GONAL-F

PRE-FILLED PEN 300 IU - 450 IU - 900 IU

900 IU - 450 IU - 300 IU

900 IU - 450 IU - 300 IU

Injection instuctions

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INJECTION INSTRUCTIONS

GONAL-f® Instructions for Use

1.

How to use the GONAL-f pre-filled pen

2.

How to use the GONAL-f pre-filled pen Treatment diary

3.

Before you start using your GONAL-f pre-filled pen

4.

Getting your GONAL-f pre-filled pen ready for injection

5.

Setting the dose prescribed by your doctor

6.

Injecting the dose

7.

After the injection

8.

GONAL-f pre-filled pen Treatment diary (see table at the end)

NOTE: Please read these instructions for use before using your GONAL-f pre-filled pen. Be sure to follow the

instructions precisely, as it may differ from your past experience.

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ENGLISH

1. How to use the GONAL-f pre-filled pen

Do not share the pen with others. The pen is for subcutaneous injection only.

The numbers on the Dose Feedback Window are measured in International Units or IUs. Your doctor will

have told you how many IUs to inject each day.

The numbers displayed in the Dose Feedback Window help you to:

a. Dial the prescribed dose

b. Verify a complete injection

c. Read the dose remaining to be injected with another pen

Give yourself the injection at the same time each day. For example:

Your doctor or pharmacist will tell you how many GONAL-f pens you will need to complete your treatment.

7:00 am

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2. How to use the GONAL-f pre-filled pen Treatment diary

A treatment diary is included on the last page of these instructions for use.

Use the treatment diary to record the amount of IUs injected each time.

Record the treatment day number (1), date (2) and time (3) of injection

In the first line of the table the content of the pen is already recorded for you (4). Circle the dose

prescribed by the doctor.

Record your prescribed dose in the ‘’Prescribed Dose’’ section (5)

Verify you dialed the right dose before injecting (6)

After the injection, read the number shown in the Dose Feedback Window

Confirm you received a complete injection (7) or record the number shown in the Dose Feedback

Window if other than ‘’0’’ (8)

When needed, inject yourself using a second pen, dialing the remaining dose written in the ‘’Amount

Displayed After Injection’’ section (8)

Record this remaining dose in the ”Amount Set to Inject’’ section in the next row (6)

NOTE:

Using the treatment diary to record your daily injections allows you to verify every day that

you received the full prescribed dose.

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ENGLISH

Examples of a treatment diary of pens of different dosages:

GONAL-f 300 IU pen

1

Treatment

day

number

2

Date

3

Time

4

Pen Content

(IU)

300 IU

5

Prescribed

Dose

(IU)

6

7

8

Dose Feedback Window

Amount Set

to Inject

Amount Displayed After Injection

1

10 / 06

07 : 00

300 IU

125

125

if "0",

injection complete

if not "0",

inject this amount ..........using new pen

2

11 / 06

07 : 00

175 IU

125

125

if “0”,

injection complete

if not “0”,

inject this amount ..........using new pen

3

12 / 06

07 : 00

50 IU

125

125

if “0”,

injection complete

if not “0”,

inject this amount ..........using new pen

3

12 / 06

07 : 00

300 IU

Not applicable

75

if “0”,

injection complete

if not “0”,

inject this amount ..........using new pen

75

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GO

f

GONAL-f 450 IU pen

1

Treatment

day

number

2

Date

3

Time

4

Pen Content

(IU)

450 IU

5

Prescribed

Dose

(IU)

6

7

8

Dose Feedback Window

Amount Set

to Inject

Amount Displayed After Injection

1

10 / 06

07 : 00

450 IU

175

175

if “0”,

injection complete

if not "0",

inject this amount ..........using new pen

2

11 / 06

07 : 00

275 IU

175

175

if “0”,

injection complete

if not “0”,

inject this amount ..........using new pen

3

12 / 06

07 : 00

100 IU

175

175

if “0”,

injection complete

if not “0”,

inject this amount ........................using new pen

3

12 / 06

07 : 00

450 IU

Not applicable

75

if “0”,

injection complete

if not “0”,

inject this amount ..........using new pen

75

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ENGLISH

GONAL-f 900 IU pen

1

Treatment

day

number

2

Date

3

Time

4

Pen Content

(IU)

900 IU

5

Prescribed

Dose

(IU)

6

7

8

Dose Feedback Window

Amount Set

to Inject

Amount Displayed After Injection

1

10 / 06

07 : 00

900 IU

350

350

if "0",

injection complete

if not "0",

inject this amount ..........using new pen

2

11 / 06

07 : 00

550 IU

350

350

if “0”,

injection complete

if not “0”,

inject this amount ..........using new pen

3

12 / 06

07 : 00

200 IU

350

350

if "0",

injection complete

if not “0”,

inject this amount ........................using new pen

3

12 / 06

07 : 00

900 IU

Not applicable

150

if “0”,

injection complete

if not “0”,

inject this amount ..........using new pen

150

Note: The 300 IU pen maximum dose setting is 300 IU, with a 450 IU pen is 450 IU and with a 900 IU pen is 450 IU.

3. Before you start using your GONAL-f pre-filled pen

Wash your hands with soap and water

Find a clean area and a flat surface

Verify the expiration date on the pen label

Gather everything you need and lay it out in front of you

Below is a diagram of what the pen and its parts look like:

Lot:

123456

EXP:

JUL 2019

L19Y0003A

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Dose setting knob

Dose Feedback Window

Plunger piston

Reservoir holder

Threaded needle connector

Pen cap

Peel-off seal tab

Removable needle

Inner needle shield

Outer needle cap

Alcohol swabs

Sharps disposal container

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4.

Getting your GONAL-f pre-filled pen ready for injection

4.1. Take off the pen cap.

4.2. Verify that the Dose Feedback Window is set to ‘’0’’.

f

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4.3. Prepare your needle for injection.

Take a new needle - only use the

“single-use” needles supplied for a

GONAL-f pre-filled pen.

Hold the outer needle cap firmly.

Check that the peel-off seal tab on the

outer needle cap is not damaged or

loose.

Remove the peel-off seal tab.

CAUTION:

If the peel-off seal tab is damaged or loose, do not use the needle. Throw it away in a sharps disposal

container. Use a new needle.

Example of

a bad seal

Example of

a good seal

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4.4. Attach the needle.

Screw the threaded needle connector of the pen into the outer needle cap until you feel light

resistance.

Warning:

Do not attach the needle too tightly; it may make it difficult to remove after the injection.

Remove the outer needle cap by pulling it gently. Put it aside for later use.

Hold the GONAL-f pre-filled pen with the needle pointing upward.

Gently remove the green inner needle shield and discard in a disposal

collection container.

f

f

f fl

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4.5. Look closely at the tip of the needle for a tiny drop of fluid.

If you see a tiny drop of fluid, proceed to Section 5: Setting

the dose prescribed by your doctor.

Warning:

Checking for a drop is ONLY done the FIRST TIME you

use a new GONAL-f pen to remove air bubbles.

CAUTION:

If you do not see a tiny drop at or near the needle tip the first time you use a new pen, you must perform

the following steps.

If you do not see a tiny drop of fluid at or near the needle tip the first time you use a new pen:

Gently turn the dose setting knob clockwise until it reads 25 in the Dose Feedback Window. You can

turn the dose setting knob backwards if you turned it past 25.

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ENGLISH

Hold the pen with the needle pointing upward.

Tap the reservoir holder gently.

Press the dose setting knob as far as it will go. A tiny drop of fluid will appear at the tip of the needle.

Verify that the number ‘’0’’ appears in the Dose Feedback Window.

Proceed to Section 5: Setting the dose prescribed by your doctor.

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5.

Setting the dose prescribed by your doctor

5.1. Your GONAL-f pen can have the following doses:

A GONAL-f pen containing 300 IU follitropin alfa. The maximum dose setting is 300 IU.

The smallest dose setting is 12.5 IU. OR

A GONAL-f pen containing 450 IU follitropin alfa. The maximum dose setting is 450 IU.

The smallest dose setting is 12.5 IU. OR

A GONAL-f pen containing 900 IU follitropin alfa. The maximum dose setting is 450 IU.

The smallest dose setting is 12.5 IU.

5.2. Turn the dose setting knob until the desired dose shows in the Dose Feedback Window.

Turn the dose setting knob forward to dial up

the desired dose

Turn the dose setting knob backward to correct

the dose

S

(f

fi

)

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ENGLISH

5.3. Set the dose that was prescribed by your doctor (for example, in the figure below, the dose is 50 IU).

Warning:

Check that the Dose Feedback Window displays your complete prescribed dose before you

move on to the next step.

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6. Injecting the dose

6.1. Choose the injection area - as your doctor or nurse has explained to you.

To minimize skin irritation, select a different injection area each day.

6.2. Clean the skin with an alcohol swab.

6.3. Verify once more that the Dose Feedback Window displays the

correct dose.

6.4. Inject the dose as you were trained to do by your doctor or nurse.

Slowly push the needle into the skin entirely (1).

Press the dose setting knob down as far as it will go and

keep the needle in the skin until the injection is complete.

Injection area

Push the needle

into the skin

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ENGLISH

Hold the dose setting knob down for a minimum of

5 seconds (s) to ensure you inject the full dose (2). The

larger the dose, the longer it will take to inject.

The dose number shown in the Dose Feedback Window will

turn back to 0.

After a minimum of 5 seconds, pull the needle out of the

skin while keeping the dose setting knob pressed down (3).

Release the dose setting knob.

Warning:

Always make sure to use a new needle for each

injection.

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7. After the injection

7.1. Verify you have given a complete injection.

Check that the Dose Feedback Window shows “0”.

Warning:

If the Dose Feedback Window shows a number higher than 0, this means that the GONAL-f

pre-filled pen is empty and that you have not received your full prescribed dose.

C

(

)

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ENGLISH

7.2. Complete a partial injection (only when needed).

The Dose Feedback Window will display the amount you still need to inject using a new pen.

Repeat Section 3 (“Before you start using your GONAL-f pre-filled pen“) and Section 4 (“Getting

your GONAL-f pre-filled pen ready for injection“) with the new pen.

Set the dose to the missing amount you recorded in the treatment diary or to the number still

displayed in the Dose Feedback Window on your previous pen, and inject.

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7.3. Removing the needle after each injection.

Place the outer needle cap on a flat surface.

Hold the GONAL-f pre-filled pen firmly with one hand, and slip the needle

into the outer needle cap.

Continue by pushing the capped needle against a firm surface until you hear a

“click”.

Grip the outer needle cap and

unscrew the needle by turning

anticlockwise. Dispose of the

needle into a sharps disposal

container.

click

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ENGLISH

Never reuse the same used needle. Never share needles.

Recap the pen.

7.4. Storing the GONAL-f pre-filled pen.

CAUTION:

Never store the pen with the needle attached. Always remove the needle from the GONAL-f pre-filled

pen before recapping the pen.

Store the pen in its original packaging in a safe place.

When the pen is empty, ask your pharmacist how to dispose of it.

Warning:

Medicine should not be disposed of via wastewater or household waste.

8. GONAL-f pre-filled pen Treatment diary

1

Treatment

day

number

2

Date

3

Time

4

Pen Content IU

300 IU

450 IU

900 IU

5

Prescribed

Dose

(IU)

6

7

8

Dose Feedback Window

Amount Set

to Inject

Amount Displayed After Injection

/

:

300/450/900 IU

if "0",

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if “0”,

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if "0",

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if “0”,

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

if "0",

if not “0”,

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ENGLISH

injection complete

inject this amount ................ using new pen

/

:

_________ IU

if "0",

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if “0”,

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if "0",

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if “0”,

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if "0",

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if “0”,

injection complete

if not “0”,

inject this amount ................ using new pen

1

Treatment

day

number

2

Date

3

Time

4

Pen Content IU

300 IU

450 IU

900 IU

5

Prescribed

Dose

(IU)

6

7

8

Dose Feedback Window

Amount Set

to Inject

Amount Displayed After Injection

/

:

_________ IU

if "0",

injection complete

if not "0",

inject this amount ................ using new pen

/

:

_________ IU

if "0",

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if "0",

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if "0",

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

if "0",

if not "0",

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ENGLISH

injection complete

inject this amount ................ using new pen

/

:

_________ IU

if "0",

injection complete

if not "0",

inject this amount ................ using new pen

/

:

_________ IU

if "0",

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if "0",

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if "0",

injection complete

if not “0”,

inject this amount ................ using new pen

/

:

_________ IU

if "0",

injection complete

if not “0”,

inject this amount ................ using new pen

Note: The maximum dose you can set with the 300 IU pen is 300 IU, with the 450 IU pen is 450 IU and with

the 900 IU pen is 450 IU.

Instructions for use were approved by the Ministry of Health in February 2016

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7:00 am

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300 IU

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450 IU

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900 IU

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Lot:

123456

EXP:

JUL 2019

L19Y0003A

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1

2

3

4

300 IU

450 IU

900 IU

5

6

7

8

/

:

300/450/900 IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

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/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

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1

2

3

4

300 IU

450 IU

900 IU

5

6

7

8

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

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/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

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7:00 am

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300 IU

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450 IU

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900 IU

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Lot:

123456

EXP:

JUL 2019

L19Y0003A

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1

2

3

4

300 IU

450 IU

900 IU

5

6

7

8

/

:

300/450/900 IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

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/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

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1

2

3

4

300 IU

450 IU

900 IU

5

6

7

8

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

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/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

/

:

_________ IU

N19Z1608A

PRE-FILLED PEN 300 IU - 450 IU - 900 IU

900 IU - 450 IU - 300 IU

900 IU - 450 IU - 300 IU

Prescribing Information

GONAL

®

F

1.

NAME OF THE MEDICINAL PRODUCT

GONAL-f 300 IU/0.5 mL (22 micrograms/0.5 mL) solution for injection in a pre-filled pen.

GONAL-f 450 IU/0.75 mL (33 micrograms/0.75 mL) solution for injection in a pre-filled pen.

GONAL-f 900 IU/1.5 mL (66 micrograms/1.5 mL) solution for injection in a pre-filled pen.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of solution contains 600 IU of follitropin alfa*, (equivalent to 44 micrograms).

Each pre-filled multidose pen delivers 300 IU (equivalent to 22 micrograms) in 0.5 mL.

Each pre-filled multidose pen delivers 450 IU (equivalent to 33 micrograms) in 0.75 mL.

Each pre-filled multidose pen delivers 900 IU (equivalent to 66 micrograms) in 1.5 mL.

* Recombinant human follicle stimulating hormone (r-hFSH) produced in Chinese Hamster Ovary (CHO)

cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection in a pre-filled pen.

Clear colourless solution.

The pH of the solution is 6.7 - 7.3.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

In adult women

Anovulation (including polycystic ovarian syndrome) in women who have been unresponsive to treatment

with clomiphene citrate.

Stimulation of multifollicular development in patients undergoing superovulation for assisted reproductive

technologies (ART) such as

in vitro

fertilization (IVF), gamete intra-fallopian transfer (GIFT) and

zygote

intra-fallopian transfer (ZIFT).

GONAL-f in association with a luteinising hormone (LH) preparation is recommended for the stimulation

of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients

were defined by an endogenous serum LH level < 1.2 IU/L

In adult men

GONAL-f is indicated for the stimulation of spermatogenesis in men who have congenital or acquired

hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotrophin (hCG) therapy.

4.2

Posology and method of administration

Treatment with GONAL-f should be initiated under the supervision of a physician experienced in the

treatment of fertility disorders.

Patients must be provided with the correct number of pens for their treatment course and educated to use the

proper injection techniques.

Posology

The dose recommendations given for GONAL-f are those in use for urinary FSH. Clinical assessment of

GONAL-f indicates that its daily doses, regimens of administration, and treatment monitoring procedures

should not be different from those currently used for urinary FSH-containing medicinal products. It is advised

to adhere to the recommended starting doses indicated below.

Comparative clinical studies have shown that on average patients require a lower cumulative dose and shorter

treatment duration with GONAL-f compared with urinary FSH. Therefore, it is considered appropriate to give

a lower total dose of GONAL-f than generally used for urinary FSH, not only in order to optimise follicular

development but also to minimise the risk of unwanted ovarian hyperstimulation. See section 5.1.

Bioequivalence has been demonstrated between equivalent doses of the monodose presentation and the

multidose presentation of GONAL-f.

Women with anovulation (including polycystic ovarian syndrome

GONAL-f may be given as a course of daily injections. In menstruating women treatment should commence

within the first 7 days of the menstrual cycle.

A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU

at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. Treatment

should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound

and/or oestrogen secretion. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to

respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should undergo

further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned

cycle.

When an optimal response is obtained, a single injection of 250 micrograms recombinant human

choriogonadotropin alfa (r-hCG) or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after

the last GONAL-f injection. The patient is recommended to have coitus on the day of, and the day following,

hCG administration. Alternatively intrauterine insemination (IUI) may be performed.

If an excessive response is obtained, treatment should be stopped and hCG withheld (see section 4.4).

Treatment should recommence in the next cycle at a dose lower than that of the previous cycle.

Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or

other assisted reproductive technologies.

A commonly used regimen for superovulation involves the administration of 150-225 IU of GONAL-f daily,

commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has

been achieved (as assessed by monitoring of serum oestrogen concentrations and/or ultrasound examination),

with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general

adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days).

A single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24-48 hours

after the last GONAL-f injection to induce final follicular maturation.

Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly

used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used

protocol, GONAL-f is started approximately 2 weeks after the start of agonist treatment, both being continued

until adequate follicular development is achieved. For example, following two weeks of treatment with an

agonist, 150-225 IU GONAL-f are administered for the first 7 days. The dose is then adjusted according to the

ovarian response.

Overall experience with IVF indicates that in general the treatment success rate remains stable during the first

four attempts and gradually declines thereafter.

Women with anovulation resulting from severe LH and FSH deficiency:

In LH and FSH deficient women (hypogonadotrophic hypogonadism), the objective of GONAL-f therapy in

association with lutropin alfa is to develop a single mature Graafian follicle from which the oocyte will be

liberated after the administration of human chorionic gonadotrophin (hCG). GONAL-f should be given as a

course of daily injections simultaneously with lutropin alfa. Since these patients are amenorrhoeic and have

low endogenous oestrogen secretion, treatment can commence at any time.

A recommended regimen commences at 75 IU of lutropin alfa daily with 75-150 IU FSH. Treatment should

be tailored to the individual patient’s response as assessed by measuring follicle size by ultrasound and

oestrogen response.

If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals

and preferably by 37.5-75 IU increments. It may be acceptable to extend the duration of stimulation in any

one cycle to up to 5 weeks.

When an optimal response is obtained, a single injection of 250 micrograms r-hCG or 5,000 IU up to

10,000 IU hCG should be administered 24-48 hours after the last GONAL-f and lutropin alfa injections. The

patient is recommended to have coitus on the day of, and on the day following, hCG administration.

Alternatively, intrauterine insemination (IUI) may be performed.

Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after

ovulation may lead to premature failure of the corpus luteum.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should

recommence in the next cycle at a dose of FSH lower than that of the previous cycle.

Men with hypogonadotrophic hypogonadism

GONAL-f should be given at a dosage of 150 IU three times a week, concomitantly with hCG, for a minimum

of 4 months. If after this period, the patient has not responded, the combination treatment may be continued;

current clinical experience indicates that treatment for at least 18 months may be necessary to achieve

spermatogenesis.

Special population

Elderly population

There is no relevant use of GONAL-f in the elderly population. Safety and effectiveness of GONAL-f in

elderly patients have not been established.

Renal or hepatic impairment

Safety, efficacy and pharmacokinetics of GONAL-f in patients with renal or hepatic impairment have not

been established.

Paediatric population

There is no relevant use of GONAL-f in the paediatric population.

Method of administration

GONAL-f is intended for subcutaneous use. The first injection of GONAL-f should be performed under direct

medical supervision. Self-administration of GONAL-f should only be performed by patients who are well

motivated, adequately trained and have access to expert advice.

As GONAL-f pre-filled pen with multidose cartridge is intended for several injections, clear instructions

should be provided to the patients to avoid misuse of the multidose presentation.

For instructions on the administration with the pre-filled pen, see section 6.6 and the "Injection Instructions".

4.3

Contraindications

hypersensitivity to the active substance or to any of the excipients listed in section 6.1

tumours of the hypothalamus or pituitary gland

ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome

gynaecological haemorrhages of unknown aetiology

ovarian, uterine or mammary carcinoma

GONAL-f must not be used when an effective response cannot be obtained, such as:

primary ovarian failure

malformations of sexual organs incompatible with pregnancy

fibroid tumours of the uterus incompatible with pregnancy

primary testicular insufficiency

4.4

Special warnings and precautions for use

GONAL-f is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and

should only be used by physicians who are thoroughly familiar with infertility problems and their

management.

Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals,

as well as the availability of appropriate monitoring facilities. In women, safe and effective use of GONAL-f

calls for monitoring of ovarian response with ultrasound, alone or preferably in combination with

measurement of serum oestradiol levels, on a regular basis. There may be a degree of inter-patient variability

in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in

others. The lowest effective dose in relation to the treatment objective should be used in both men and

women.

Porphyria

Patients with porphyria or a family history of porphyria should be closely monitored during treatment with

GONAL-f. Deterioration or a first appearance of this condition may require cessation of treatment.

Treatment in women

Before starting treatment, the couple's infertility should be assessed as appropriate and putative

contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism,

adrenocortical deficiency, hyperprolactinemia and appropriate specific treatment given.

Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or for

ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to the

recommended GONAL-f dose and regimen of administration, and careful monitoring of therapy will minimise

the incidence of such events. For accurate interpretation of the indices of follicle development and maturation,

the physician should be experienced in the interpretation of the relevant tests.

In clinical trials, an increase of the ovarian sensitivity to GONAL-f was shown when administered with

lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day

intervals and preferably with 37.5-75 IU increments.

No direct comparison of GONAL-f/LH versus human menopausal gonadotropin (hMG) has been performed.

Comparison with historical data suggests that the ovulation rate obtained with GONAL-f/LH is similar to that

obtained with hMG.

Ovarian Hyperstimulation Syndrome (OHSS)

A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more

commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment.

In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with

increasing degree of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an

increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and,

rarely, in the pericardial cavities.

The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal

distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms

including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration,

electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress.

Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as

pulmonary embolism, ischemic stroke or myocardial infarction.

Independent risk factors for developing OHSS include polycystic ovarian syndrome high absolute or rapidly

rising serum oestradiol levels (e.g. > 900 pg/mL or > 3,300 pmol/L in anovulation; > 3,000 pg/mL or

> 11,000 pmol/L in ART) and large number of developing ovarian follicles (e.g. > 3 follicles of ≥ 14 mm in

diameter in anovulation; ≥ 20 follicles of ≥ 12 mm in diameter in ART).

Adherence to recommended GONAL-f dose, regimen of administration can minimise the risk of ovarian

hyperstimulation (see sections 4.2 and 4.8). Monitoring of stimulation cycles by ultrasound scans as well as

oestradiol measurements are recommended to early identify risk factors.

There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be

more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur

such as serum oestradiol level > 5,500 pg/mL or > 20,200 pmol/L and/or ≥ 40 follicles in total, it is

recommended that hCG be withheld and the patient be advised to refrain from coitus or to use barrier

contraceptive methods for at least 4 days. OHSS may progress rapidly (within 24 hours) or over several days

to become a serious medical event. It most often occurs after hormonal treatment has been discontinued and

reaches its maximum at about seven to ten days following treatment. Therefore patients should be followed

for at least two weeks after hCG administration.

In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.

Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that

gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy

be started.

Multiple pregnancy

In patients undergoing ovulation induction, the incidence of multiple pregnancy is increased compared with

natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high

order, carries an increased risk of adverse maternal and perinatal outcomes.

To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.

In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of

embryos replaced, their quality and the patient age.

The patients should be advised of the potential risk of multiple births before starting treatment.

Pregnancy loss

The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of

follicular growth for ovulation induction or ART than following natural conception.

Ectopic pregnancy

Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy is obtained by

spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after ART, was

reported to be higher than in the general population.

Reproductive system neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in

women who have undergone multiple treatment regimens for infertility treatment. It is not yet established

whether or not treatment with gonadotropins increases the risk of these tumours in infertile women.

Congenital malformation

The prevalence of congenital malformations after ART may be slightly higher than after spontaneous

conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm

characteristics) and multiple pregnancies.

Thromboembolic events

In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors

for thromboembolic events, such as personal or family history, treatment with gonadotropins may further

increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin

administration need to be weighed against the risks. It should be noted however that pregnancy itself as well

as OHSS also carry an increased risk of thromboembolic events.

Treatment in men

Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to

GONAL-f/hCG therapy. GONAL-f should not be used when an effective response cannot be obtained.

Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of

the response.

Sodium & Sucrose content

GONAL-f contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

GONAL-f contains Sucrose 60 mg per ml.

4.5

Interaction with other medicinal products and other forms of interaction

Concomitant use of GONAL-f with other medicinal products used to stimulate ovulation (e.g. hCG,

clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or

antagonist to induce pituitary desensitisation may increase the dose of GONAL-f needed to elicit an adequate

ovarian response. No other clinically significant medicinal products interaction has been reported during

GONAL-f therapy.

4.6

Fertility, pregnancy and lactation

Pregnancy

There is no indication for use of GONAL-f during pregnancy. Data on a limited number of exposed

pregnancies (less than 300 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of

follitropin alfa.

No teratogenic effect has been observed in animal studies (see section 5.3). In case of exposure during

pregnancy, clinical data are not sufficient to exclude a teratogenic effect of GONAL-f.

Breast

-feeding

GONAL-f is not indicated during breast-feeding.

Fertility

GONAL-f is indicated for use in infertility (see section 4.1).

4.7

Effects on ability to drive and use machines

GONAL-f is expected to have no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions are headache, ovarian cysts and local injection site reactions

(e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection).

Mild or moderate ovarian hyperstimulation syndrome (OHSS) has been commonly reported and should be

considered as an intrinsic risk of the stimulation procedure. Severe OHSS is uncommon (see section 4.4).

Thromboembolism may occur very rarely (see section 4.4).

List of adverse reactions

The following definitions apply to the frequency terminology used hereafter: 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).

Treatment in women

Immune system disorders

Very rare:

Mild to severe hypersensitivity reactions including anaphylactic reactions and shock

Nervous system disorders

Very common:

Headache

Vascular disorders

Very rare:

Thromboembolism (both in association with and separate from OHSS)

Respiratory, thoracic and mediastinal disorders

Very rare:

Exacerbation or aggravation of asthma

Gastrointestinal disorders

Common:

Abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea

Reproductive system and breast disorders

Very common:

Ovarian cysts

Common:

Mild or moderate OHSS (including associated symptomatology)

Uncommon:

Severe OHSS (including associated symptomatology) (see section 4.4)

Rare:

Complication of severe OHSS

General disorders and administration site conditions

Very common:

Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site

of injection)

Treatment in men

Immune system disorders

Very rare:

Mild to severe hypersensitivity reactions including anaphylactic reactions and shock

Respiratory, thoracic and mediastinal disorders

Very rare:

Exacerbation or aggravation of asthma

Skin and subcutaneous tissue disorders

Common:

Acne

Reproductive system and breast disorders

Common:

Gynaecomastia, Varicocele

General disorders and administration site conditions

Very common:

Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site

of injection)

Investigations

Common:

Weight gain

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. 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.gov.il

4.9

Overdose

The effects of an overdose of GONAL-f are unknown, nevertheless, there is a possibility that OHSS may

occur (see section 4.4).

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins,

ATC code: G03GA05.

In women, the most important effect resulting from parenteral administration of FSH is the development of

mature Graafian follicles. In women with anovulation, the object of GONAL-f therapy is to develop a single

mature Graafian follicle from which the ovum will be liberated after the administration of hCG.

Clinical efficacy and safety in women

In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level

<1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are

variations between LH measurements performed in different laboratories.

In clinical studies comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table below) and in

ovulation induction, GONAL-f was more potent than urinary FSH in terms of a lower total dose and a shorter

treatment period needed to trigger follicular maturation.

In ART, GONAL-f at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher

number of oocytes retrieved when compared to urinary FSH.

Table: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of

GONAL-f with urinary FSH in assisted reproduction technologies)

GONAL-f

(n = 130)

urinary FSH

(n = 116)

Number of oocytes retrieved

11.0 ± 5.9

8.8 ± 4.8

Days of FSH stimulation required

11.7 ± 1.9

14.5 ± 3.3

Total dose of FSH required (number

of FSH 75 IU ampoules)

27.6 ± 10.2

40.7 ± 13.6

Need to increase the dose (%)

56.2

85.3

Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed.

Clinical efficacy and safety in men

In men deficient in FSH, GONAL-f administered concomitantly with hCG for at least 4 months induces

spermatogenesis.

5.2

Pharmacokinetic properties

Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an

initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The

steady state volume of distribution and total clearance are 10 l and 0.6 l/h, respectively. One-eighth of the

follitropin alfa

dose is excreted in the urine.

Following subcutaneous administration, the absolute bioavailability is about 70%. Following repeated

administration, follitropin alfa accumulates 3-fold achieving a

steady-state within 3-4 days. In women whose

endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively

stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.

5.3

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated

dose toxicity and genotoxicity additional to that already stated in other sections of this Prescribing

Information.

Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa

40 IU/kg/day) for extended periods, through reduced fecundity.

Given in high doses (

5 IU/kg/day) follitropin alfa caused a decrease in the number of viable foetuses

without being a teratogen, and dystocia similar to that observed with urinary Menopausal Gonadotropin

(hMG). However, since GONAL-f is not indicated in pregnancy, these data are of limited clinical relevance.

6.

PHARMACEUTICAL PARTICULARS

6.1

list of excipients

Poloxamer 188

Sucrose

Methionine

Sodium dihydrogen phosphate monohydrate

Disodium phosphate dihydrate

m-Cresol

O-Phosphoric acid, 85 %

Sodium hydroxide

Water for injections

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years.

Once opened, the medicinal product may be stored for a maximum of 28 days at or below 25°C. The patient

should write on the GONAL-f pre-filled pen the day of the first use.

6.4

Special precautions for storage

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

Before opening and within its shelf life, the medicinal product may be removed from the refrigerator, without

being refrigerated again, for up to 3 months at or below 25°C. The product must be discarded if it has not been

used after 3 months.

Store in the original package, in order to protect from light.

For in-use storage conditions, see section 6.3.

6.5

Nature and content of container

GONAL-f 300 IU/0.5 mL (22 micrograms/0.5 mL):

mL of solution for injection in 3 mL cartridge (type I glass), with a plunger stopper (halobutyl rubber) and

an aluminum crimp cap with a black rubber inlay.

Pack of one pre filled pen and 8 needles to be used with the pen for administration.

GONAL-f 450 IU/0.75 mL (33 micrograms/0.75 mL):

0.75 mL of solution for injection in 3 mL cartridge (Type I glass), with a plunger stopper (halobutyl rubber)

and an aluminium crimp cap with a black rubber inlay.

Pack of one pre filled pen and 12 needles to be used with the pen for administration.

GONAL-f 900 IU/1.5 mL (66 micrograms/1.5 mL):

1.5 mL of solution for injection in 3 mL cartridge (Type I glass), with a plunger stopper (halobutyl rubber)

and an aluminium crimp cap with a black rubber inlay.

Pack of one pre filled pen and 20 needles to be used with the pen for administration.

6.6

Special precautions for disposal

and other handling

See the "Injection Instruction"

The solution should not be administered if it contains particles or is not clear.

Any unused solution must be discarded not later than 28 days after first opening.

GONAL-f 300 IU/0.5 mL (22 micrograms/0.5 mL), GONAL-f 450 IU/0.75 mL (33 micrograms/0.75 mL),

GONAL-f 900 IU/1.5 mL (66 micrograms/1.5 mL) are not designed to allow the cartridge to be removed.

Discard used needles immediately after injection.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7.

MARKETING AUTHORISATION HOLDER

Merck Serono Ltd., 18 Hakishon St., Yavne 81220.

8.

MARKETING AUTHORISATION NUMBER

131-55-31061-00

9.

MANUFACTURER

Merck Serono S.A., Geneva, Switzerland

10.

DATE OF REVISION OF THE TEXT

The Israeli Ministry of Health has determined this leaflet format and its content was checked and approved in

October 2017.