.

presence of fibrin/fibrinogen degradation products (FDP).

Other parameters for DIC are a clearly prolonged thrombin

time, prothrombin time or aPTT. In patients with inhibitor

hemophilia or with acquired inhibitors to factors VIII, IX

and/or XI, the aPTT is prolonged by the underlying disease.

Patients with inhibitor hemophilia or with acquired inhibitors

to coagulation factors, who are treated with FEIBA NF, may

have increased bleeding tendency as well as increased risk of

thrombosis at the same time.

Laboratory tests and clinical efficacy

In vitro tests, such as aPTT, whole blood coagulation time

(WBCT) and thromboelastograms (TEG) as proof of efficacy

do not have to correlate with the clinical picture. Therefore,

attempts to normalize these values by increasing the dose of

FEIBA NF cannot be successful, and are even to be strongly

rejected because of the possible risk of triggering a DIC

through overdosing.

Significance of the thrombocyte count

If the response to treatment with FEIBA NF is inadequate,

conducting a thrombocyte count is recommended since a

sufficient number of functionally intact thrombocytes is

necessary for the efficacy of FEIBA NF.

PRECAUTIONS

Thromboembolic Complications

In the following situations, FEIBA NF is to be applied only if

no reaction to treatment with suitable blood coagulation

factor concentrates can be expected – e.g. in case of a high

inhibitor titer and a life-threatening hemorrhage or risk of

bleeding (e.g. post-traumatically or postoperatively):

Disseminated intravascular coagulation

(DIC): laboratory findings and/or clinical

symptoms

Liver

damage:

delayed

clearance of activated coagulation factors,

patients with impaired liver function are at

increased risk of developing DIC.

Coronary heart disease, acute thrombosis

and/or embolism.

Patients who receive FEIBA NF should be monitored for the

development of DIC, acute coronary ischemia, and signs and

symptoms of other thromboembolic events. At the first signs

or symptoms of thrombotic and thromboembolic events, the

infusion should be stopped immediately and appropriate

diagnostic and therapeutic measures initiated.

Discordant Response to Bypassing Agents

Due to patient-specific factors the response to a bypassing

agent can vary, and in a given bleeding situation patients

experiencing insufficient response to one agent may respond

to another agent. In case of insufficient response to one

bypassing agent, use of another agent should be considered.

Anamnestic Responses

Administration of FEIBA NF to patients with inhibitors may

result in an initial “anamnestic” rise in inhibitor levels. Upon

continued administration of FEIBA NF, inhibitors may

decrease over time. Clinical and published data suggest that

the efficacy of FEIBA NF is not reduced.

Hepatitis B Surface Antibodies and Test Interpretation

After administration of high doses of FEIBA NF, the

transitory rise of passively transferred Hepatitis B surface

antibodies may result in misleading interpretation of positive

Laboratory Tests and Clinical Efficacy

In vitro tests, such as aPTT, whole blood

clotting

time

(WBCT)

thromboelastograms (TEG) as proof of

efficacy do not have to correlate with the

clinical picture. Therefore, attempts to

normalise these values by increasing the

dose of FEIBA NF cannot be successful,

and are even to be strongly rejected because

of the possible risk of triggering a DIC

through overdosing.

Significance of Platelet Count

In case of inadequate response to treatment

with FEIBA NF it is recommended to

perform a platelet count, since a sufficient

number of functionally intact platelets are

considered necessary for the efficacy of

FEIBA NF.

Measures to prevent transmission of

infectious agents

Standard measures to prevent infections

resulting from the use of medicinal products

prepared from human blood or plasma

include selection of donors, screening of

individual donations and plasma pools for

specific

makers

infection

inclusion of effective manufacturing steps

for the inactivation/removal of viruses.

Despite this, when medicinal products

prepared from human blood or plasma are

administered, the possibility of transmitting

infective agents cannot be totally excluded.

This also applies to unknown or emerging

viruses or other pathogens.

The measures taken are considered effective

for enveloped viruses such as human

immunodeficiency virus (HIV), hepatitis B

virus (HBV) and hepatitis C virus (HCV),

and for the non-enveloped virus hepatitis A

virus (HAV) and Parvovirus B19.

Appropriate vaccination (against hepatitis A

and B) should be considered for patients in

regular/repeated receipt of plasma-derived

products including FEIBA NF.

In the interest of patients, it is strongly

recommended that name and batch number

of the product be recorded every time

FEIBA is administered in order to be able to

link patient and product batch.

Other Precautions

Discordant Response to Bypassing Agents

Due to patient-specific factors the response

to a bypassing agent can vary, and in a

given bleeding situation patients

experiencing insufficient response to one

agent may respond to another agent. In case

of insufficient response to one bypassing

agent, use of another agent should be

considered.

Anamnestic Responses

Administration of FEIBA to patients with

inhibitors may result in an initial

results in serological testing.

Pediatrics

Case reports and limited clinical trial data suggest that FEIBA

NF can be used in children younger than 6 years of age. The

same dose regimen as in adults should be adapted to the

child’s clinical condition.

Prophylactic use in hemophilia B patients with inhibitors

Due to the rarity of the disease, only limited clinical data is

available for the prophylaxis of bleeding in hemophilia B

patients (literature case reports, n = 4, and clinical data in

prophylaxis study 090701, n = 1).

Transmission of infectious agents

Standard measures to prevent infections resulting from the

use of medicinal products prepared from human blood or

plasma include selection of donors, screening of individual

donations and plasma pools for specific markers of infection

and the inclusion of effective manufacturing steps for the

inactivation / removal of viruses. Despite this, when

medicinal products prepared from human blood or plasma are

administered, the possibility of transmitting infective agents

cannot be totally excluded. This also applies to unknown or

emerging viruses and other pathogens.

The measures taken are considered effective for enveloped

viruses such as HIV, HBV and HCV, and for the non-

enveloped virus HAV. The measures taken may be of limited

value against non-enveloped viruses such as parvovirus B19.

Parvovirus B19 infection may be serious for pregnant women

(fetal infection) and for individuals with immunodeficiency

or increased erythropoiesis (e.g. haemolytic anaemia).

It is strongly recommended that every time that FEIBA NF is

administered to the patient, the name and batch number of the

product are recorded in order to maintain a link between the

patient and the batch of the product.

Appropriate vaccination (hepatitis A and B) should be

considered for patients in regular/ repeated receipt of human

plasma-derived products including FEIBA NF.

Excipient related considerations

FEIBA NF contains approximately 4 mg sodium (calculated)

per ml; it is approx. 80 mg sodium for the presentation 500 U

and 1000 U FEIBA NF.

This is to be taken into

consideration in patients on a low sodium diet.

Risk of Thrombotic and Thromboembolic Events

Thrombotic

thromboembolic

events,

including

disseminated

intravascular

coagulation

(DIC),

venous

thrombosis, pulmonary embolism, myocardial infarction, and

stroke, have occurred in the course of treatment with FEIBA

The risk of thrombotic and thromboembolic events may be

increased with high doses of FEIBA NF. Some of these

events occurred with doses above 200 U/kg/day or in patients

with other risk factors for thromboembolic events. The

possible presence of such risk factors should always be

considered

patients

with

congenital

acquired

hemophilia.

A single dose of 100 U/kg body weight and a daily dose of

200 U/kg body weight should not be exceeded unless the

severity of bleeding warrants and justifies the use of higher

doses. Patients receiving more than 100 U/kg body weight

must be monitored for the development of DIC and/or acute

anamnestic rise in inhibitor levels. Upon

continued administration of FEIBA,

inhibitors may decrease over time.

Clinical and published data suggest that the

efficacy of FEIBA is not reduced.

Hepatitis B Surface Antibodies and Test

Interpretation

After administration of high doses of

FEIBA, the transitory rise of passively

transferred Hepatitis B surface antibodies

may result in misleading interpretation of

positive results in serological testing.

Prophylactic use

Only limited clinical data is available on the

application of FEIBA for the prophylaxis of

bleeding in hemophilia patients.

Pediatrics

Case reports and limited clinical trial data

suggest that FEIBA can be used in children

younger than 6 years of age.

coronary ischemia. When used to stop bleeding, the product

should be given only for as long as absolutely necessary to

achieve the therapeutic goal.

In the following situations FEIBA NF should only be used

when no reaction to treatment with other appropriate

coagulation factor concentrates is to be expected- such as in

case of a high inhibitor titre and a life-threatening

haemorrhage or risk of bleeding e.g. posttraumatic or

postoperative.

Disseminated Intravascular Coagulation (DIC):

Liver damage

delayed

clearance

activated

coagulation factors, patients with impaired liver

function are at increased risk of developing DIC.

Coronary heart disease, acute thrombosis and/or

embolism.

Allergic-Type Hypersensitivity Reactions

As with any intravenously administered plasma products,

allergic type hypersensitivity reactions may occur. Patients

should be informed of the early signs of hypersensitivity

reactions including hives, generalised urticaria, tightness of

the chest, wheezing, drop in blood pressure and anaphylactic

shock. If these symptoms occur, patients should be advised to

discontinue the treatment and to contact their physician

immediately. Shock is treated according to the rules of

modern shock therapy.

When considering re-exposure to FEIBA NF in patients with

suspected hypersensitivity to the product or any of its

components, the expected benefit and the risk of re-exposure

must be carefully weighed, taking into account the known or

suspected type of the patient’s hypersensitivity (allergic or

non-allergic),

including

potential

remedial

and/or

preventative therapy or alternative therapeutic agents.

In patients with a history of hypersensitivity reactions to

plasma

derivatives

prophylactic

administration

antihistamines may be indicated.

Appropriate vaccination should be considered in patients

with an inhibitor against a coagulation factor.

As the quantity of sodium in the maximum daily dose may

exceed 200 mg, special care should be taken with

individuals on a low sodium diet.

Monitoring of Therapy

Individual doses of 100 U/kg body weight and daily doses of

200 U/kg body weight must not be exceeded. Patients who

receive an individual dose of 100 U/kg body weight are to be

monitored

carefully,

particularly

with

regard

development of a DIC or the occurrence of symptoms of

acute coronary ischaemia. High doses of FEIBA NFshould be

administered only as long as strictly necessary to stop a

haemorrhage.

If clinically significant changes in blood pressure or pulse

rate, respiratory distress, coughing or chest pain occur, the

infusion is to be discontinued immediately and appropriate

diagnostic and therapeutic measures are to be initiated.

Laboratory parameters indicative at DIC are decreased

fibrinogen values, decreased platelet count and/or the

presence of fibrin/fibrinogen degradation products (FDP).

Other parameters of DIC include significantly prolonged

thrombin time, prothrombin time, or aPTT.

If coagulation parameters are suspicious of DIC, a physician

experienced in coagulation therapies should be consulted.

There is insufficient data in children under 6 years of age to

recommend the use of FEIBA NF. However, inhibitor

formation is a common occurrence in haemophilic children

undergoing factor VIII replacement therapy. Case studies

have shown the successful use of FEIBA NF in the young age

group.

FEIBA NF 500 U and FEIBA NF 1000 U contain approx. 80

mg sodium (calculated) per vial. This has to be attended for

patients on low sodium diet.

Acquired haemophilia

Patients

with

inhibitor

haemophilia

with

acquired

inhibitors to coagulation factors, who are treated with FEIBA

NF, may have increased bleeding tendency as well as

increased risk of thrombosis at the same time.

Laboratory Tests and Clinical Efficacy

In vitro tests, such as aPTT, whole blood clotting time

(WBCT) and thromboelastograms (TEG) as proof of efficacy

do not have to correlate with the clinical picture. Therefore,

attempts to normalise these values by increasing the dose of

FEIBA NF cannot be successful, and are even to be strongly

rejected because of the possible risk of triggering a DIC

through overdosing.

Significance of Platelet Count

In case of inadequate response to treatment with FEIBA NF it

is recommended to perform a platelet count, since a sufficient

number of functionally intact platelets are considered

necessary for the efficacy of FEIBA NF.

Measures to prevent transmission of infectious agents

Standard measures to prevent infections resulting from the

use of medicinal products prepared from human blood or

plasma include selection of donors, screening of individual

donations and plasma pools for specific makers of infection

and the inclusion of effective manufacturing steps for the

inactivation/removal of viruses. Despite this, when medicinal

products prepared from human blood or plasma are

administered, the possibility of transmitting infective agents

cannot be totally excluded. This also applies to unknown or

emerging viruses or other pathogens.

The measures taken are considered effective for enveloped

viruses such as human immunodeficiency virus (HIV),

hepatitis B virus (HBV) and hepatitis C virus (HCV), and for

the non-enveloped virus hepatitis A virus (HAV) and

Parvovirus B19.

Appropriate vaccination (against hepatitis A and B) should be

considered for patients in regular/repeated receipt of plasma-

derived products including FEIBA NF.

In the interest of patients, it is strongly recommended that

name and batch number of the product be recorded every

time FEIBA is administered in order to be able to link patient

and product batch.

Other Precautions

Discordant Response to Bypassing Agents

Due to patient-specific factors the response to a bypassing

agent can vary, and in a given bleeding situation patients

experiencing insufficient response to one agent may respond

to another agent. In case of insufficient response to one

bypassing agent, use of another agent should be considered.

Anamnestic Responses

Administration of FEIBA to patients with inhibitors may

result in an initial anamnestic rise in inhibitor levels. Upon

continued administration of FEIBA, inhibitors may decrease

over time. Clinical and published data suggest that the

efficacy of FEIBA is not reduced.

Hepatitis B Surface Antibodies and Test Interpretation

After administration of high doses of FEIBA, the transitory

rise of passively transferred Hepatitis B surface antibodies

may result in misleading interpretation of positive results in

serological testing.

Prophylactic use

Only limited clinical data is available on the application of

FEIBA for the prophylaxis of bleeding in hemophilia

patients.

Pediatrics

Case reports and limited clinical trial data suggest that FEIBA

can be used in children younger than 6 years of age.

Interaction with

Other Medicaments

and Other Forms of

Interaction

recommended

antifibrinolytics

such

epsilon-

aminocaproic acid in combination with

FEIBA NF.

If treatment with both antifibrinolytics such

as epsilon-aminocaproic acid and FEIBA

NF is indicated, the two products should be

administered at least 6 hours apart.

No adequate and well-controlled studies of the combined or

sequential use of FEIBA NF and recombinant Factor VIIa or

antifibrinolytics have been conducted.

The possibility of

thromboembolic events should be considered when systemic

antifibrinolytics such as tranexamic acid and aminocaproic

acid are used during treatment with FEIBA NF. Therefore,

antifibrinolytics should not be used for approximately 6 to

12 hours after the administration of FEIBA NF.

In cases of concomitant rFVIIa use a

potential drug

interaction cannot be excluded according to available in vitro

data and clinical observations (potentially resulting in adverse

events such as thromboembolic event).

It is not recommended to use antifibrinolytics such as epsilon-

aminocaproic acid in combination with FEIBA NF.

If treatment with both antifibrinolytics such as epsilon-

aminocaproic acid and FEIBA NF is indicated, the two

products should be administered at least 6 hours apart.

Fertility, pregnancy

and Lactation

Effects on ability to

drive and use machines

No effects of FEIBA NF on the ability to

drive and operate machinery have been

observed.

FEIBA NF has no, or negligible, influence on the ability to

drive or to use machines.

No effects of FEIBA NF on the ability to drive and operate

machinery have been observed.

Adverse events

Following adverse reactions have been

reported within the framework of either post

marketing surveillance or clinical trials. The

frequency cannot be estimated due to the

nature of the data and therefore is

categorized as unknown:

The adverse reactions presented in this section have been

reported from post marketing surveillance as well as from 2

studies with FEIBA NF for the treatment of bleeding episodes

in pediatric and adult patients with hemophilia A or B and

inhibitors to factors VIII or IX. One study also enrolled

acquired hemophilia patients with factor VIII inhibitors (2 of

49 patients). The adverse reactions from a third study

comparing prophylaxis with on-demand treatment have been

added.

Frequency categories are defined according t the following

convention:

very common

≥ 1/10

common

≥ 1/100 to <1/10

uncommon

≥ 1/1,000 to <1/100

rare

≥ 1/10,000 to <1/1,000

very rare

< 1/10,000

System organ

classes according

to MedDRA

Preferred

MedDRA term

Blood and lymphatic

system disorders

Disseminated

intravascular

coagulation (DIC)

Increase of inhibitor

titer (anamnestic

response

Immune system

disorders

Hypersensitivity

Urticaria

Anaphylactic

reaction

Nervous system

disorders

Paraesthesia

Hypoaesthesia

Thrombotic stroke

Embolic stroke

Headache

Somnolence

Dizziness

Dysgeusia

Cardiac disorders

Myocardial

infarction

Tachycardia

Vascular disorders

Arterial and venous

thrombosis

Hypotension

Hypertension

Flushing

Respiratory,

Thoracic, and

Mediastinal

disorders

Pulmonary embolism

Bronchospasm

Wheezing

Cough

Dyspnea

Gastrointestinal

disorders

Vomiting

Diarrhea

Abdominal

discomfort

Nausea

Skin and

subcutaneous tissue

disorders

Hypoaesthesia facial

Angioedema

Urticaria

Pruritus

Rash

General disorders

and administration

site

conditions (Disorder

s during injection)

Injection site pain

Malaise

Feeling hot

Chills

Pyrexia

Chest pain

Chest discomfort

Investigations

Blood pressure

decreased

Increase of inhibitor titer (anamnestic

response) [not a MedDRA PT] is the rise of

previously existing inhibitor titers occurring after

the administration of FEIBA NF. See Special

Warnings and Special Precautions for Use.

unknown

cannot be estimated from the available

data

Adverse Reactions

System organ

class (SOC)

Preferred

MedDRA (version

15.1) Term

Frequency*

Category

Blood and

lymphatic system

disorders

Disseminated

intravascular

coagulation (DIC)

Increase of

inhibitor titer

(anamnestic

response)

Unknown

Unknown

Immune system

disorders

Hypersensitivity

Urticaria

Anaphylactic

reaction

Common

Unknown

Unknown

Nervous system

disorders

Paresthesia

Hypaesthesia

Thrombotic stroke

Embolic stroke

Headache

Somnolence

Dizziness

Dysgeusia

Unknown

Unknown

Unknown

Unknown

Commonn

Unknown

Common

Unknown

Cardiac disorders

Cardiac infarction

Tachycardia

Unknown

Unknown

Vascular disorders

Thrombosis,

Venous thrombosis

Arterial thrombosis

Embolism

(thromboembolic

complications)

Hypotension

Hypertension

Flushing

Unknown

Unknown

Unknown

Unknown

Common

Unknown

Unknown

Respiratory,

Thoracic, and

Mediastinal

disorders

Pulmonary

embolism

Bronchospasm

Wheezing

Cough

Dyspnea

Unknown

Unknown

Unknown

Unknown

Unknown

Gastrointestinal

disorders

Vomiting

Diarrhea

Abdominal

discomfort

Nausea

Unknown

Unknown

Unknown

Unknown

Skin and

subcutaneous tissue

disorders

Sensation of

numbness in the

face

Angioedema

Urticaria

Pruritus

Rash

Unknown

Unknown

Unknown

Unknown

Common

General disorders

and administration

site conditions

Pain at the

injection site

Malaise

Feeling hot

Chills

Pyrexia

Chest pain

Chest discomfort

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Investigations

Drop in blood

pressure

Hepatitis B surface

antibody positive

Unknown

Common

A precise estimate of the rate of these adverse reactions is not possible

from the available data.

Increase of inhibitor titer (anamnestic response) [not a MedDRA PT] is

the rise of previously existing inhibitor titers occurring after the

administration of FEIBA NF. See Section 4.4.

ADR reported in the original and prophylaxis studies. Frequency shown

is from the prophylaxis study only.

ADR reported in the prophylaxis study. Frequency shown is from the

prophylaxis study

Class Reactions

Other symptoms of hypersensitivity reactions to plasma-derived

products include lethargy and restlessness.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of

FEIBA NF is important. It allows continued monitoring of

benefit/risk

balance

FEIBA

Healthcare

professionals are asked to report any suspected adverse

reactions to the Ministry of Health according to the National

Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/

getsequence.aspx?

formType=AdversEffectMedic@moh.health.gov.il

) or by

email (

adr@MOH.HEALTH.GOV.IL

System organ

classes according

to MedDRA

Preferred

MedDRA term

Blood and lymphatic

system disorders

Disseminated

intravascular

coagulation (DIC)

Increase of inhibitor

titer (anamnestic

response

Immune system

disorders

Hypersensitivity

Urticaria

Anaphylactic

reaction

Nervous system

disorders

Paraesthesia

Hypoaesthesia

Thrombotic stroke

Embolic stroke

Headache

Somnolence

Dizziness

Dysgeusia

Cardiac disorders

Myocardial

infarction

Tachycardia

Vascular disorders

Arterial and venous

thrombosis

Hypotension

Hypertension

Flushing

Respiratory,

Thoracic, and

Mediastinal

disorders

Pulmonary embolism

Bronchospasm

Wheezing

Cough

Dyspnea

Gastrointestinal

disorders

Vomiting

Diarrhea

Abdominal

discomfort

Nausea

Skin and

subcutaneous tissue

disorders

Hypoaesthesia facial

Angioedema

Urticaria

Pruritus

Rash

General disorders

and administration

site

conditions (Disorder

s during injection)

Injection site pain

Malaise

Feeling hot

Chills

Pyrexia

Chest pain

Chest discomfort

Investigations

Blood pressure

decreased

Increase of inhibitor titer (anamnestic response) [not a

MedDRA PT] is the rise of previously existing inhibitor titers

occurring after the administration of FEIBA NF. See Special

Warnings and Special Precautions for Use.

Overdosage

Pharmacological

properties

Pharmacotherapeutic

group:

Activated

prothrombin complex against factor VIII

antibody,

ATC Code: B02BD03

Pharmacodynamic properties

Although FEIBA was developed in the

early 1970s and its factor VIII inhibitor

bypassing activity has been demonstrated

both in vitro and in vivo, its active principle

is still the subject of scientific debate.

However, recent scientific work indicates a

role of specific components of the activated

prothrombin complex, zymogen

prothrombin (F II) and activated Factor X

(FXa), in the FEIBA NF mode of action.

Pharmacokinetic properties

Since FEIBA NF is composed of different

coagulation factors with varying half-lives

for the single components, it is not possible

to make any definite statement with regard

to the pharmacokinetic properties of FEIBA

Pharmacodynamic properties

Pharmacotherapeutic group: blood coagulation factors, ATC

code: B02BD03.

Although FEIBA NF was developed in the early seventies

and its factor VIII inhibitor bypassing activity has been

proven in vitro as well as in vivo, its mode of action is still

the subject of scientific discussion. FEIBA NF, as found with

activity assays, is composed of prothrombin complex

zymogens which are both procoagulant (prothrombin FVII,

FIX, FX) and anticoagulant (protein C) in relatively equal

quantities to the arbitrary FEIBA NF potency unit but its

procoagulant enzyme content is relatively low. FEIBA NF,

thus, contains the proenzymes of the prothrombin complex

factors, but only very small amounts of their activation

products, with the contents of FVIIa being the highest.

[Turecek PL and Schwarz HP. Chapter 4: Factor Eight

Inhibitor Bypassing Activity, in Production of Plasma

Proteins for Therapeutic Use, eds. Joseph Bertolini, Neil

Goss, John Curling, Wiley 2013, ISBN: 978-0-470-92431-0].

Current scientific works point to the role of specific

components

activated

prothrombin

complex,

prothrombin (F II) and activated factor X (FXa) in the mode

of action of FEIBA NF. [Turecek PL, Varadi K, Gritsch H,

et al. Factor Xa and Prothrombin: Mechanism of Action of

FEIBA NF. Vox Sang. 77: 72-79, 1999]

FEIBA NF controls bleeding by induction and facilitation of

thrombin generation, a process for which the formation of the

prothrombinase-complex is crucial. A number of biochemical

in vitro and in vivo studies have shown that FXa and

prothrombin play a critical role in the activity of FEIBA NF.

The prothrombinase complex has been found to be a major

target site for FEIBA NF. Apart from prothrombin and FXa,

FEIBA NF contains other proteins of the prothrombin

complex,

which

could

also

facilitate

haemostasis

haemophilia patients with inhibitors.

Treatment of hemophilia B patients with inhibitors

The experience in hemophilia B patients with factor IX

inhibitors is limited due to the rarity of the disease. Five

hemophilia B patients with inhibitors were treated with

FEIBA

during

clinical

trials

either

on-demand,

prophylactically or for surgical interventions:

In a prospective open-label, randomized, parallel clinical study

in hemophilia A or B patients with persistent high-titer

inhibitors (090701, PROOF), 36 patients were randomized to

either 12 months ± 14 days of prophylactic or on-demand

therapy. The 17 patients in the prophylaxis arm received 85 ±

15 U/kg FEIBA NF administered every other day and the 19

patients in the on-demand arm were treated individually

determined by the physician. Two hemophilia B patients with

inhibitors were treated in the on-demand arm and one

hemophilia B patient was treated in the prophylactic arm.

The median ABR (annualized bleeding rate) for all types of

bleeding episodes in patients in the prophylaxis arm (median

ABR = 7.9) was less than that of patients in the on-demand

arm (median ABR = 28.7), which amounts to a 72.5%

reduction in median ABRs between treatment arms.

another

completed

prospective

non-interventional

surveillance study of the perioperative use of FEIBA NF

(PASS-INT-003, SURF) a total of 34 surgical procedures

were performed in 23 patients. The majority of patients (18)

were congenital hemophilia A patients with inhibitors, two

were hemophilia B patients with inhibitors and three were

patients with acquired hemophilia A with inhibitors. The

duration of FEIBA NF exposure ranged from 1 to 28 days,

with a mean of 9 days and a median of 8 days. The mean

cumulative dose was 88,347 U and the median dose was

59,000 U. For hemophilia B patients with inhibitors, the

longest exposure to FEIBA NF was 21 days and the maximum

dose applied was 7324 U.

In addition 36 case reports are available when FEIBA NF was

used for treatment and prevention of bleeding episodes in

hemophilia B patients with factor IX inhibitor (24 hemophilia

B patients with inhibitors were treated on-demand, four

hemophilia

patients

with

inhibitors

were

treated

prophylactically and eight hemophilia B patients with

inhibitors were treated for surgical procedures).

There are also isolated reports on the use of FEIBA NF in the

treatment of patients with acquired inhibitors to factors X, XI

and XIII.

Pharmacokinetic properties

As the mode of action of FEIBA NF is still being discussed,

it is not possible to make a conclusive statement about the

pharmacokinetic properties.

Pharmacotherapeutic group: Activated prothrombin complex

against factor VIII antibody,

ATC Code: B02BD03

Pharmacodynamic properties

Although FEIBA was developed in the early 1970s and its

factor VIII inhibitor bypassing activity has been demonstrated

both in vitro and in vivo, its active principle is still the subject

of scientific debate. However, recent scientific work indicates

a role of specific components of the activated prothrombin

complex, zymogen prothrombin (F II) and activated Factor X

(FXa), in the FEIBA NF mode of action.

Pharmacokinetic properties

Since FEIBA NF is composed of different coagulation factors

with varying half-lives for the single components, it is not

possible to make any definite statement with regard to the

pharmacokinetic properties of FEIBA NF.

Preclinical Safety Data

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."רשואו קדבנ ונכותו תואירבה דרשמ י"ע עבקנ הז ןולע טמרופ"

:רשואמ ןולע

19/4/2015

“This leaflet format has been determined by the Ministry of Health and the content thereof has been checked and

approved.”

Date of approval: 19/4/2015.

SUMMARY OF PRODUCT CHARACTERISTICS

FEIBA NF

Factor VIII Inhibitor Bypassing Activity

Powder for Solution for Injection

1. NAME OF THE MEDICINAL PRODUCT

FEIBA NF (Factor VIII Inhibitor Bypassing Activity)

Powder and solvent for the production of a solution for intravenous administration.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

(a) Powder: each glass vial contains:

FEIBA NF

500 U*

1000 U*

Active ingredient:

Human Plasma Protein with a Factor Eight

Inhibitor Bypassing Activity of

200-600 mg

500 units

400-1200 mg

1000 units

Other ingredients:

Sodium Chloride

160 mg

160 mg

Sodium Citrate dihydrate

80 mg

80 mg

*) A solution containing 1 U of FEIBA NF shortens the activated partial thromboplastin time (aPTT) of a factor VIII

inhibitor plasma to 50% of the buffer value (blank).

FEIBA NF also contains factors II, IX and X mainly in non-activated form as well as activated factor VII;

factor VIII coagulant antigen (F VIII C:Ag) is present in a concentration of up to 0.1 U/1 U FEIBA NF. The

factors of the kallikrein-kinin system are present only in trace amounts, if at all.

(b) Solvent: each glass vial contains 20 ml sterile water for injections.

3. PHARMACEUTICAL FORM AND CONTENTS

Powder and solvent for solution for injection.

White, off-white or pale green freeze-dried powder or friable solid. The pH value of the reconstituted

solution is between 6.8 and 7.6.

FEIBA NF is available in strengths of 500 U and 1000 U, to be dissolved in 20 ml of sterilised water for

injections.

The reconstituted product is intended for intravenous administration.

4. CLINICAL PARTICULARS

4.1 Therapeutical Indications

Control of bleeding episodes in haemophilia A patients with Factor VIII inhibitors and also in

patients with acquired Factor VIII inhibitors.

Control of bleeding in hemophilia B patients with inhibitors, if no other specific treatment is

available.

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4.2. Posology and Method of Administration

The treatment should be initiated and supervised by a physician experienced in the management of

coagulation disorders.

Posology

Dosage and duration of the therapy depend on the severity of the haemostasis disorders, the localization

and the extent of the bleeding, as well as the clinical condition of the patient.

Dosage and frequency of administration should always be guided by the clinical efficacy in the individual

case.

As a general guideline a dose of 50 to 100 U of FEIBA NF per kg body weight (bw) is recommended; a

single dose of 100 U/kg body weight and a maximum daily dose of 200 U/kg body weight must not be

exceeded unless the severity of bleeding warrants and justifies the use of higher doses. See Section 4.4.

Paediatric use (children)

The experience in children under 6 years of age is limited; the same dose regimen as in adults should be

adapted to the child’s clinical condition.

1) Spontaneous Bleeding

Joint, Muscle and Soft Tissue Haemorrhage

A dose of 50-75 U/kg body weight at 12-hour intervals is recommended for minor to moderately severe

bleeding The treatment should be continued until a clear improvement of the clinical symptoms, e.g.

reduction relief of pain, decrease of swelling or increase of joint mobility occurs.

For severe muscle and soft tissue bleeding, e.g. retroperitoneal hemorrhages, a dose of 100 U/kg body

weight at 12-hour intervals is recommended.

Mucous Membrane Haemorrhage

A dose of 50 U/kg body weight every 6 hours under careful monitoring of the patient (visual control of

bleeding, repeated determination of hematocrit) is recommended. If the bleeding does not stop, the dose

may be increased to 100 U/kg body weight, however a daily dose of 200 U/kg body weight must not be

exceeded.

Other Severe Haemorrhages

In severe hemorrhage, such as CNS bleeding, a dose of 100 U/kg body weight at 12-hour intervals is

recommended. In individual cases, FEIBA NF may be administered at 6-hour intervals, until clear

improvement of the clinical condition is achieved. (The maximum daily dose of 200 U/kg body weight must

not be exceeded!)

2) Surgery

In surgical interventions, an initial dose of 100 U/kg body weight may be administered preoperatively, and

a further dose of 50 – 100 U/kg body weight may be administered after 6 – 12 hours. As a postoperative

maintenance dose, 50 – 100 U/kg body weight may be administered at 6 – 12-hour intervals; dosage,

dosage

intervals

duration

peri-

postoperative

therapy

guided

surgical

intervention, the patient’s general condition and the clinical efficacy in each individual case. (The

maximum daily dose of 200 U/kg body weight must not be exceeded!)

3) Use of FEIBA NF in special patient groups

See Section 5.1 for information in relation to hemophilia B patients with factor IX inhibitor.

In combination with factor VIII concentrate, FEIBA NF was also used for long term therapy to achieve

complete and permanent elimination of the factor VIII inhibitor.

Monitoring

In case of inadequate response to treatment with the product, it is recommended that a platelet count be

performed because a sufficient number of functionally intact platelets is considered to be necessary for

the efficacy of the product.

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Due to the complex mechanism of action, no direct monitoring of active ingredients is available.

Coagulation tests such as the whole blood coagulation time (WBCT), the thromboelastogram (TEG, r-

value) and the aPTT usually show only little reduction and do not necessarily correlate with the clinical

efficacy. Therefore these tests have little significance in the monitoring of the therapy with FEIBA NF. See

Section 4.4.

Method of Administration

Reconstitute the product as described in Section 6.6 RECONSTITUTION OF THE POWDER FOR

SOLUTION FOR INJECTION WITH THE BAXJECT II HI-FLOW OR RECONSTITUTION OF THE

POWDER FOR SOLUTION FOR INJECTION WITH TRANSFER NEEDLE, and inject or infuse slowly by

the intravenous route only. Do not exceed an injection/infusion rate of 2 U/kg bw per minute.

4.3 CONTRAINDICATIONS

FEIBA NF must not be used in the following situations if therapeutic alternatives to FEIBA NF are

available:

Hypersensitivity to the product or any of the components.

Disseminated Intravascular Coagulation (DIC).

Acute thrombosis or embolism (including myocardial infarction).

See Section 4.4.

4.4 SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

WARNINGS

Hypersensitivity Reactions

FEIBA

precipitate

allergic-type

hypersensitivity

reactions

that

have

included,

urticaria,

angioedema, gastrointestinal manifestations, bronchospasm, and hypotension; these reactions can be

severe and can be systemic (e.g., anaphylaxis with urticaria and angioedema, bronchospasm, and

circulatory shock). Other infusion reactions, such as chills, pyrexia, and hypertension have also been

reported.

Patients should be informed of the early signs of hypersensitivity reactions, for example erythema, skin

rash,

generalized

urticaria,

pruritus,

breathing

difficulties/dyspnoea,

tightness

chest,

general

indisposition, dizziness and drop in blood pressure up to allergic shock.

At the first sign or symptom of an infusion/hypersensitivity reaction, FEIBA NF administration should be

stopped and medical care initiated as appropriate.

When considering re-exposure to FEIBA NF in patients with suspected hypersensitivity to the product or

any of its components, the expected benefit and the risk of re-exposure must be carefully weighed, taking

into account the known or suspected type of the patient’s hypersensitivity (allergic or non-allergic),

including potential remedial and/or preventative therapy or alternative therapeutic agents.

Thromboembolic Events

Thromboembolic events, including disseminated intravascular coagulation (DIC), venous thrombosis,

pulmonary embolism, myocardial infarction, and stroke, have occurred in the course of treatment with

FEIBA NF. Some of these events occurred with doses above 200 U/kg/day or in patients with other risk

factors (including DIC, advanced atherosclerotic disease, crush injury or septicemia) for thromboembolic

events. Concomitant treatment with recombinant Factor Vlla may increase the risk of developing a

thromboembolic event.

The possible presence of such risk factors should always be considered in patients with congenital and

acquired hemophilia.

FEIBA NF should be used with particular caution and only if there are no therapeutic alternatives in

patients with an increased risk of thromboembolic complications. These include, but are not limited to,

patients with a history of coronary heart disease, liver disease, DIC, arterial or venous thrombosis, post-

operative immobilization, elderly patients and neonates.

If signs or symptoms of thrombotic and thromboembolic events are observed, the infusion should be

stopped immediately and appropriate diagnostic and therapeutic measures initiated.

A single dose of 100 U/kg body weight and a daily dose of 200 U/kg body weight should not be exceeded

unless the severity of bleeding warrants and justifies the use of higher doses. When used to stop

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bleeding, the product should be given only for as long as absolutely necessary to achieve the therapeutic

goal.

Therapy monitoring

Individual doses of 100 U/kg body weight and daily doses of 200 U/kg body weight must not be exceeded.

Patients receiving more than 100 U/kg body weight must be monitored for the development of DIC and/or

acute coronary ischemia.. High doses of FEIBA NF should be administered only as long as strictly

necessary – in order to stop a hemorrhage.

If clinically significant changes in blood pressure or pulse rate, respiratory distress, coughing or chest pain

occur,

infusion

discontinued

immediately

appropriate

diagnostic

therapeutic

measures are to be initiated. Significant laboratory parameters for DIC are a drop in fibrinogen, a drop of

thrombocyte

count

and/or the presence of fibrin/fibrinogen degradation products (FDP). Other

parameters for DIC are a clearly prolonged thrombin time, prothrombin time or aPTT. In patients with

inhibitor hemophilia or with acquired inhibitors to factors VIII, IX and/or XI, the aPTT is prolonged by the

underlying disease.

Patients with inhibitor hemophilia or with acquired inhibitors to coagulation factors, who are treated with

FEIBA NF, may have increased bleeding tendency as well as increased risk of thrombosis at the same

time.

Laboratory tests and clinical efficacy

In vitro tests, such as aPTT, whole blood coagulation time (WBCT) and thromboelastograms (TEG) as

proof of efficacy do not have to correlate with the clinical picture. Therefore, attempts to normalize these

values by increasing the dose of FEIBA NF cannot be successful, and are even to be strongly rejected

because of the possible risk of triggering a DIC through overdosing.

Significance of the thrombocyte count

response

treatment

with

FEIBA

inadequate,

conducting

thrombocyte

count

recommended since a sufficient number of functionally intact thrombocytes is necessary for the efficacy of

FEIBA NF.

PRECAUTIONS

Thromboembolic Complications

In the following situations, FEIBA NF is to be applied only if no reaction to treatment with suitable blood

coagulation factor concentrates can be expected – e.g. in case of a high inhibitor titer and a life-

threatening hemorrhage or risk of bleeding (e.g. post-traumatically or postoperatively):

Disseminated intravascular coagulation (DIC): laboratory findings and/or clinical symptoms

Liver damage: Due to the delayed clearance of activated coagulation factors, patients with

impaired liver function are at increased risk of developing DIC.

Coronary heart disease, acute thrombosis and/or embolism.

Patients who receive FEIBA NF should be monitored for the development of DIC, acute coronary

ischemia, and signs and symptoms of other thromboembolic events. At the first signs or symptoms of

thrombotic and thromboembolic events, the infusion should be stopped immediately and appropriate

diagnostic and therapeutic measures initiated.

Discordant Response to Bypassing Agents

Due to patient-specific factors the response to a bypassing agent can vary, and in a given bleeding

situation patients experiencing insufficient response to one agent may respond to another agent. In case

of insufficient response to one bypassing agent, use of another agent should be considered.

Anamnestic Responses

Administration of FEIBA NF to patients with inhibitors may result in an initial “anamnestic” rise in inhibitor

levels. Upon continued administration of FEIBA NF, inhibitors may decrease over time. Clinical and

published data suggest that the efficacy of FEIBA NF is not reduced.

Hepatitis B Surface Antibodies and Test Interpretation

After administration of high doses of FEIBA NF, the transitory rise of passively transferred Hepatitis B

surface antibodies may result in misleading interpretation of positive results in serological testing.

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Pediatrics

Case reports and limited clinical trial data suggest that FEIBA NF can be used in children younger than 6

years of age. The same dose regimen as in adults should be adapted to the child’s clinical condition.

Prophylactic use in hemophilia B patients with inhibitors

Due to the rarity of the disease, only limited clinical data is available for the prophylaxis of bleeding in

hemophilia B patients (literature case reports, n = 4, and clinical data in prophylaxis study 090701, n = 1).

Transmission of infectious agents

Standard measures to prevent infections resulting from the use of medicinal products prepared from

human blood or plasma include selection of donors, screening of individual donations and plasma pools

for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation /

removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are

administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to

unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for

the non-enveloped virus HAV. The measures taken may be of limited value against non-enveloped

viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (fetal

infection)

individuals

with

immunodeficiency

increased

erythropoiesis

(e.g.

haemolytic

anaemia).

It is strongly recommended that every time that FEIBA NF is administered to the patient, the name and

batch number of the product are recorded in order to maintain a link between the patient and the batch of

the product.

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/ repeated receipt

of human plasma-derived products including FEIBA NF.

Excipient related considerations

FEIBA NF contains approximately 4 mg sodium (calculated) per ml; it is approx. 80 mg sodium for the

presentation 500 U and 1000 U FEIBA NF. This is to be taken into consideration in patients on a low

sodium diet.

4.5 Interactions with other medicinal products and other forms of interaction

No adequate and well-controlled studies of the combined or sequential use of FEIBA NF and recombinant

Factor VIIa or antifibrinolytics have been conducted. The possibility of thromboembolic events should be

considered when systemic antifibrinolytics such as tranexamic acid and aminocaproic acid are used

during treatment with FEIBA NF. Therefore, antifibrinolytics should not be used for approximately 6 to

12 hours after the administration of FEIBA NF.

In cases of concomitant rFVIIa use a potential drug interaction cannot be excluded according to available

in vitro data and clinical observations (potentially resulting in adverse events such as thromboembolic

event).

4.6 Fertility, pregnancy and lactation

There are no adequate data from the use of FEIBA NF in pregnant or lactating women. Physicians should

balance the potential risks and only prescribe FEIBA NF if clearly needed, taking into consideration that

pregnancy and the postpartum period confer an increased risk of thromboembolic events, and several

complications of pregnancy that are associated with an increased risk of DIC.

No animal reproduction studies have been conducted with FEIBA NF, and the effects of FEIBA NF on

fertility have not been established in controlled clinical trials.

4.7 Effects on the ability to drive and use machines

FEIBA NF has no, or negligible, influence on the ability to drive or to use machines.

4.8 Undesirable effects

The adverse reactions presented in this section have been reported from post marketing surveillance as

well as from 2 studies with FEIBA NF for the treatment of bleeding episodes in pediatric and adult patients

with hemophilia A or B and inhibitors to factors VIII or IX. One study also enrolled acquired hemophilia

patients with factor VIII inhibitors (2 of 49 patients). The adverse reactions from a third study comparing

prophylaxis with on-demand treatment have been added.

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Frequency categories are defined according t the following convention:

very common

≥ 1/10

common

≥ 1/100 to <1/10

uncommon

≥ 1/1,000 to <1/100

rare

≥ 1/10,000 to <1/1,000

very rare

< 1/10,000

unknown

cannot be estimated from the available data

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Adverse Reactions

System organ class

(SOC)

Preferred MedDRA (version 15.1) Term

Frequency*

Category

Blood and lymphatic

system disorders

Disseminated intravascular coagulation (DIC)

Increase of inhibitor titer (anamnestic response)

Unknown

Unknown

Immune system disorders

Hypersensitivity

Urticaria

Anaphylactic reaction

Common

Unknown

Unknown

Nervous system disorders

Paresthesia

Hypaesthesia

Thrombotic stroke

Embolic stroke

Headache

Somnolence

Dizziness

Dysgeusia

Unknown

Unknown

Unknown

Unknown

Commonn

Unknown

Common

Unknown

Cardiac disorders

Cardiac infarction

Tachycardia

Unknown

Unknown

Vascular disorders

Thrombosis,

Venous thrombosis

Arterial thrombosis

Embolism (thromboembolic complications)

Hypotension

Hypertension

Flushing

Unknown

Unknown

Unknown

Unknown

Common

Unknown

Unknown

Respiratory, Thoracic,

and Mediastinal disorders

Pulmonary embolism

Bronchospasm

Wheezing

Cough

Dyspnea

Unknown

Unknown

Unknown

Unknown

Unknown

Gastrointestinal disorders

Vomiting

Diarrhea

Abdominal discomfort

Nausea

Unknown

Unknown

Unknown

Unknown

Skin and subcutaneous

tissue disorders

Sensation of numbness in the face

Angioedema

Urticaria

Pruritus

Rash

Unknown

Unknown

Unknown

Unknown

Common

General disorders and

administration site

conditions

Pain at the injection site

Malaise

Feeling hot

Chills

Pyrexia

Chest pain

Chest discomfort

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Investigations

Drop in blood pressure

Hepatitis B surface antibody positive

Unknown

Common

A precise estimate of the rate of these adverse reactions is not possible from the available data.

Increase of inhibitor titer (anamnestic response) [not a MedDRA PT] is the rise of previously existing inhibitor titers

occurring after the administration of FEIBA NF. See Section 4.4.

ADR reported in the original and prophylaxis studies. Frequency shown is from the prophylaxis study only.

ADR reported in the prophylaxis study. Frequency shown is from the prophylaxis study

Class Reactions

Other symptoms of hypersensitivity reactions to plasma-derived products include lethargy and

restlessness.

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Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of FEIBA NF is important. It allows continued

monitoring of the benefit/risk balance of FEIBA NF. Healthcare professionals are asked to report any

suspected adverse reactions to the Ministry of Health according to the National Regulation by using an

online form

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.health

.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).

4.9 OVERDOSAGE

Some of the reported thromboembolic events occurred with doses above 200 U/kg. If signs or symptoms

of thromboembolic events are observed, the infusion should be stopped immediately and appropriate

diagnostic and therapeutic measures initiated. See Section 4.4

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: blood coagulation factors, ATC code: B02BD03.

Although FEIBA NF was developed in the early seventies and its factor VIII inhibitor bypassing activity has

been proven in vitro as well as in vivo, its mode of action is still the subject of scientific discussion. FEIBA

NF, as found with activity assays, is composed of prothrombin complex zymogens which are both

procoagulant (prothrombin FVII, FIX, FX) and anticoagulant (protein C) in relatively equal quantities to the

arbitrary FEIBA NF potency unit but its procoagulant enzyme content is relatively low. FEIBA NF, thus,

contains the proenzymes of the prothrombin complex factors, but only very small amounts of their

activation products, with the contents of FVIIa being the highest. [Turecek PL and Schwarz HP. Chapter 4:

Factor Eight Inhibitor Bypassing Activity, in Production of Plasma Proteins for Therapeutic Use, eds.

Joseph Bertolini, Neil Goss, John Curling, Wiley 2013, ISBN: 978-0-470-92431-0].

Current scientific works point to the role of specific components of the activated prothrombin complex,

prothrombin (F II) and activated factor X (FXa) in the mode of action of FEIBA NF. [Turecek PL, Varadi K,

Gritsch H, et al. Factor Xa and Prothrombin: Mechanism of Action of FEIBA NF. Vox Sang. 77: 72-79,

1999]

FEIBA NF controls bleeding by induction and facilitation of thrombin generation, a process for which the

formation of the prothrombinase-complex is crucial. A number of biochemical in vitro and in vivo studies

have shown that FXa and prothrombin play a critical role in the activity of FEIBA NF. The prothrombinase

complex has been found to be a major target site for FEIBA NF. Apart from prothrombin and FXa, FEIBA

NF contains other proteins of the prothrombin complex, which could also facilitate haemostasis in

haemophilia patients with inhibitors.

Treatment of hemophilia B patients with inhibitors

The experience in hemophilia B patients with factor IX inhibitors is limited due to the rarity of the disease.

Five hemophilia B patients with inhibitors were treated with FEIBA NF during clinical trials either on-

demand, prophylactically or for surgical interventions:

In a prospective open-label, randomized, parallel clinical study in hemophilia A or B patients with

persistent high-titer inhibitors (090701, PROOF), 36 patients were randomized to either 12 months ± 14

days of prophylactic or on-demand therapy. The 17 patients in the prophylaxis arm received 85 ± 15 U/kg

FEIBA NF administered every other day and the 19 patients in the on-demand arm were treated

individually determined by the physician. Two hemophilia B patients with inhibitors were treated in the on-

demand arm and one hemophilia B patient was treated in the prophylactic arm.

The median ABR (annualized bleeding rate) for all types of bleeding episodes in patients in the

prophylaxis arm (median ABR = 7.9) was less than that of patients in the on-demand arm (median ABR =

28.7), which amounts to a 72.5% reduction in median ABRs between treatment arms.

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In another completed prospective non-interventional surveillance study of the perioperative use of FEIBA

NF (PASS-INT-003, SURF) a total of 34 surgical procedures were performed in 23 patients. The majority

of patients (18) were congenital hemophilia A patients with inhibitors, two were hemophilia B patients with

inhibitors and three were patients with acquired hemophilia A with inhibitors. The duration of FEIBA NF

exposure ranged from 1 to 28 days, with a mean of 9 days and a median of 8 days. The mean cumulative

dose was 88,347 U and the median dose was 59,000 U. For hemophilia B patients with inhibitors, the

longest exposure to FEIBA NF was 21 days and the maximum dose applied was 7324 U.

In addition 36 case reports are available when FEIBA NF was used for treatment and prevention of

bleeding episodes in hemophilia B patients with factor IX inhibitor (24 hemophilia B patients with inhibitors

were treated on-demand, four hemophilia B patients with inhibitors were treated prophylactically and eight

hemophilia B patients with inhibitors were treated for surgical procedures).

There are also isolated reports on the use of FEIBA NF in the treatment of patients with acquired inhibitors

to factors X, XI and XIII.

5.2 Pharmacokinetic properties

As the mode of action of FEIBA NF is still being discussed, it is not possible to make a conclusive

statement about the pharmacokinetic properties.

5.3 Preclinical Safety data

Based on acute toxicity studies with factor VIII knockout mice and normal mice and rats with higher doses

than the maximum daily dose for humans (> 200 U/kg of body weight), it can be concluded that the side

effects in connection with FEIBA NF mainly result from hypercoagulation due to the pharmacological

properties.

Toxicity

studies

with

repeated

administration

animal

experiments

practically

unfeasible

interference occurs through the development of antibodies to heterologous proteins.

Since human blood coagulation factors are not seen as carcinogenic or mutagenic, experimental animal

studies, especially in heterologous species, were not considered necessary.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder:

Sodium chloride

Sodium citrate

Solvent:

Sterilized Water for Injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except the solvent mentioned in

Section 6.6.

As in all blood coagulation preparations, the efficacy and tolerance of the medicinal product may be

impaired by being mixed with other medicinal products. It is advisable to rinse a common venous access

with a suitable solution, e.g. with isotonic saline solution, before and after the administration of FEIBA NF.

Coagulation factors derived from human plasma may be adsorbed by the inner surfaces of certain types

of injection/infusion devices. If this were to occur, it could result in failure of therapy. Therefore, only

approved plastic infusion devices may be used with FEIBA NF.

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6.3 Shelf life of the reconstituted product

Chemical and physical stability of the reconstituted product has been demonstrated for 3 hours at a

temperature of 20

C –25

From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial

contamination (controlled and validated aseptic conditions), the product should be used immediately. If not

used immediately, in-use storage times and conditions are the responsibility of the user.

Reconstituted product must not be refrigerated.

6.4 Special Precautions for Storage

Do not store above 25° C. Do not freeze

Store in the original package to protect contents from light.

For storage conditions of the reconstituted medicinal product – see Section 6.3.

Store out of the reach of children.

6.5 Nature and contents of the container

Powder and solvent come in glass vials made of surface-treated, colourless glass (hydrolytic class II). The

product vial is closed with a chlorobutyl rubber stopper, while the solvent vial is closed with a bromobutyl

rubber stopper.

Each package contains either:

1 rubber-capped vial of FEIBA NF 500 or 1000 U (powder for reconstituting solution for intravenous

administration).

1 rubber-capped vial containing 20 ml sterile water for injections.

1 disposable syringe (20 ml capacity).

1 disposable needle.

1 butterfly needle with clamp (winged set for injection).

1 filter needle.

1 transfer needle.

1 aeration needle.

1 rubber-capped vial with FEIBA NF – powder for solution for intravenous

administration

1 rubber-capped vial with 20 ml sterilised Water for Injections

1 Baxject II Hi-Flow – Needleless transfer device intended for transferring and mixing drugs contained in

two vials into a syringe

1 disposable syringe

1 disposable needle

1 butterfly needle with clamp (winged set for injection)

6.6. Special precautions for disposal and other handling advice

To prepare the FEIBA NF solution, use only the sterilised water for injections and the reconstitution device

provided in the pack. Use aseptic technique throughout entire procedure. FEIBA NF is to be reconstituted

only immediately before administration. The solution should then be used straight away (the solution does

not contain preservatives). Swirl gently until all material is dissolved. Ensure that FEIBA NF is completely

dissolved; otherwise, less FEIBA NF Units will pass through the device filter. After reconstitution, the

solution should be inspected for particulate matter and discoloration prior to administration.

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Do not use solutions which are cloudy or have deposits. Open containers must not be re-used. Do not

use if the needleless transfer device or the transfer needle, its sterile barrier system or its packaging is

damaged or shows any sign of deterioration.

Use only the included sterilized Water for Injections and the included device set for reconstitution. If

devices other than those enclosed are used, ensure the use of an adequate filter with a pore size of at

least 149 µm.

Any unused medicinal product or waste material is to be disposed of in accordance with national

requirements.

RECONSTITUTION OF THE POWDER FOR SOLUTION FOR INJECTION WITH THE BAXJECT II HI-

FLOW:

Warm solvent (sterilised water for injections) vial to room temperature (15

C – 25

C), for

example by using a water bath for several minutes (max. 37°C).

Remove the protective caps from the FEIBA NF vial and solvent vial and cleanse the rubber

stoppers of both. Place the vials on a flat surface.

Open the BAXJECT II Hi-Flow device package by peeling away the paper lid without touching the

inside (Fig a). Do not remove the device from the package.

Turn the package over and insert the clear plastic spike through the solvent stopper (Fig. b). Grip

the package at its edge and pull the package off BAXJECT II Hi-Flow (Fig. c). Do not remove the

blue cap from BAXJECT II Hi-Flow device.

With BAXJECT II Hi-Flow attached to the solvent vial, invert the system so that the solvent vial is

on top of the device. Insert the purple plastic spike through the FEIBA vial stopper. The vacuum

will draw the solvent into the FEIBA NF vial (Fig. d)

Swirl gently until all material is dissolved. Ensure that FEIBA NF is completely dissolved,

otherwise active material will not pass through the device filter.

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FEIBA NF 500U, 1000U with BAXJECT II Hi-Flow Device_ SPC_

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Instructions for Injection/Infusion:

Remove the blue cap from BAXJECT II Hi-Flow. Take the syringe and connect it to BAXJECT II

Hi-Flow (DO NOT DRAW AIR INTO THE SYRINGE) (Fig. e).

Invert the system (with FEIBA NF vial on top). Draw the FEIBA NF solution into the syringe by

pulling the plunger back slowly (Fig. f)

Disconnect the syringe.

Slowly inject the solution intravenously with a winged set for injection (or a disposable needle)

Do not exceed an injection speed of 2 U FEIBA NF/kg body weight per minute.

RECONSTITUTION OF THE POWDER TO PREPARE A SOLUTION FOR INJECTION WITH

TRANSFER NEEDLE:

Warm the unopened vial containing the solvent (sterile water for injections) to room temperature, e.g.

using a sterile water bath for warming within several minutes (max. +37°C).

Remove protective caps from the concentrate vial and solvent vial (fig. 1) and disinfect the rubber

stoppers of both 2 vials.

Remove protective covering from one end of the supplied "transfer needle" by twisting and pulling

(fig. 2). Insert the exposed needle through the rubber stopper of the solvent vial (fig. 3).

Remove protective covering from the other end of the transfer needle taking care not to touch the

exposed end.

Invert the solvent vial over the concentrate vial, and insert the free end of the transfer needle through

the rubber stopper of the concentrate vial (fig. 4). The solvent will be drawn into the concentrate vial by

vacuum.

Disconnect

vials

removing

needle

from

concentrate

vial

(fig.

Gently agitate or rotate the concentrate vial to accelerate dissolution.

Upon complete reconstitution of the concentrate, insert the enclosed "aeration needle" provided

(fig. 6) and any foam will collapse. Remove aeration needle.

INJECTION/INFUSION:

Remove protective covering from the supplied "filter needle" by twisting and pulling and fit the needle

onto a sterile disposable syringe. Draw the solution into the syringe (fig. 7).

Disconnect the filter needle from the syringe and slowly inject the solution intravenously by means of

the enclosed infusion set (and disposable needle, respectively).

Do not exceed an injection/infusion rate of 2 units FEIBA NF per kg of body weight per minute.

After injection/infusion: put all needles together with the syringe and/or the venepuncture instruments into

the product box without closing them to avoid endangering other persons.

The administration of the preparation must be documented by means of the attached adhesive labels in

the anamnesis.

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7. REGISTRATION NUMBERS:

FEIBA NF 500 Units: 026 14 25389 00

FEIBA NF 1000 Units: 026 15 25390 00

8. MANUFACTURER

Baxter AG

Industriestrasse 67

A-1220 Vienna, Austria.

9. LICENCE HOLDER

Takeda Israel Ltd.,

25 Efal st., Petach Tikva 4951125.