Cetrotide

1.

NAME OF THE MEDICINAL PRODUCT

Cetrotide 0.25 mg powder and solvent for solution for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 0.25 mg cetrorelix (as acetate).

After reconstitution with the solvent provided, each ml of the solution contains 0.25 mg cetrorelix.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Appearance of the powder: white lyophilisate

Appearance of the solvent: clear and colourless solution

The pH of the reconstituted solution is 4.0 – 6.0

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Prevention of premature ovulation in patients undergoing a controlled ovarian stimulation, followed

by oocyte pick-up and assisted reproductive techniques.

In clinical trials Cetrotide was used with human menopausal gonadotropin (HMG), however, limited

experience with recombinant follicule-stimulating hormone (FSH) suggested similar efficacy.

4.2 Posology and method of administration

Cetrotide should only be prescribed by a specialist experienced in this field.

The first administration of Cetrotide should be performed under the supervision of a physician and

under conditions where treatment of possible allergic/pseudo-allergic reactions (including life-

threatening anaphylaxis) is immediately available. The following injections may be self-administered

as long as the patient is made aware of the signs and symptoms that may indicate hypersensitivity, the

consequences of such a reaction and the need for immediate medical intervention.

The contents of 1 vial (0.25 mg cetrorelix) are to be administered once daily, at 24 h intervals, either in

the morning or in the evening. Following the first administration, it is advised that the patient be kept

under medical supervision for 30 minutes to ensure there is no allergic/pseudo-allergic reaction to the

injection.

Cetrotide is for subcutaneous injection into the lower abdominal wall.

The injection site reactions may be minimised by rotating the injection sites, delaying injection at the

same site and injecting the product in a slow rate to facilitate the progressive absorption of the product.

Administration in the morning: Treatment with Cetrotide should commence on day 5 or 6 of ovarian

stimulation (approximately 96 to 120 hours after start of ovarian stimulation) with urinary or

recombinant gonadotropins and is to be continued throughout the gonadotropin treatment period

including the day of ovulation induction.

2

Administration in the evening: Treatment with Cetrotide should commence on day 5 of ovarian

stimulation (approximately 96 to 108 hours after start of ovarian stimulation) with urinary or

recombinant gonadotropins and is to be continued throughout the gonadotropin treatment period until

the evening prior to the day of ovulation induction.

Additional information on special populations :

There is no relevant indication for the use of Cetrotide in children or geriatric populations.

For instructions for preparation, see section 6.6.

4.3 Contraindications

• Hypersensitivity to the active substance or any structural analogues of gonadotropin-releasing

hormone (GnRH), extrinsic peptide hormones or to any of the excipients.

• Pregnancy and lactation.

• Postmenopausal women.

• Patients with moderate and severe renal and hepatic impairment.

4.4 Special warnings and precautions for use

Special care should be taken in women with signs and symptoms of active allergic conditions or

known history of allergic predisposition. Treatment with Cetrotide is not advised in women with

severe allergic conditions.

During or following ovarian stimulation an ovarian hyperstimulation syndrome can occur. This event

must be considered as an intrinsic risk of the stimulation procedure with gonadotropins.

An ovarian hyperstimulation syndrome should be treated symptomatically, e.g. with rest, intravenous

electrolytes/colloids and heparin therapy.

Luteal phase support should be given according to the reproductive medical centre´s practice.

There is limited experience up to now with the administration of Cetrotide during a repeated ovarian

stimulation procedure. Therefore Cetrotide should be used in repeated cycles only after a careful

risk/benefit evaluation.

4.5 Interaction with other medicinal products and other forms of interaction

In vitro investigations have shown that interactions are unlikely with medicinal products that are

metabolised by cytochrome P450 or glucuronised or conjugated in some other way. However,

although there has been no evidence of drug-interactions, especially with commonly used medicinal

products, gonadotropins or products that may induce histamine release in susceptible individuals, the

possibility of an interaction cannot be totally excluded.

4.6 Pregnancy and lactation

Cetrotide is not intended to be used during pregnancy and lactation (see section 4.3).

Studies in animals have indicated that cetrorelix exerts a dose related influence on fertility,

reproductive performance and pregnancy. No teratogenic effects occurred when the medicinal product

was administered during the sensitive phase of gestation.

3

4.7 Effects on ability to drive and use machines

Cetrotide has no or negligible influence on the ability to drive or use machines.

4.8 Undesirable effects

The most commonly reported side effects are local injection site reactions such as erythema, swelling

and pruritus that are usually transient in nature and mild in intensity. In clinical trials, these effects

were observed with a frequency of 9.4% following multiple injections of Cetrotide 0.25 mg.

Mild to moderate ovarian hyperstimulation syndrome (OHSS) (WHO grade I or II) have been

commonly reported and should be considered as an intrinsic risk of the stimulation procedure.

Inversely, severe OHSS remains uncommon.

Uncommonly, cases of hypersensitivity reactions including pseudo-allergic/anaphylactoid reactions

have been reported.

The adverse reactions reported below are classified according to frequency of occurrence as follows:

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

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Immune system disorders

Uncommon

Systemic allergic/pseudo-

allergic reactions including life-

threatening anaphylaxis.

Nervous system disorders

Uncommon

Headache

Gastrointestinal disorders

Uncommon

Nausea

Reproductive system and breast

disorders

Common

Mild to moderate ovarian

hyperstimulation syndrome

(WHO grade I or II) can occur

which is an intrinsic risk of the

stimulation procedure (see

section 4.4).

Uncommon

Severe ovarian hyperstimulation

syndrome (WHO grade III)

General disorders and

administration site conditions

Common

Local reactions at the injection

site (e.g. erythema, swelling and

pruritus) have been reported.

Usually they were transient in

nature and of mild intensity.

The frequency as reported in

clinical trials was 9.4%

following multiple injections of

0.25 mg cetrorelix.

4.9 Overdose

Overdosage in humans may result in a prolonged duration of action but is unlikely to be associated

with acute toxic effects.

4

In acute toxicity studies in rodents non-specific toxic symptoms were observed after intraperitoneal

administration of cetrorelix doses more than 200 times higher than the pharmacologically effective

dose after subcutaneous administration.

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anti-gonadotropin-releasing hormones, ATC code: H01CC02.

Cetrorelix is a luteinising hormone releasing hormone (LHRH) antagonist. LHRH binds to membrane

receptors on pituitary cells. Cetrorelix competes with the binding of endogenous LHRH to these

receptors. Due to this mode of action, cetrorelix controls the secretion of gonadotropins (LH and

FSH).

Cetrorelix dose-dependently inhibits the secretion of LH and FSH from the pituitary gland. The onset

of suppression is virtually immediate and is maintained by continuous treatment, without initial

stimulatory effect.

In females, cetrorelix delays the LH surge and consequently ovulation. In women undergoing ovarian

stimulation the duration of action of cetrorelix is dose dependent. Following a single dose of 3 mg of

cetrorelix a duration of action of at least 4 days has been evaluated. On day 4 the suppression was

approximately 70%. At a dose of 0.25 mg per injection repeated injections every 24 hours will

maintain the effect of cetrorelix.

In animals as well as in humans, the antagonistic hormonal effects of cetrorelix were fully reversible

after termination of treatment.

5.2 Pharmacokinetic properties

The absolute bioavailability of cetrorelix after subcutaneous administration is about 85%.

The total plasma clearance and the renal clearance are 1.2 ml x min -1 x kg -1 and 0.1 ml x min -1 x kg -1 ,

respectively. The volume of distribution (V d ) is 1.1 l x kg -1 . The mean terminal half-lives following

intravenous and subcutaneous administration are about 12 h and 30 h, respectively, demonstrating the

effect of absorption processes at the injection site. The subcutaneous administration of single doses

(0.25 mg to 3 mg cetrorelix) and also daily dosing over 14 days show linear kinetics.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

No target organ toxicity could be observed from acute, subacute and chronic toxicity studies in rats

and dogs following subcutaneous administration of cetrorelix. No signs of medicinal product-related

local irritation or incompatibility were noted in dogs after intravenous, intra-arterial and paravenous

injection when cetrorelix was administered in doses clearly above the intended clinical use in man.

Cetrorelix showed no mutagenic or clastogenic potential in gene and chromosome mutation assays.

5

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder :

Mannitol

Solvent :

Water for injections

6.2 Incompatibilities

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

section 6.6.

6.3 Shelf life

2 years.

The solution should be used immediately after preparation.

6.4 Special precautions for storage

Do not store above 25 °C. Keep the vial(s) in the outer carton in order to protect from light.

6.5 Nature and contents of container

Packs with 1 or 7 Type I glass vials sealed with a rubber stopper.

Additionally for each vial the packs contain:

1 pre-filled syringe (Type I glass cartridge closed with rubber stoppers) with 1 ml solvent for

parenteral use

1 injection needle (20 gauge)

1 hypodermic injection needle (27 gauge)

2 alcohol swabs.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Cetrotide should only be reconstituted with the solvent provided, using a gentle, swirling motion.

Vigorous shaking with bubble formation should be avoided.

The reconstituted solution is without particles and clear. Do not use if the solution contains particles or

if the solution is not clear.

Withdraw the entire contents of the vial. This ensures a delivery to the patient of a dose of at least

0.23 mg cetrorelix.

The solution should be used immediately after reconstitution.

6

7.

MARKETING AUTHORISATION HOLDER

Merck Serono Europe Limited

56 Marsh Wall

London E14 9TP

United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/99/100/001

EU/1/99/100/002

9.

DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 April 1999

Date of first renewal: 15 April 2004

Date of latest renewal: 13 April 2009

10. DATE OF REVISION OF THE TEXT

7

1.

NAME OF THE MEDICINAL PRODUCT

Cetrotide 3 mg powder and solvent for solution for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 3 mg cetrorelix (as acetate). After reconstitution with the solvent provided, each ml

of the solution contains 1 mg cetrorelix.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Appearance of the powder: white lyophilisate

Appearance of the solvent: clear and colourless solution

The pH of the reconstituted solution is 4.0 – 6.0

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Prevention of premature ovulation in patients undergoing a controlled ovarian stimulation, followed

by oocyte pick-up and assisted reproductive techniques.

In clinical trials Cetrotide was used with human menopausal gonadotropin (HMG), however, limited

experience with recombinant follicule-stimulating hormone (FSH) suggested similar efficacy.

4.2 Posology and method of administration

Cetrotide should only be prescribed by a specialist experienced in this field.

The first administration of Cetrotide should be performed under the supervision of a physician and

under conditions where treatment of possible allergic/pseudo-allergic reactions (including life-

threatening anaphylaxis) is immediately available. The following injections may be self-administered

as long as the patient is made aware of the signs and symptoms that may indicate hypersensitivity, the

consequences of such a reaction and the need for immediate medical intervention.

The contents of 1 vial (3 mg cetrorelix) are to be administered on day 7 of ovarian stimulation

(approximately 132 to 144 hours after start of ovarian stimulation) with urinary or recombinant

gonadotropins. Following the first administration, it is advised that the patient be kept under medical

supervision for 30 minutes to ensure there is no allergic/pseudo-allergic reaction to the injection.

If the follicle growth does not allow ovulation induction on the fifth day after injection of Cetrotide

3 mg, additionally 0.25 mg cetrorelix (Cetrotide 0.25 mg) should be administered once daily

beginning 96 hours after the injection of Cetrotide 3 mg until the day of ovulation induction.

Cetrotide is for subcutaneous injection into the lower abdominal wall.

The injection site reactions may be minimised by injecting the product in a slow rate to facilitate the

progressive absorption of the product.

8

Additional information on special populations:

There is no relevant indication for the use of Cetrotide in children or geriatric populations.

For instructions for preparation, see section 6.6.

4.3 Contraindications

• Hypersensitivity to the active substance or any structural analogues of gonadotropin-releasing

hormone (GnRH), extrinsic peptide hormones or to any of the excipients.

• Pregnancy and lactation.

• Postmenopausal women.

• Patients with moderate and severe renal and hepatic impairment.

4.4 Special warnings and precautions for use

Special care should be taken in women with signs and symptoms of active allergic conditions or

known history of allergic predisposition. Treatment with Cetrotide is not advised in women with

severe allergic conditions.

During or following ovarian stimulation an ovarian hyperstimulation syndrome can occur. This event

must be considered as an intrinsic risk of the stimulation procedure with gonadotropins.

An ovarian hyperstimulation syndrome should be treated symptomatically, e.g. with rest, intravenous

electrolytes/colloids and heparin therapy.

Luteal phase support should be given according to the reproductive medical centre´s practice.

There is limited experience up to now with the administration of Cetrotide during a repeated ovarian

stimulation procedure. Therefore Cetrotide should be used in repeated cycles only after a careful

risk/benefit evaluation.

4.5 Interaction with other medicinal products and other forms of interaction

In vitro investigations have shown that interactions are unlikely with medicinal products that are

metabolised by cytochrome P450 or glucuronised or conjugated in some other way. However,

although there has been no evidence of drug-interactions, especially with commonly used medicinal

products, gonadotropins or products that may induce histamine release in susceptible individuals, the

possibility of an interaction cannot be totally excluded.

4.6 Pregnancy and lactation

Cetrotide is not intended to be used during pregnancy and lactation (see section 4.3).

Studies in animals have indicated that cetrorelix exerts a dose related influence on fertility,

reproductive performance and pregnancy. No teratogenic effects occurred when the medicinal product

was administered during the sensitive phase of gestation.

4.7 Effects on ability to drive and use machines

Cetrotide has no or negligible influence on the ability to drive or use machines.

9

4.8 Undesirable effects

The most commonly reported side effects are local injection site reactions such as erythema, swelling

and pruritus that are usually transient in nature and mild in intensity.

Mild to moderate ovarian hyperstimulation syndrome (OHSS) (WHO grade I or II) have been

commonly reported and should be considered as an intrinsic risk of the stimulation procedure.

Inversely, severe OHSS remains uncommon.

Uncommonly, cases of hypersensitivity reactions including pseudo-allergic/anaphylactoid reactions

have been reported.

The adverse reactions reported below are classified according to frequency of occurrence as follows:

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

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Immune system disorders

Uncommon

Systemic allergic/pseudo-

allergic reactions including life-

threatening anaphylaxis.

Nervous system disorders

Uncommon

Headache

Gastrointestinal disorders

Uncommon

Nausea

Reproductive system and breast

disorders

Common

Mild to moderate ovarian

hyperstimulation syndrome

(WHO grade I or II) can occur

which is an intrinsic risk of the

stimulation procedure (see

section 4.4).

Uncommon

Severe ovarian hyperstimulation

syndrome (WHO grade III)

General disorders and

administration site conditions

Common

Local reactions at the injection

site (e.g. erythema, swelling and

pruritus) have been reported.

Usually they were transient in

nature and of mild intensity.

The frequency as reported in

clinical trials was 8.0%.

4.9 Overdose

Overdosage in humans may result in a prolonged duration of action but is unlikely to be associated

with acute toxic effects.

In acute toxicity studies in rodents non-specific toxic symptoms were observed after intraperitoneal

administration of cetrorelix doses more than 200 times higher than the pharmacologically effective

dose after subcutaneous administration.

10

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anti-gonadotropin-releasing hormones, ATC code: H01CC02.

Cetrorelix is a luteinising hormone releasing hormone (LHRH) antagonist. LHRH binds to membrane

receptors on pituitary cells. Cetrorelix competes with the binding of endogenous LHRH to these

receptors. Due to this mode of action, cetrorelix controls the secretion of gonadotropins (LH and

FSH).

Cetrorelix dose-dependently inhibits the secretion of LH and FSH from the pituitary gland. The onset

of suppression is virtually immediate and is maintained by continuous treatment, without initial

stimulatory effect.

In females, cetrorelix delays the LH surge and consequently ovulation. In women undergoing ovarian

stimulation the duration of action of cetrorelix is dose dependent. Following a single dose of 3 mg of

cetrorelix a duration of action of at least 4 days has been evaluated. On day 4 the suppression was

approximately 70%. At a dose of 0.25 mg per injection repeated injections every 24 hours will

maintain the effect of cetrorelix.

In animals as well as in humans, the antagonistic hormonal effects of cetrorelix were fully reversible

after termination of treatment.

5.2 Pharmacokinetic properties

The absolute bioavailability of cetrorelix after subcutaneous administration is about 85%.

The total plasma clearance and the renal clearance are 1.2 ml x min -1 x kg -1 and 0.1 ml x min -1 x kg -1 ,

respectively. The volume of distribution (V d ) is 1.1 l x kg -1 . The mean terminal half-lives following

intravenous and subcutaneous administration are about 12 h and 30 h, respectively, demonstrating the

effect of absorption processes at the injection site. The subcutaneous administration of single doses

(0.25 mg to 3 mg cetrorelix) and also daily dosing over 14 days show linear kinetics.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

No target organ toxicity could be observed from acute, subacute and chronic toxicity studies in rats

and dogs following subcutaneous administration of cetrorelix. No signs of medicinal product-related

local irritation or incompatibility were noted in dogs after intravenous, intra-arterial and paravenous

injection when cetrorelix was administered in doses clearly above the intended clinical use in man.

Cetrorelix showed no mutagenic or clastogenic potential in gene and chromosome mutation assays.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder :

Mannitol

Solvent :

Water for injections

11

6.2 Incompatibilities

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

section 6.6.

6.3 Shelf life

2 years.

The solution should be used immediately after preparation.

6.4 Special precautions for storage

Do not store above 25 °C. Keep the vial in the outer carton in order to protect from light.

6.5 Nature and contents of container

Pack with 1 Type I glass vial sealed with a rubber stopper.

Additionally the pack contains:

1 pre-filled syringe (Type I glass cartridge closed with rubber stoppers) with 3 ml solvent for

parenteral use

1 injection needle (20 gauge)

1 hypodermic injection needle (27 gauge)

2 alcohol swabs.

6.6 Special precautions for disposal and other handling

Cetrotide should only be reconstituted with the solvent provided, using a gentle, swirling motion.

Vigorous shaking with bubble formation should be avoided.

The reconstituted solution is without particles and clear. Do not use if the solution contains particles or

if the solution is not clear.

Withdraw the entire contents of the vial. This ensures a delivery to the patient of a dose of at least

2.82 mg cetrorelix.

The solution should be used immediately after reconstitution.

7.

MARKETING AUTHORISATION HOLDER

Merck Serono Europe Limited

56 Marsh Wall

London E14 9TP

United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/99/100/003

12

9.

DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 April 1999

Date of first renewal: 15 April 2004

Date of latest renewal: 13 April 2009

10. DATE OF REVISION OF THE TEXT

13

ANNEX II

A. MANUFACTURING AUTHORISATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OF THE MARKETING AUTHORISATION

14

A

MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH

RELEASE

Name and address of the manufacturer responsible for batch release

Baxter Oncology GmbH

Kantstraße 2

D-33790 Halle

Germany

Æterna Zentaris GmbH

Weismüllerstraße 50

D-60314 Frankfurt

Germany

The printed package leaflet of the medicinal product must state the name and address of the

manufacturer responsible for the release of the concerned batch.

B

CONDITIONS OF THE MARKETING AUTHORISATION

• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON

THE MARKETING AUTHORISATION HOLDER

Medicinal product subject to medical prescription.

• CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT

Not applicable

• OTHER CONDITIONS

Risk Management Plan

The MAH commits to performing pharmacovigilance activities detailed in version 2.0 (20/11/2008) of

the Risk Management Plan (RMP) presented in Module 1.8.2 of the Marketing Authorisation and any

subsequent updates of the RMP agreed by the CHMP.

As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any

updated RMP should be submitted at the same time as the following Periodic Safety Update Report

(PSUR).

In addition, an updated RMP should be submitted

When new information is received that may impact on the current Safety Specification,

Pharmacovigilance Plan or risk minimisation activities

Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being

reached

At the request of the EMEA

PSURs

PSURs will have to be submitted with a 2-year frequency, until otherwise specified by the CHMP.

15

ANNEX III

LABELLING AND PACKAGE LEAFLET

16

A. LABELLING

17

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

BOX OF 1 VIAL AND 1 PRE-FILLED SYRINGE

1.

NAME OF THE MEDICINAL PRODUCT

Cetrotide 0.25 mg powder and solvent for solution for injection

cetrorelix

2.

STATEMENT OF ACTIVE SUBSTANCE(S)

1 vial with powder contains:

0.25 mg cetrorelix (as acetate).

3.

LIST OF EXCIPIENTS

Excipient: Mannitol.

1 pre-filled syringe with solvent contains: 1 ml water for injections.

4.

PHARMACEUTICAL FORM AND CONTENTS

1 vial with powder for solution for injection.

1 pre-filled syringe with solvent for parenteral use.

Additionally, the pack contains:

1 injection needle (20 gauge)

1 hypodermic injection needle (27 gauge)

2 alcohol swabs.

5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Subcutaneous use.

Read the package leaflet before use

6.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7.

OTHER SPECIAL WARNING(S), IF NECESSARY

8.

EXPIRY DATE

EXP

18

9.

SPECIAL STORAGE CONDITIONS

Do not store above 25 °C. Keep the vial in the outer carton in order to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Serono Europe Limited

56 Marsh Wall

London E14 9TP

United Kingdom

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/100/001

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

cetrotide 0.25 mg

19

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

BOX OF 7 VIALS AND 7 PRE-FILLED SYRINGES

1.

NAME OF THE MEDICINAL PRODUCT

Cetrotide 0.25 mg powder and solvent for solution for injection

cetrorelix

2.

STATEMENT OF ACTIVE SUBSTANCE(S)

1 vial with powder contains:

0.25 mg cetrorelix (as acetate).

3.

LIST OF EXCIPIENTS

Excipient: Mannitol.

1 pre-filled syringe with solvent contains: 1 ml water for injections.

4.

PHARMACEUTICAL FORM AND CONTENTS

7 vials with powder for solution for injection.

7 pre-filled syringes with solvent for parenteral use.

Additionally, the pack contains :

7 injection needle (20 gauge)

7 hypodermic injection needle (27 gauge)

14 alcohol swabs.

5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Subcutaneous use.

Read the package leaflet before use

6.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7.

OTHER SPECIAL WARNING(S), IF NECESSARY

8.

EXPIRY DATE

EXP

20

9.

SPECIAL STORAGE CONDITIONS

Do not store above 25 °C. Keep the vial(s) in the outer carton in order to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Serono Europe Limited

56 Marsh Wall

London E14 9TP

United Kingdom

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/100/002

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

cetrotide 0.25 mg

21

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

CETROTIDE 0.25 MG VIAL LABEL

1.

NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Cetrotide 0.25 mg powder for solution for injection

cetrorelix

Subcutaneous use

2.

METHOD OF ADMINISTRATION

Read the package leaflet before use

3.

EXPIRY DATE

EXP

4.

BATCH NUMBER

Batch

5.

CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

0.25 mg

6.

OTHER

22

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

SOLVENT PRE-FILLED SYRINGE LABEL

1.

NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Solvent for Cetrotide 0.25 mg

Water for injections

2.

METHOD OF ADMINISTRATION

3.

EXPIRY DATE

EXP

4.

BATCH NUMBER

Batch

5.

CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

1 ml

6.

OTHER

23

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

BOX OF 1 VIAL AND 1 PRE-FILLED SYRINGE

1.

NAME OF THE MEDICINAL PRODUCT

Cetrotide 3 mg powder and solvent for solution for injection

cetrorelix

2.

STATEMENT OF ACTIVE SUBSTANCE(S)

1 vial with powder contains:

3 mg cetrorelix (as acetate).

3.

LIST OF EXCIPIENTS

Excipient: Mannitol.

1 pre-filled syringe with solvent contains: 3 ml water for injections.

4.

PHARMACEUTICAL FORM AND CONTENTS

1 vial with powder for solution for injection.

1 pre-filled syringe with solvent for parenteral use.

Additionally, the pack contains:

1 injection needle (20 gauge)

1 hypodermic injection needle (27 gauge)

2 alcohol swabs.

5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Subcutaneous use.

Read the package leaflet before use

6.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7.

OTHER SPECIAL WARNING(S), IF NECESSARY

8.

EXPIRY DATE

EXP

24

9.

SPECIAL STORAGE CONDITIONS

Do not store above 25 °C. Keep the vial in the outer carton in order to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Serono Europe Limited

56 Marsh Wall

London E14 9TP

United Kingdom

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/100/003

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

cetrotide 3 mg

25

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

CETROTIDE 3 MG VIAL LABEL

1.

NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Cetrotide 3 mg powder for solution for injection

cetrorelix

Subcutaneous use

2.

METHOD OF ADMINISTRATION

Read the package leaflet before use

3.

EXPIRY DATE

EXP

4.

BATCH NUMBER

Batch

5.

CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

3 mg

6.

OTHER

26

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

SOLVENT PRE-FILLED SYRINGE LABEL

1.

NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Solvent for Cetrotide 3 mg

Water for injections

2.

METHOD OF ADMINISTRATION

3.

EXPIRY DATE

EXP

4.

BATCH NUMBER

Batch

5.

CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

3 ml

6.

OTHER

27

B. PACKAGE LEAFLET

28

PACKAGE LEAFLET: INFORMATION FOR THE USER

Cetrotide 0.25 mg powder and solvent for solution for injection

Cetrorelix

Read all of this leaflet carefully before you start using this medicine.

-

Keep this leaflet. You may need to read it again.

-

If you have any further questions, ask your doctor or pharmacist.

-

This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even

if their symptoms are the same as yours.

-

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist.

In this leaflet :

1.

What Cetrotide is and what it is used for

3.

How to use Cetrotide

4.

Possible side effects

5

How to store Cetrotide

6.

Further information

1.

WHAT CETROTIDE IS AND WHAT IT IS USED FOR

Cetrotide blocks the receptors of a natural hormone, called luteinising hormone releasing hormone

(LHRH) and thus indirectly the effect of this hormone. LHRH controls the production and release of

another hormone, called luteinising hormone (LH) which stimulates ovulation during the menstrual

cycle.

Cetrotide is used to prevent the premature release of LH and thus, the premature release from the

ovaries of an egg (oocyte) (i.e. premature ovulation) that may be immature. Premature ovulation is

actually undesirable during treatment inducing ovaries to produce more eggs (ovarian stimulation) as

premature release of LH triggers oocytes release before it is possible to collect them (oocyte pick-up)

by a simple procedure for assisted reproductive technologies.

In clinical trials Cetrotide was used with human menopausal gonadotropin (HMG). Limited, post-

marketing experience with another hormone, i.e. recombinant follicle stimulating hormone (FSH)

suggested similar efficacy. HMG and FSH are hormones promoting egg maturation.

2.

BEFORE YOU USE CETROTIDE

Do not use Cetrotide

• if you are allergic (hypersensitive) to cetrorelix acetate, exogenous peptide hormones

(medicines similar to Cetrotide) or any of the other ingredients.

• if you are pregnant or breast-feeding

• if you have already reached your menopause

• if you have a moderate or severe kidney or liver disease.

Take special care with Cetrotide

Special care should be taken in women with an active allergic condition or a known history of allergy.

If you present such a condition, it is important that you inform your doctor.

29

2.

Before you use Cetrotide

During or following hormonal stimulation of the ovaries an ovarian hyperstimulation syndrome can

occur. This event is related to the stimulation procedure with gonadotropins (hormones promoting egg

maturation). For symptoms and suitable measures please refer to the Patient Information Leaflet of the

gonadotropin-containing medicine prescribed for you.

Luteal phase support (a measure to increase the uterus receptivity to embryo implantation and to

support early pregnancy, generally by administering progesterone or human chorionic gonadotropin)

should be given according to the reproductive medical centre’s practice.

Because experience of using Cetrotide during repeated ovarian stimulation procedures is still small,

you should use the medicine in repeated cycles only after your doctor has carefully evaluated the

benefits and risks.

Using other medicines

In vitro investigations have shown that interactions are unlikely with medicines that are degraded by

the liver. However, though there has been no evidence of drug- interactions, especially with

commonly used medicines, gonadotropins or products that may induce histamine release in susceptible

individuals, the possibility of an interaction cannot be totally excluded.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,

including medicines obtained without a prescription.

Pregnancy and breast-feeding

You must not use Cetrotide if you are already pregnant, or suspect that you might be pregnant, or if

you are breast-feeding.

Driving and using machines

The use of Cetrotide is not expected to affect your ability to drive and use machines.

3.

HOW TO USE CETROTIDE

Always use Cetrotide exactly as your doctor has told you. You should check with your doctor if you

are not sure. The following statements apply to Cetrotide unless otherwise prescribed by your doctor.

Please observe these instructions for use, otherwise you will not fully benefit from Cetrotide.

Cetrotide is intended for subcutaneous use, that means given by injection just under the skin. It is for

single use only.

The first injection of Cetrotide should be supervised by your doctor. You can carry out the following

injections yourself as long as your doctor has made you aware of the symptoms that may indicate

allergy and of its consequences (serious, potentially life-threatening allergic reaction, causing

difficulty in breathing or dizziness, may occur and need immediate treatment).

Cetrotide is for injection under the skin of the lower abdominal wall, preferably around the navel. To

minimise local irritation, please select a different injection site each day and inject slowly.

Dissolve Cetrotide powder only with the water contained in the pre-filled syringe. Do not use a

Cetrotide solution if it is not clear or contains particles.

Before you administer Cetrotide yourself, please read the following instructions carefully

1.

Wash your hands. Your hands and all items you use should be as clean as possible.

30

2.

Lay out on a clean surface everything you need (one vial, one pre-filled syringe, one injection

needle with a yellow mark, one injection needle with a grey mark and two alcohol swabs).

3.

Flip off the plastic cover of the vial. Wipe the aluminium ring and the rubber stopper with an

alcohol swab.

4.

Take the injection needle with the yellow mark and remove the wrapping. Take the pre-filled

syringe and remove the cover. Put the needle on the syringe and remove the cover of the needle.

5.

Push the needle through the centre of the rubber stopper of the vial. Inject the water into the vial

by slowly pushing the plunger of the syringe.

6.

Leave the syringe on the vial. Gently agitate the vial until the solution is clear and without

residue. Avoid forming bubbles during dissolution.

7.

Draw the whole contents of the vial into the syringe. If solution is left in the vial, invert the vial,

pull back the needle until the opening of the needle is just inside the stopper. If you look from

the side through the gap in the stopper, you can control the movement of the needle and the

liquid. Make sure that you withdraw the entire contents of the vial.

8.

Detach the syringe from the needle and lay down the syringe. Take the injection needle with the

grey mark and remove its wrapping. Put the needle on the syringe and remove the cover of the

needle.

9.

Invert the syringe and push the plunger until all air bubbles have been expelled. Do not touch

the needle or allow the needle to touch any surface.

10. Choose an injection site at the lower abdominal wall, preferably around the navel. Take the

second alcohol swab and clean the skin at the injection site. Hold the syringe in one hand.

Gently pinch up the skin surrounding the site of injection and hold firmly with the other hand.

11. Hold the syringe as you would hold a pencil, insert the needle completely into the skin at an

angle of about 45 degree.

12. Once the needle has been inserted completely, release your grasp of the skin.

13. Pull back gently the plunger of the syringe. If blood appears continue as described in step 14. If

no blood appears, inject the solution slowly by pushing the plunger gently forward. After all of

the solution is injected, withdraw the needle slowly, applying gentle pressure with the alcohol

swab on the skin where the needle was inserted. Withdraw the needle at the same angle as it was

inserted.

14. If blood appears, withdraw the needle with the syringe and gently apply pressure to the injection

site. Do not use this solution but empty the syringe in a sink. Start again with step 1.

15. Use the syringe and needles only once. Throw away the syringe and needles immediately after

use (put the covers on the needles to avoid injury).

The contents of one vial (0.25 mg cetrorelix) are to be injected once daily, at 24 h intervals, either in

the morning or in the evening.

Administration in the morning: Treatment with Cetrotide should begin on day 5 or 6 of ovarian

stimulation (approximately 96 to 120 hours after start of ovarian stimulation) with urinary or

recombinant gonadotropin(s) and is to be continued throughout the ovarian stimulation treatment

period including the day of ovulation induction.

31

Administration in the evening: Treatment with Cetrotide should begin on day 5 of ovarian stimulation

(approximately 96 to 108 hours after start of ovarian stimulation) with urinary or recombinant

gonadotropin(s) and is to be continued throughout the ovarian stimulation treatment period until the

evening prior to the day of ovulation induction.

If you use more Cetrotide than you should

Overdosage of Cetrotide may result in a prolonged duration of action but is unlikely to be associated

with sudden untoward/damaging effects. Therefore, in case of overdosage no specific measures are

required.

If you forget to take Cetrotide

Do not take a double dose to make up for a forgotten dose, please contact your doctor.

Ideally Cetrotide should be injected at 24 hours intervals. But if you missed giving it at the right time

you can inject this dose at a different time of the same day.

4.

POSSIBLE SIDE EFFECTS

Like all medicines, Cetrotide can cause side effects, although not everybody gets them.

If you experience severe generalised allergic reactions such as difficulty in breathing or dizziness

which could be potentially life-threatening, stop using Cetrotide, contact your doctor immediately or

seek urgent medical attention.

The frequency of possible side effects listed below is defined using the following convention:

very common: affects more than 1 user in 10

common: affects 1 to 10 users in 100

uncommon: affects 1 to 10 users in 1,000

rare:

affects 1 to 10 users in 10,000

very rare:

affects less than 1 user in 10,000

Common:

• Mild and transient reactions may occur at the injection site like reddening, itching, and swelling.

• Mild to moderate ovarian hyperstimulation syndrome (OHSS). Symptoms like abdominal pain,

tension, nausea, vomiting and diarrhoea may indicate an OHSS. If you feel such symptoms,

please inform your doctor immediately.

Uncommon:

• Severe generalised allergic reactions (including serious, potentially life-threatening allergic

reaction which causes difficulty in breathing or dizziness).

• Severe ovarian hyperstimulation syndrome (OHSS). Symptoms may be abdominal pain,

abdominal distension, nausea, vomiting, diarrhoea, weight gain, reduced urine flow and

breathing difficulties. Complications may include blood clotting. If you feel such symptoms,

please inform your doctor immediately.

• Nausea.

• Headache.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please

tell your doctor or pharmacist.

5.

HOW TO STORE CETROTIDE

Keep out of the reach and sight of children.

32

Do not use Cetrotide after the expiry date which is stated on the vial after EXP. The expiry date refers

to the last day of that month.

The Cetrotide powder in the vial and the solvent in the pre-filled syringe have the same expiry date. It

is printed on the labels and on the carton.

Do not store above 25°C.

Keep the vial in the outer carton in order to protect from light.

The solution should be used immediately after preparation.

Do not use Cetrotide if the white pellet in the vial has changed in appearance or if the solvent solution

in the vial is no longer clear and colourless or if it contains particles.

If you have any further questions please consult your doctor or pharmacist.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to

dispose of medicines no longer required. These measures will help to protect the environment.

6.

FURTHER INFORMATION

What Cetrotide contains

Each vial contains 0.25 mg cetrorelix (as acetate).

The other ingredient is mannitol.

The solvent is Water for injections.

What Cetrotide looks like and contents of the pack

Cetrotide is a white powder for solution for injection. It is available in packs of one or seven vials.

Additionally, for each vial the packs contain

• one pre-filled syringe with solvent (water for injections) for parenteral use for dissolving the

powder in the vial

• one injection needle with a yellow mark for injecting the water into the vial and withdrawing

the solution from the vial

• one injection needle with a grey mark for injecting the solution

• two alcohol swabs for cleaning purposes.

Marketing Authorisation Holder

Merck Serono Europe Limited, 56 Marsh Wall, London E14 9TP,United Kingdom

Manufacturer

Baxter Oncology GmBH, Kantstrasse 2, D-33790 Halle, Germany

or

Æterna Zentaris GmbH, Weismüllerstrasse 50, D-60314 Frankfurt, Germany

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder.

33

België/Belgique/Belgien

MERCK NV/SA

Brusselsesteenweg 288

B-3090 Overijse

Tél/Tel: +32-2-686 07 11

Luxembourg/Luxemburg

MERCK NV/SA

Brusselsesteenweg 288

B-3090 Overijse, Belgique/Belgien

Tél/Tel: +32-2-686 07 11

България

Мерк България" ЕАД

Бул. Проф. Цветан Лазаров“ 83

София 1582

България

Teл: +359 28075 111

Magyarország

Merck Kft.

Bocskai út 134-146.

H-1113 Budapest

Tel: +36-1-463-8100

Česká republika

Merck spol.s.r.o

Na Hrebenech II. 1718/10

CZ-140 00 Praha 4

Tel. +420 272084211

Malta

Cherubino Ltd

Delf Building

Sliema Road

MT-GZR 06 Gzira Malta

Tel: +356-21-343270/1/2/3/4

Danmark

E. Merck AB

Strandvejen 102 B, 4th

DK-2900 Hellerup

Tlf: +45 35253550

Nederland

Merck BV

Tupolevlaan 41-61

NL-1119 NW Schiphol-Rijk

Tel: +31-20-6582800

Deutschland

Merck Serono GmbH

Alsfelder Straße 17

D-64289 Darmstadt

Tel: +49-6151-6285-0

Norge

Merck Serono Norge

Luhrtoppen 2

N-1470 Lørenskog

Tlf: +47 67 90 35 90

Eesti

Merck Serono OÜ

Ahtri 12,

EE-10151, Tallinn

Tel: +372 6116220

Österreich

Merck GesmbH.

Zimbagasse 5

A-1147 Wien

Tel: +43 1 57600-0

Ελλάδα

Merck A.E.

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GR-151 23 Μαρούσι

Αθήνα

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Merck Sp. z o.o.

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Tel.: +48 22 53 59 700

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Merck S.L.

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Línea de Información: 900 200 400

Tel: +34-91-745 44 00

Portugal

Merck, s.a.

Rua Alfredo da Silva, 3-C

P-1300-040 Lisboa

Tel: +351-21-361 35 00

34

France

Merck Serono s.a.s.

37, rue Saint-Romain

F-69379 Lyon cedex 08

Tél.: +33-4-72 78 25 25

Numéro vert : 0 800 888 024

România

MERCK d.o.o.,

Dunajska cesta 119

SI-1000 Lubliana, Slovenia

Tel: +386 1 560 3 800

Ireland

Merck Serono Ltd

Bedfont Cross, Stanwell Road

Feltham, Middlesex TW14 8NX

United Kingdom

Tel: +44-20 8818 7200

Slovenija

MERCK d.o.o.

Dunajska cesta 119

SI-1000 Ljubljana

Tel: +386 1 560 3 800

Ísland

Icepharma hf

Lynghálsi 13

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Tel: + 354 540 8000

Slovenská republika

Merck spol. s r.o.

Tuhovská 3

SK-831 06 Bratislava

Tel: + 421 2 49 267 111

Italia

Merck Serono S.p.A.

Via Casilina 125

I-00176 Roma

Tel: +39-06-70 38 41

Suomi / Finland

Merck Oy

Pihatörmä 1 C

FIN-02240 Espoo

Puh/Tel: +358-9-8678 700

Κύπρος

Χρ. Γ. Παπαλοϊζου Λτδ

Λεωφόρος Κιλκίς 35,

CY-2234 Λατσιά, Λευκωσία

Τηλ.: +357 22490305

Sverige

E. Merck AB

S-195 87 Stockholm

Tel: +46-8-562 445 00

Latvija

Merck Serono SIA

Duntes iela 23A

LV-1005, Rīga

Tel: +371 67152500

United Kingdom

Merck Serono Ltd

Bedfont Cross, Stanwell Road

Feltham, Middlesex TW14 8NX - UK

Tel: +44-20 8818 7200

Lietuva

Merck Serono UAB

Savanoriu pr. 192,

LT-44151 Kaunas

Tel: +370 37320603

This leaflet was last approved in

35