GRANOCYTE 34

Israel - English - Ministry of Health

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Active ingredient:
LENOGRASTIM 33.6 MIU/ML
Available from:
SANOFI - AVENTIS ISRAEL LTD
ATC code:
L03AA10
Pharmaceutical form:
LYOPHILIZED POWDER FOR INJECTION
Administration route:
I.V, S.C
Manufactured by:
SANOFI WINTHROP INDUSTRIE, FRANCE
Therapeutic group:
LENOGRASTIM
Therapeutic indications:
- Reduction in duration of neutropenia and associated complications in patients undergoing bone marrow transplantation or cytotoxic chemotherapy associated with a febrile neutropenia. - Autologous mobilization of Peripheral Blood Progenitor Cells. As an adjunct to allogenic mobilization of peripheral blood progenitor cells (PBPCs).
Authorization number:
103662867300
Authorization date:
2011-12-01

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Patient Information leaflet Patient Information leaflet - Arabic

17-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

17-01-2021

רשואוקדבנונכותותואירבהדרשמי"עעבקנהזןולעטמרופ ץרמב 2012

ו"משתה(םירישכת)םיחקורהתונקתיפלןכרצלןולע - 1986

אפורםשרמבתבייחוזהפורת

הפורתבשמתשתםרטבופוסדעןולעהתאןויעבארק

GRANOCYTE34

הסימתתנכהלסממוהקבא תירועתתהקרזהל א יוריעו ידירוךות

:בכרה Lenograstim 33.6 MIU (263 mcg)

:םיליעפיתלבםירמוח

הקבאהןוקובקב ףסונבליכמ :

D-mannitol,Polysorbate 20,L-arginine,L-phenylananine,L-methionine,Hydrochloric acid

סממהקרזמ ליכמ Water for injections

טיופארתהצובק :תי גוסמןובלח granulocyte colony-stimulating factor ) G-CSF גוסמםדיאתרוצידדועמה(

.םיליפורטיונ

.םינושםיבצמב(הנבלהםדהתריפסבהדירי)הינפורטיונהךשמרוציק:תיאופרתוליעפ

דוינ ימצע םיאתתלתשהלשהרקמבירפירפהםדלעזגיאתלש .

?רישכתבשמתשהלןיאיתמ

הקינמךניהרשאכהפורתבישמתשתלא .

.הפורתהיביכרממדחאלתושיגרהעודיםאשמתשהלןיא

מםילבוסהםילוחלצאשמתשהלןיא - Myeloid cancer – םא:םימיוסמםירקמבתתלןתינםלוא

םעתנחבואהנורחאל acute myeloid leukemia ו םא ליגלעמךנה 55 .

ןיא שמתשהל טייסונרגב 24 ירחאואינפלתועש יפרתומיכלופיטתלבק , י/האר ןיבתובוגתףיעס

תויתפורת .

לופיטהתלחתהינפלאפורבץעוויהלילבמהפורתבשמתשהלןיא

ןוירהבךניהםא ןוירהתננכתמוא .

:דוקפתביוקילמרבעבתלבסואת/לבוסךניהםא ןוגכ)םדהתכרעמ,ןתשהתכרעמ/הילכה,דבכה

'וכוהשירק .םצעהחמ,(

(ןינלאלינפליכמרישכתה)האירונוטקלינפמלבוסךנהםא .

:תורהזא

.לופיטהךשמתעיבקםשלםדתוקידבךורעלשיוזהפורתבלופיטהתפוקתב

ןינאלאלינפליכמרישכתה .

:תויתפורתןיבתובוגת

,תפסונהפורתת/לטונךניהםא תיפסותואםשרמאללתורכמנהתופורתללוכ הנוז התעהזתרמגםאוא

יאואםינוכיסעונמלידכלפטמהאפורלחוודלךילעתרחאהפורתבלופיטה - ןיבתובוגתמםיעבונהתוליעי -

:תואבהתוצובקהמתופורתיבגל,דחוימב.תויתפורת

,השירקתודגונתופורת ןטרסבלופיטלתופורת – ןיא שמתשהל טייסונרגב 24 תועש ואינפל תלבקירחא

.יפרתומיכהלופיט

:יאוולתועפות

,תופורתהלכבומכ עיפוהלתולולעהבשומישהןמזב,הפורתהלשהיוצרהתוליעפלףסונב תועפות יאוול .

:םאאפורלעדוהוהפורתבלופיטהקספה

ןוילעהקלחבבאכשחךנה ןטבהלשילאמשה וא ב תילאמשהףתכ – הזוןכתיי לןמיס תלדגה ,לוחטה וז

ות .לוחטהתעירקלליבוהלהלוכיםירידנםירקמבםלואהחיכשהעפ

תיגרלאהבוגתבשחךנה – ואהמישנבתויעב,רועבהחירפויהיםינימסתההזהרקמב העילבב תוחיפנ,

,םייתפש ב ,םינפ ב ואןושל ב ןורג – .(רידנ)

יטקליפנאקושתארקנההרומחהבוגתהווחךנה – יהיםינימסתההזהרקמב ,תופלעתהתשגרהו

םינפהתוחיפנוהמישניישק,השלוח - (רידנ)

ללוכההמישניישקהווחךנה םי ואםוחולועיש תשוחת קנחמ (רידנ) .

הנפ :תואבהיאוולהתועפותמתחאשחךנהםאאפורל

הבוגת (חיכש)הקרזההרוזאב

,תועורזבתוחיפנותוימומדאןוגכרועבתויעב ב םיתיעלוםיילגר ב וםינפ ב םוחבהוולמהראווצ

לןמיס) Sweet’s syndrome לןמיס)שאריבאכוםוחבהוולמתומודאתויחופלשוא( Lyell’s

syndrome תוירועתועפותונכתיי.( ןוגכתורחא תוחופנתורובח ףוגהלעםיביכואםיילגרהלע

וולמ םי .(תורידנולאתועפות)םיקרפיבאכוםוחב

יאוולתועפות תורחא

,םירירשותומצעיבאכ ,בגבאכ (חיכש)שארבאכ – לקהלןתינםיעיפומםא לע יככשמםעבאכה

םיבאכ

ךנהםא םצעחמלשאירבםרות :

:םאדימאפורלעדוה

תילאמשהףתכבואןטבהלשילאמשהןוילעהקלחבבאכשחךנה – לןמיסהזוןכתיי תלדגה וז,לוחטה

םלואהחיכשהעפות .לוחטהתעירקלליבוהלהלוכיםירידנםירקמב

םינימסתההזהרקמב.טייסונרגהלשןושארהןתמהרחאלהעיפומםאםג,תיגרלאהבוגתבשחךנה

,םייתפשבתוחיפנ,העילבבואהמישנבתויעב,רועבהחירפויהי ב ,םינפ ב ואןושל ב .(רידנ) ןורג

ויהיםינימסתההזהרקמב,םייחתנכסמהבוגתוז,יטקליפנאקושתארקנההרומחהבוגתהווחךנה

םינפהתוחיפנוהמישניישק,השלוח,תופלעתהתשגרה - (רידנ)

הווחךנה וםוחלועיש (רידנ)המישניישק

:תואבהתוחיכשהיאוולהתועפותמתחאשחךנהםאאפורלהנפ

גותומצעיבאכ הליחבוא/וםוח,שארבאכ ,ב

דבלשתוגירחתואצות הדוקפתלתורושקשולאללוכםדהתוקי דבכ תורזוחתואצותהללכךרדב.

הליגרההמר .הפורתבשומישהתקספהרחאל

תופייעתשגרה םצעהחמתמורתרחאל הדיריהתובקעבתאזו רפסמב ןכתת.םימודאהםדהיאת

הלוכיהתויסטהרפסמבהדיריםג םילוחכםינמיסואםימומידתעפוהלםורגל רתיב תמועלתולק

.ילמרונהבצמ

תיללכהךתשגרהביונישלחםאוא,הזןולעבוניוצאלשיאוולתועפותה/שיגרמךניהובשהרקמלכב

.דימאפורהםעץעייתהלךילע

:ןונימ

דבלבאפורהתוארוהיפל

תצלמומההנמהלערובעלןיא

הניאוזהפורת .םייתנשליגלתחתמםידלילותוקוניתלללכךרדבתדעוימ

לעעבקנשיפכםיבוצקםינמזבוזהפורתבשמתשהלשי - .לפטמהאפורהידי

שומישהןפוא תירועתתהקרזהל : .(תונומתבהוולמהקרזההםוקמושומישהןפוארבסהףרוצמהןולעב)

ליעפהרמוחהתאליכמהןוקובקב:הליכמהזיראה. lenograstim 263 mcg.

וכותבודחאקרזמ 1 .הקרזהלםימלשל"מ

םיטחמיתש – .ןבלהסכמתלעבהיינשוםוחהסכמתלעבתחא

.ןוקובקבהלעמקיטסלפההסכמתאי/רסה.

.לוהוכלאבגופסןפגרמצתרזעבימוגהיוסיכתי/הקנ.

תאי/רבחוקרזמהמןגמההסכמתאי/רסה. .קרזמלןבלהיוסיכהםעטחמה

.ןוקובקבלקרזמהןכותתאי/קרזהוןוקובקבהךותלקרזמלתרבוחמהטחמהתאי/רדחה.

כךשמלתונידעבןוקובקבהתאי/רענ. - 5 .!הקזוחברענלןיא.תוינש

.לזונהךותבאצמנטחמההצקיכי/אדוו.קרזמלרבוחמודועבןוקובקבהתאיכ/ךופה.

אבי/יבאש. תאתויטי מתשרדנהתומכה .ןוקובקבה

.םוחהיוסיכהםעטחמהתאי/רבחהמוקמב.ןבלהיוסיכהםעטחמהתאי/רסה.

.קרזמהתנכובתפיחדוקרזמהףוגלעןידעףופיתי"עריוואתועובי/אצוה.

.הקרזהלשרדנהחפנהתאםאתהשרדנםא הוכלאבגופסןפגרמצתרזעבהקרזההםוקמתאי/הקנ .לו

י/קרזה. דימ תא םינמוסמהתומוקמהתשמחמדחאבקרזמהןכות .(ךשמהבםישרתהאר)

****************************************

?לופיטהתחלצהלעייסל'/לכותדציכ

****************************************

לעץלמוהשלופיטהתאםילשהלךילע - אפורהידי

צמברופישלחםאםג אפורםעתוצעייתהאללהפורתבלופיטהקיספהלןיאךתואירבב

!הלערהענמ

לעותוקוניתוא/וםידלילשםדיגשיהלץוחמרוגסםוקמברומשלשיתרחאהפורתלכווזהפורת - ךכידי

.הלערהענמת

תיבלשןוימרדחלדימהנפ,הפורתהןמדליעלבתועטבםאוארתיתנמתלטנםא - הו,םילוח תזיראאב

.ךתיאהפורתה

האקהלםורגלןיא איה,ת/רחאהלוחב,ךתלחמבלופיטלהמשרנוזהפורת!אפורמתשרופמהארוהאלל

לא.קיזהלהלולע ןתית .ךירכמואךינכש,ךיבורקלוזהפורת !ךשוחבתופורתלוטילןיא תיוותהקודב

הנמהו םעפלכב זךניהםאםייפקשמי/בכרה.הפורתלטונךניהש .םהלה/קוק

:הנסחא

לעמןסחאלןיא °C 30 .איפקהלןיא,

ןיבררקמברומשלואדימשמתשהלשיהנכההרחאל °C 2 ל + - °C 8 ךותשמתשהלו + 24 תועש

ךיראתלבלםישלאנ.דבלבתלבגומהפוקתלתורמשנתופורת,םיצלמומההנסחא/הזיראהיאנתיפלםג

!רישכתהלשהגופתה .הפורתהתאךלקפיסשחקורבץעוויהלךילע,קפסלשהרקמלכב

.הזיראהתואבתונושתופורתןסחאלןיא

הנפאנאהמרבדבחוטבךניאואיהשלכהלאשךלשיםא.רישכתהלעעדימהלכתאללוכאלהזןולע

אפורל

:הפורתהםושיר'סמ 1036628673

:ןרצי יפונאס - פורטניוו תוישעת .תפרצ:תבותכ

יפונאס:םושירהלעב - סיטנווא לארשי ד.ת:תבותכ מ"עב 8090 הינתנ, 42504 .

1

ופ רשואוקדבנונכותותואירבהדרשמי"עעבקנהזןולעטמר ץרמב 2012

1. NAME OFTHE MEDICINAL PRODUCT

Granocyte ® 34, lyophilized powder andsolvent for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Lenograstim* (rHuG-CSF) 33.6 million International Units (equivalent to 263 micrograms)

per mlafter reconstitution.

* Produced fromChinese Hamster Ovary (CHO) cells using recombinant DNA technology

Excipient with a specific effect: phenylalanine.

For a full list of excipients, see Section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection or infusion:

White powder.

Solvent: clear, colorless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

- Reduction in duration of neutropenia and associated complicationsin patients

undergoing bone marrowtransplantationor cytotoxic chemotherapy associated

with a febrile neutropenia.

- Autologous mobilization of Peripheral BloodProgenitor Cells. As an adjunct to

allogenic mobilization of peripheral blood progenitor cells (PBPCs).

4.2 Posology and method of administration

Treatment must be instituted and monitored in collaboration witha specialized oncology

and/or hematology center.

Granocyte can be administered asa subcutaneous injection orby intravenous infusion. Special

recommendations for handling and preparing the medicinal product are given in Section 6.6.

The recommended dose of Granocyte is 150 µg (19.2 millionIU) per m 2 body surface area per

day, equivalent to 5 µg (0.64 millionIU) per kg bodyweight per day:

following bone marrow transplantation (BMT) orperipheral stemcell transplantation;

following use of well-established cytotoxic chemotherapy protocols;

in PBPC mobilizationfollowing chemotherapy.

Granocyte 34million IU/ml is used in patients with a body surface area of up to 1.8 m 2 .

2

In PBPC mobilization, using Granocyte alone,the recommended dose is 10 µg (1.28 million

IU) per kg bodyweight per day.

4.2.1 Adults

Following bone marrow or peripheral stemcell transplantation, Granocyte should be

administered daily at the recommended dose of 150 µg (19.2 million IU) per m 2 body surface

area per dayas a 30-minute intravenous (IV)infusion diluted in normal saline, or by

subcutaneous (SC) injection. The first dose mustnot be administered within 24 hours of bone

marrow transplantation.

Treatment should continue until the expecteddate of the nadir has passed and until the

neutrophil count has returned to a stable level enabling treatment discontinuation. If necessary,

treatment may continue for up to 28 days.

It is anticipated that by day 14 post-bone marrow transplantation, 50% ofpatients will have

recovered a normal neutrophil count or a neutrophil count enabling treatment discontinuation.

Following use of an established cytotoxic chemotherapy protocol, Granocyte should be

administered daily at the recommended dose of 150 µg (19.2 million IU) per m 2 body surface

area per day by SC injection. The first dose must not be administered during the 24 hours

following completion of cytotoxic chemotherapy (see Sections 4.4 and 4.5).

Daily administration of Granocyte should continueuntil the expected date of the nadir has

passed and until the neutrophil count has returnedto a stable level enabling treatment

discontinuation. If necessary, treatment may continue for up to 28 days.

A transient increase in neutrophil count may occur during the first two days of treatment.

However, treatment with Granocyte must notbe discontinued, as the nadir usually occurs

earlier and recovery is fasterwhen treatment is continued.

In PBPC mobilization after chemotherapy, Granocyte should be administered daily at the

recommended dose of 150 µg (19.2 million IU) per m 2 body surface area per day by SC

injection, starting between the first and fifthday after completion of chemotherapy, depending

on the chemotherapy protocol used for mobilization.

Granocyte treatment must be maintained until the last leukapheresis.

Leukapheresis should be carried outwhen the post-nadir leukocyte count increases or after

determining the CD34+ cell count using a validated method. In patients who have not been

intensively pre-treated with chemotherapy, oneleukapheresis is generally sufficient to obtain

the minimum acceptable threshold of more than 2.0 million CD34+ cellscollected per kg.

In order to mobilize PBPCs with Granocyte alone, the medicinal product should be

administered daily at the recommended dose of 10 µg (1.28 million IU) per kg bodyweight

per day by SCinjection for 4 to 6 days.

Leukapheresis should be performed between days 5 and 7.

In patients who have not been intensively pre-treated with chemotherapy,one leukapheresis is

3

generally sufficient to obtain the minimumacceptable threshold ofnot less than 2.0 x 106

CD34+ cells collected per kg.

In healthy donors, a 10 µg/kg daily dose administered subcutaneously for 5-6 days is

sufficient to collect not less than 3.0 x 106 CD34+ cells, with a single leukapheresis in 83% of

subjects and 2 leukaphereses in 97% of subjects.

4.2.2 Elderly patients

Clinicaltrials with Granocytehave included a small number ofpatients aged up to 70 years,

but specific studies have notbeen conducted in the elderly. Therefore, specific dose

recommendations cannot be made.

4.2.3 Children

The safety and efficacy of Granocyte in bone marrow transplantation havebeen established in

children over 2 years of age.

4.3 Contraindications

Granocyte must not be administered to patients with known hypersensitivity to lenograstimor

to one of the excipients.

Granocyte should not be used toincrease dose intensity in cytotoxic chemotherapy regimens

beyond established doses and combinations, asthe drug may reduce myelotoxicity without

affecting the overall toxicity of chemotherapy.

It should not be administered concomitantly with cytotoxic chemotherapy.

It should not be administered to patients:

with myeloid neoplasia other thande novo acute myeloid leukemia;

under 55 years of age with de novoacute myeloid leukemia; and/or

with de novo acute myeloid leukemia with normalcytogenetics, i.e. t(8;21), t(15;17) and inv

(16).

4.4 Special warnings and precautions for use

Malignant cell growth

Granulocyte-colony stimulating factors (G-CSFs) can promote growth of myeloid cellsin

vitroand similar effects may be observed in somenon-myeloid cellsin vitro.

The safety and efficacy of Granocyte in patients with myelodysplastic syndrome, secondary

acute myeloid leukemia or chronic myeloid leukemia have not been established. Therefore, it

should not be used in these indications. Particular care should be taken to distinguish blast

transformation of chronic myeloid leukemia from acute myeloid leukemia.

Clinical trials have not established whetherGranocyte has aneffecton the progression of

myelodysplastic syndromeinto acute myeloid leukemia.

4

Special caution must therefore be exercised whenusing Granocyte in any patients with pre-

leukemic syndrome.

As somenon-specific tumors may exceptionallyexpress a G-CSF receptor, patients should be

monitored for potential tumor regrowth during G-CSF treatment.

Hyperleukocytosis

During clinical trials, a leukocyte count of more than 50 x 10 9 /l was never observed in any of

the 174 patients treated with 5μg/kg/day (0.64 million IU/kg/day) following bone marrow

transport. A leukocyte count of more than 70 x 10 9 /l was observed in less than 5% of patients

who received chemotherapy and weretreated with Granocyte at 5μg/kg/day (0.64 million

IU/kg/day). No adverse events directly attributable to thisdegree of hyperleukocytosis have

been reported.

In view of the potential risks associatedwith severe hyperleukocytosis, a leukocyte count

should be performed at regular intervals during Granocyte therapy.

If the number of leukocyte count exceeds 50 x 10 9 /l after the expecteddate of the nadir,

Granocyte should be discontinued immediately.

When Granocyte is administered to mobilize Peripheral Blood Progenitor Cells (PBPCs),

treatment must be discontinued ifthe number of leucocyte exceeds 70 x 10 9 /l.

Adverse pulmonary effects

Rare adverse pulmonary effects (> 0.01% and <0.1%), particularly interstitial pneumonia,

have been reported after administration of G-CSFs.

The risk of these effects may be increased inpatients recently diagnosed with pulmonary

infiltration or pneumonia.

The onset of pulmonary signs such as cough, fever and dyspnea in combination with

radiological signs of pulmonaryinfiltration and deterioratedpulmonary function may be

preliminary signs of acute respiratory distress syndrome(ARDS).

Granocyte should be discontinued immediately and appropriate treatment initiated.

Bone marrowand peripheral stem cell transplantation

Particular attention should bepaid to platelet regeneration, ascontrolled studies have shown a

lower mean platelet count in patients treated with Granocytethan in patients receiving

placebo.

The effect of Granocyte on the incidence and severity of acute and chronic graft-versus-host

disease (GVHD) has not yet been clearly determined.

5

Use during established cytotoxic chemotherapyregimens

The use of Granocyte isnot recommended inthe 24-hour period before chemotherapy until 24

hours after the completion of chemotherapy (see Section 4.5).

The safety ofGranocyte when co-administratedwith anticancer agents that have cumulative

or predominant platelet lineage myelotoxicity (nitrosurea, mitomycin) has not been

established. Granocyte may in this case even cause enhanced toxicity,especiallyplatelet

toxicity.

Risks associated with increased chemotherapy doses

The safety and efficacy of Granocyte remain tobe established in the context of intensified

chemotherapy.

Granocyte should not be used to reduce theintervals between chemotherapy cycles beyond

the established limits, nor to increase the established dosesof chemotherapy. In a phase II

chemotherapy intensification trial with Granocyte, non-myeloid toxicities were shown to be

the limiting factors.

Special precautions in PBPC mobilization

Choice of mobilization method

Clinical trials carried out in a single patientpopulation showed that PBPC mobilization was

higher when Granocyte was administered after chemotherapy than when used alone

(measurements carried out by the samelaboratory). However, the choice between these two

mobilizationmethods should take into consideration the overall therapeutic objectivesfor

each patient.

Previous exposure to cytotoxicagents and/or radiotherapy

In patients who have undergone previous intensive chemotherapy and/or radiotherapy, it may

be difficult to obtain the minimum acceptablethreshold of PBPCs (not less than 2 X 10 6

CD34+ cells/kg), and therefore to achieve sufficient hematological recovery.

PBPC transplantation should be planned early inthe treatment course, and particular attention

should be paid to the number of PBPCs mobilized before administration of high-dose

chemotherapy. If yields prove insufficient, transplantation should be replaced by other forms

of treatment.

Determination of PBPC yields

Particular attention should bepaid to the method of quantification of PBPCs collected, as the

results of flow cytometric analysis of CD34+cells vary between different laboratories. The

recommended minimum threshold of not less than 2 X 10 6 CD34+ cells/kg to obtain

acceptable hematological recovery isbased on results published in the literature. However,

the minimum threshold is not clearlydefined. Yields of more than 2 X 10 6 CD34+ cells/kg

are associated with faster recovery, including platelet recovery, while lower yields are

associated with slower recovery.

6

PBPC mobilization in healthy donors

PBPC mobilization, a procedure without direct benefit to healthy donors, must complystrictly

with national regulationsrelative to bone marrow donation, where these regulations have been

established.

The efficacy and safety of Granocyte have notbeen established in donors over 60 years of age.

Therefore, PBPC mobilization isnot recommended in these subjects. According to national

regulations, and given the lack ofspecific studies,minors mustnot be considered as donors.

PBPC mobilization should onlybe considered in donors satisfy clinical and laboratory

criteria, in particular hematological criteria, required for bone marrow donation.

Hyperleukocytosis (WBCnot less than 50 x 10 9 /l) was observed in 24% of study subjects.

Apherisis-related thrombocytopenia(platelet count less than 100 x 10 9 /l) was observed in

42% of study subjects, and occasionally subjects had values of less than 50 x 10 9 /l following

leukopheresis with no clinical signs, returning to normal values in all cases.

For this reason, PBPC mobilization should not be carried out in donors receiving

anticoagulant treatment or who have hemostasisdisturbances. If morethan one leukopheresis

is required, particular attention should be paid to donors witha platelet count of less than 100

x 10 9 /l prior to apheresis. Apheresis should generallynot be performed if platelet count is less

than 75 x 10 9 /l.

Donor selection should take into account the quality of venous access and,wherever possible,

central catheterization should be avoided.

Transient cytogenetic changes have been observed in healthydonors following use of G-CSF.

The implications of these changes are not known.

Long-termmonitoring of safety parametersin donors is ongoing. Nevertheless, the

development of clones of malignantmyeloid cells is a risk thatcannot be ruled out. It is

recommended that each donor be systematicallyregistered and monitored by cytapheresis

units for at least 10 years so thatlong-termsafety can be monitored.

In healthy donors pulmonary adverse events (hemoptysis, pulmonary haemorrhage,

pulmonary infiltrates, dyspnea and hypoxia) havebeen reported in post-marketing experience.

In case of suspected or confirmed pulmonaryadverse events, discontinuation of treatment

with Granocyte should be considered and appropriate medical care instituted.

Recipients ofallogenic stem cells obtained after mobilizationby Granocyte

Allogenic stem-cell grafting may be related toan increased risk of chronic GVHD, but long-

termdata on graft functioning remain sparse.

7

Other precautions

The safety and efficacy of Granocyte have not beenestablished in patients with renal or liver

insufficiency.

In patients with reduced bone marrow reserves, for exampleafter intensive chemotherapy or

extensive radiotherapy, the neutrophil response is sometimes reduced and the safety of

Granocyte has not been established.

Following administration of G-CSFs, generallyasymptomatic cases of splenomegaly and

isolated cases of splenic rupture have been reported in healthy donors and patients. Therefore,

the size of the spleen must be closely monitored (physical examination, ultrasound).

A diagnosis of splenic rupture must be considered when the patient reports having pain in the

upper left abdomen or outer shoulder.

Granocyte contains phenylalanine, which can be harmful topatients with phenylketonuria.

4.5 Interaction with other medicinal products and other forms of interaction

Granocyte treatment is not recommended during the 24-hour period preceding or following

chemotherapy because of the sensitivity ofrapidly dividing myeloid cells to cytotoxic

chemotherapy (see Section 4.4).

Possible interactions with other hematopoieticgrowth factors or cytokines remain to be

determined in clinical trials.

4.6 Pregnancy and lactation

Pregnancy

There are no available data on the use of lenograstimin pregnant women.

Animal studies have shown reproduction toxicity (see Section 5.3)

The potential risk in humans is not known.

Granocyte must not be used during pregnancy unlessabsolutely necessary.

Lactation

There are no data on theexcretion of lenograstimin breast milk. Excretion in breast milk has

not been studied in animals. Breast-feedingmust be discontinuedduring treatment with

Granocyte.

4.7 Effects on ability todrive and use machines

Effects on the ability to drive and use machines have not been studied.

8

4.8 Undesirable effects

Bone marrowor peripheral stem cell transplantation

In double-blind placebo-controlled trials, the mean number of platelets was lower inpatients

treated with Granocyte comparedwith placebo, without an increase in incidence of events

related to blood loss and the median number ofdays between the transplantation and the last

platelet infusion was similar inboth groups (see Section 4.4).

Bone marrowor peripheral stem cell transplantation and chemotherapy-induced

neutropenia

In clinicaltrials, the incidence ofreportedadverse events (15%) was the samein patients

treated with Granocyte and placebo.

These adverse events were those usually observedwith this type of treatment and in cancer

patients treated with chemotherapy.

The most commonly reported adverse eventswere: infection/inflammation of the buccal

cavity, septicemia and infection, fever, diarrhea, abdominal pain, vomiting, nausea, rash,

alopecia, and headache.

PBPC mobilization in healthy donors.

The most frequently reported undesirable effects were transient and mild to moderate: pain,

bone pain, back pain, asthenia, fever, headache and nausea, increased ALT, AST, blood

alkaline phosphatase and HDL levels .

Aphaeresis -related thrombocytopenia and hyperleukocytosis were observed in 42% and 24%

respectively of study subjects.

Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic

rupture have been reported.

Rare pulmonary adverse reactions have beenreported like dyspnoea, hypoxia or hemoptysis,

including very rare Acute Respiratory Distress Syndrome (ARDS) (see section 4.4).

Allergic reactions including anaphylaxis have been reportedvery rarely after the first

subcutaneous administration of lenograstim.

Frequency of adverse reactions occurring during clinicaltrials and post-marketing

surveillance data:

Very common (≥10%); common (≥1/100 to < 1/10); uncommon (≥1/1000 to≤1/100); rare

(≥1/10000 to≤1/1000); very rare (≤1/10000); not known (cannot beestimated fromthe

available data).

9

MedDRA System

Organ Class

Verycommon Common Uncommon Rare Veryrare

Investigations

ElevatedLDH

Blood and

lymphatic system

disorders

Leukocytosis,

Thrombocytopenia Enlarged spleen

size

Splenic rupture

(5)

Nervous system

disorders

Headache,

Fatigue

Respiratory,

thoracic and

madiastinal

disorders

Pulmonary

edema,

Interstitial

pneumonia (3),

Pulmonary

infiltrates,

Pulmonary

fibrosis

Gastrointestinal

disorders

Abdominal pain

Skin and

subcutaneous

tissuedisorders

Cutaneous

vasculitis,

Acute febrile

neutrophilic

dermatosis

(Sweet's

syndrome) (4),

Erythema

nodosum,

Pyoderma

gangrenosum,

Lyell'ssyndrome

Musculoskeletal

and connective

tissuedisorders

Bone pain,

Back pain

Pain (1)

General disorders

and

administration

site conditions

Injection site

reaction

Immunesystem

disorders

Allergicreaction,

Anaphylactic

shock

Hepatobiliary

disorders

Elevated

AST/ALT (2),

Elevatedalkaline-

phosphatase

1 / The risk of occurrenceof pain is increased insubjects with a high peak WBC value, especially

when WBC≥50 x10 9 /l.

10

2 / Transient increase of AST and/or ALT was observed. In most cases, liver function abnormalities

improved after discontinuation of lenograstim.

3 / Someof the reported respiratory cases resulted in respiratoryfailure or acute respiratorydistress

syndrome(ARDS) which maybe fatal.

4 / Acute febrile neutrophilic dermatosis(Sweet'ssyndrome), erythema nodosumand pyoderma

gangrenosum weremainlydescribed in patients withhematological malignancies, that are known to

be associated with neutrophilic dermatosis,but also innon-malignant neutropenia.

5 / Splenic ruptures have been reported in healthydonors and patients after G-CSFs administration

(see Section 4.4)

4.9 Overdose

The effects of Granocyte overdose havenot been established (see Section 5.3).

The discontinuation of Granocyte treatment isusually accompanied by a 50% decrease in

circulating neutrophils within 1 to 2 days, witha return to normal levels in 1 to 7 days. A

leukocyte count of approximately 50 x 10 9 /l was observed in 1of the 3 patients having

received the highest dosesofGranocyte, i.e.40 µg/kg/day (5.12 million IU/kg/day) onthe

fifth day of treatment.

In man, doses of up to 40 µg/kg/day were not associated withtoxic effects, with the exception

of bone and muscle pain.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: cytokines, ATC code: L03AA10

Lenograstim (rHuG-CSF) belongsto the group of cytokines,which are biologically active

proteins regulating cell differentiation and growth.

rHuG-CSF stimulates the growth of neutrophil progenitor cells, as shown by CFU-S and

CFU-GM cell count increases in peripheral blood.

Granocyte induces a marked increase in the peripheral blood neutrophil count in the 24 hours

following administration. This increase is dose-dependent, within the range of 1 to 10

µg/kg/day.

At the recommended dose, repeated administrationleads to an increase inneutrophil response.

Neutrophils produced in response to Granocyte show normal chemotaxis and phagocytosis

functions.

As with other hematopoietic growth factors, G-CSF has shown stimulating properties on

human endothelial cells in vitro.

Use of Granocyte in patients undergoing bone marrow transplantation or who are treated with

cytotoxic chemotherapy leads to a significantdecrease in the duration of neutropenia and

related complications.

11

Administration of Granocyte,either alone or after chemotherapy, mobilizes PBPCs

(Peripheral Blood Progenitor Cells), which can be collectedand infused after high dose

chemotherapy, either in place of or in combination with bone marrow transplantation.The

infused PBPCs obtained by mobilization with Granocyte have proved capable of

reconstituting hematopoiesisand accelerating grafting.

Consequently, time to platelet transfusion independence was reducedafter autologous bone

marrow transplantation.

A pooled analysis of data from3 double-blind placebo-controlled studies conducted in 861

patients (n =411, 55 years and older) showed afavorable benefit/risk ratio of lenograstim

administration in patients aged 55 years andolder receiving conventional chemotherapy for

de novo acute myeloid leukemia, with the exception of AML patients with normal

cytogenetics, i.e. t(8;21), t(15;17) and inv (16).

In the sub-group of patients over 55 years of age,the benefits of Granocyte administration

appeared in terms of acceleratedneutrophil recovery, a greater percentageof patients without

infectious episodes, reduced duration of infection, shorter hospitalization and reduced IV

antibiotic therapy. However, these beneficial results were accompanied neither by a decrease

in severeor life-threatening infections, nor by decreasedinfection-related mortality.

Data froma double-blindplacebo-controlledstudy conducted in 446 patients with de novo

AML showed that:

in the subgroup of 99 patients with normal cytogenetics, event-free survival times were

significantly shorter inthe lenograstim armthan in the placebo arm.In addition, overall

survival times tended to be shorter in thelenograstimarmthan in the placebo arm;

the sameresults concerning survival werenot found in the subgroup of patients with

abnormal cytogenetics.

5.2 Pharmacokinetic properties

The pharmacokinetics of Granocyte are dose- and time-dependent.

Following repeated administration ofGranocyte, peak serumconcentrations at the endof IV

infusion or after SC injection are proportional tothe injected dose, with no evidence of a

cumulative effect.

At the recommended dose, the absolute bioavailability of Granocyte is30%. The apparent

volume of distribution (Vdss) is approximately1l/kg, and the mean residence time is close to

7 hours following SC administration.

The apparent serumhalf-life of Granocyte after SC injectionis approximately 3-4 hours at

steady state (repeated administration), and shorter (1-1.5 hours) after repeated IV infusion.

Plasmaclearance of rHuG-CSF increased 3-fold(from50 to150 ml/min) following repeated

SC administration.

A very small amount of lenograstim is excretedunchanged in urine (less than 1% ofthe

dose), as the drug must bemetabolized toendogenous peptides. Peak serum lenograstim

concentrations are close to 100 pg/ml/kg atthe recommended dose after repeated SC

injections. Apositive correlation exists between dose and serum concentration ofGranocyte

12

and between neutrophil responseand the total amount of lenograstimfound in serum.

5.3 Preclinical safety data

In acute toxicity studies (up to 1000 µg/kg/day inmice) and sub-acute toxicity studies (up to

100 µg/kg/day in monkeys), overdose effects werelimited to a reversible exacerbation of

pharmacological effects.

In rat and rabbit studies, Granocyte showed no teratogenic effects.An increased incidence of

spontaneous abortions was observed in the rabbit, but no malformations were reported.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder:

L-Arginine

L-Phenylalanine

L-Methionine

D-Mannitol

Polysorbate 20

Hydrochloric acid (for pH adjustment)

Solvent:

Water for injection

6.2 Incompatibilities

This medicinal product must not be mixed withother medicines, except for those mentioned

in Section 6.6.

6.3 Shelf-life

2 years.

After reconstitution ordilution, immediate use is recommended.

However, the reconstituted or diluted medicinal product has been shown to have 24-hour

stability between + 2°C and +8°C (in the refrigerator).

6.4 Special precautions for storage

Do not store at temperatures exceeding + 30°C.

Do not freeze.

For storage conditions for the reconstituted ordiluted medicinal product, see Section 6.3.

6.5 Nature and contents of container

263 µg of powder in a type I glass vial with type I butyl rubber stopper+ 1 mlof solvent in a

pre-filled syringe(type I glass); box of 1 or 5.

Not all pack sizes may be marketed.

13

6.6 Instructions for use, handling and disposal

Any unused medicine, solution or waste productmust be disposed of as per current

regulations.

Instructions for preparation

Granocyte vials are for single use.

Granocyte must be reconstituted before subcutaneous or intravenous administration.

Preparationof the reconstituted Granocyte solution

Using the 19G needle provided in the pack, and the pre-filled disposable syringe with the

solvent for GRANOCYTE ready for immediate useaseptically add the extractable contents of

one pre-filled syringe of solventfor GRANOCYTE to the GRANOCYTE

Agitate gently until completely dissolved. Do not shake vigorously.

The reconstituted parenteralsolution appears transparent andfree ofparticles.

The reconstituted solution should preferablybe used immediately after preparation.

For storage conditions of thereconstituted/diluted medicinal product, see Section 6.3.

Preparationfor subcutaneous administration

Prepare a reconstituted Granocyte solution as described above.

While keeping the syringe with theneedle inthe vial, withdraw therequired volumeof

reconstituted solution fromthe vial. Remove the needle used for reconstitution and fit the

syringe witha needle thatis suitable for subcutaneous injection.

Keeping the needle 19G and the syringe attachedto the vial , withdraw the required volume

of reconstituted solution fromthe vial. Replacethe needle used for reconstitution and fit the

syringe with the 26G needle provided for subcutaneous injection.

Administer immediately by subcutaneous injection (see Section 4.2 for administration

recommendations).

Preparationof the solution for infusion for intravenous administration

For intravenous use, Granocyte mustbe diluted after reconstitution.

Prepare a reconstituted Granocyte solution as described above.

Keeping the needle andthe syringe in the vial, extract the required volumeofreconstituted

solution from the vial.

Dilute the reconstituted Granocytesolution tothe required concentration by injecting the

required volume into either a 0.9% sodiumchloride or a 5% glucose solution.

Administer intravenously (see Section4.2 for administration recommendations).

Granocyte iscompatible withthe commonly used administration sets for injection when

diluted either in a 0.9% sodiumchloride solution (in polyvinyl chloridebags or glass bottles)

or in a 5% glucose solution (in glass bottles).

14

Dilution of Granocyte 34million IU/ml to a final concentration of less than 0.32 million

IU/ml (2 µg/ml) is not recommended. 1 vialofreconstituted Granocyte 34million IU/ml

should not be diluted in more than 100 ml.

7. MARKETING AUTHORIZATION HOLDER

Sanofi-aventis Israel ltd. Israel

8. MANUFACTURER

Sanofi Winthrop Industries France

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