Package Insert: Information for the User

GONAL-f 900 IU/1.44 ml pre-filled injectable solution

Follitropin alfa

Read this package insert carefully before starting to use this medication, as it contains important information for you.

• Keep this package insert, as you may need to refer to it again.
• If you have any questions, consult your doctor or pharmacist.
• This medication has been prescribed to you alone, and you should not give it to others who may have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this package insert. See section 4.

Instructions for Use

What is GONAL-f

GONAL-f contains a substance called “folitropin alfa”. Folitropin alfa is a type of ‘follicle-stimulating hormone’ (FSH), which belongs to the family of hormones called ‘gonadotropins’. Gonadotropins are involved in reproduction and fertility.

How is GONAL-f used

In adult women,GONAL-f is used:

• to help release an egg from the ovary (ovulation) in women who cannot ovulate and who have not responded to treatment with a substance called ‘clomiphene citrate’.
• along with another substance called ‘lutropin alfa’ (‘luteinizing hormone’ or LH), to help release an egg from the ovary (ovulation) in women whose body produces very small amounts of gonadotropins (FSH and LH).
• to help develop multiple follicles (each containing an egg) in women undergoing assisted reproductive techniques (techniques that may help her become pregnant), such as ‘in vitro fertilization’, ‘intratubal gamete transfer’ or ‘intratubal embryo transfer’.

In adult men,GONAL-f is used:

• along with another substance called ‘human chorionic gonadotropin’ (hCG), to help produce sperm in men who are infertile due to low concentrations of certain hormones.

Before starting treatment, your fertility and that of your partner should be evaluated by an experienced doctor in the treatment of fertility disorders.

Do not use GONAL-f

• if you are allergic to follicle-stimulating hormone or any of the other components of this medication (listed in section 6).
• if you have a tumor in the pituitary gland or the hypothalamus (both are parts of the brain).
• if you area woman:

• with large ovaries or fluid-filled sacs in the ovaries (ovarian cysts) of unknown origin.
• with unexplained vaginal bleeding.
• with ovarian, uterine, or breast cancer.
• if you have a condition that normally makes pregnancy impossible, such as premature ovarian insufficiency (early menopause) or a reproductive organ malformation.

• if you area man:

• with damaged testicles that cannot be cured.

Do not use GONAL-f if any of the above conditions apply to you. If you are unsure, consult your doctor before starting to use this medication.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use GONAL-f.

Porphyria

Inform your doctor before starting treatment if you or a family member has porphyria (a condition that prevents the breakdown of porphyrins that can be passed down from parents to children).

Inform your doctor immediately if:

• your skin becomes fragile and you get blisters easily, especially in areas exposed to the sun frequently, and/or
• if you have stomach pain, arm, or leg pain.

In these cases, your doctor may recommend that you stop treatment.

Hyperstimulation syndrome (HSS)

If you are a woman, this medication increases the risk of developing HSS. This occurs when your follicles develop too much and become large cysts. If you have pelvic pain, rapid weight gain, nausea, vomiting, or difficulty breathing, consult your doctor immediately, who may stop treatment (see section 4).

In cases where you do not ovulate and the recommended dose and treatment schedule are followed, this syndrome is less likely to occur. GONAL-f treatment rarely causes severe HSS, unless the medication used for final follicular maturation (containing human chorionic gonadotropin, hCG) is administered. If you develop HSS, your doctor may not prescribe hCG for this treatment cycle and advise you to avoid intercourse or use barrier contraceptive methods for at least 4 days.

Multiple pregnancy

If you use GONAL-f, you have a higher risk of becoming pregnant with more than one baby at a time (‘multiple pregnancy’, usually twins), than if you become pregnant naturally. Multiple pregnancy can cause medical complications for you and your babies. You can reduce the risk of multiple pregnancy by using the correct dose of GONAL-f at the right time. If you undergo assisted reproduction techniques, the risk of multiple pregnancy is related to your age and the quality and number of eggs fertilized or embryos placed inside you.

Abortion

If you undergo assisted reproduction techniques or ovarian stimulation to produce eggs, the likelihood of having an abortion is higher than the average for women.

Blood clotting disorders (thromboembolic episodes)

If you or a family member has had, in the past or recently, blood clots in the leg or lung, heart attack, or stroke, you may have a higher risk of developing these problems or of them worsening with GONAL-f treatment.

Males with high FSH levels in the blood

If you are a man, high FSH levels in the blood may be a sign of testicular damage. GONAL-f is usually not effective in these cases.

If your doctor decides to try treatment with GONAL-f, to monitor treatment, your doctor may ask you to have a semen analysis, 4 to 6 months after starting treatment.

Children and adolescents

GONAL-f should not be used in children and adolescents under 18 years of age.

Other medications and GONAL-f

Inform your doctor if you are taking, have taken recently, or may need to take any other medication.

• If you use GONAL-f with other medications that help ovulation (e.g., hCG or clomiphene citrate), the response of your follicles may be increased.
• If you use GONAL-f at the same time as a GnRH agonist or antagonist (these medications decrease sex hormone levels and stop ovulation), you may need a higher dose of GONAL-f to produce follicles.

Pregnancy and breastfeeding

Do not use GONAL-f if you are pregnant or breastfeeding.

Driving and operating machinery

This medication is not expected to affect your ability to drive and use machines.

GONAL-f contains sodium

This medication contains less than 1 mmol of sodium (23 mg) per dose; it is essentially “sodium-free”.

Follow exactly the administration instructions of this medication as indicated by your doctor. In case of doubt, consult your doctor or pharmacist again.

Use of this medication

• GONAL-f is designed to be administered by injection just below the skin (subcutaneously). The preloaded pen can be used for multiple injections.
• The first injection of GONAL-f must be administered under the supervision of your doctor.
• Your doctor or nurse will teach you how to use the GONAL-f preloaded pen to administer the medication.
• If you self-administer GONAL-f, read and carefully follow the "Instructions for use".

What dose to use

Your doctor will decide what dose of medication to administer and how often. The doses described below are expressed in International Units (IU).

Women

If you are not ovulating and have irregular or no menstruation

• GONAL-f is usually administered every day.
• If you have irregular menstruation, start using GONAL-f on the first 7 days of your menstrual cycle. If you do not have menstruation, you can start using the medication on any day that is convenient for you.
• The initial dose of GONAL-f is usually individualized and may be adjusted in a stepwise manner.
• The daily dose of GONAL-f should not exceed 225 IU.
• When the desired response is obtained, a single injection of 250 micrograms of recombinant hCG (r-hCG, a hCG manufactured in a laboratory using a special DNA technique) or 5,000 to 10,000 IU of hCG will be administered 24 to 48 hours after the last injection of GONAL-f. The best time for sexual intercourse is the same day as the hCG injection and the next day.

If your doctor does not observe the desired response, the continuation of that treatment cycle with GONAL-f should be evaluated and managed according to standard clinical practice.

If an excessive response is obtained, treatment will be interrupted and hCG will not be administered (see section 2, "Ovarian Hyperstimulation Syndrome (OHSS)"). For the next cycle, your doctor will administer a lower dose of GONAL-f than the previous cycle.

If you have been diagnosed with very low levels of FSH and LH hormones

• The usual initial dose of GONAL-f is 75 to 150 IU, along with 75 IU of lutropin alfa.
• You will use these two medications every day for a period of five weeks.
• The dose of GONAL-f may be increased every 7 or 14 days, by 37.5 to 75 IU, until the desired response is obtained.
• When the desired response is obtained, a single injection of 250 micrograms of recombinant hCG (r-hCG, a hCG manufactured in a laboratory using a special DNA technique) or 5,000 to 10,000 IU of hCG will be administered 24 to 48 hours after the last injection of GONAL-f and lutropin alfa. The best time for sexual intercourse is the same day as the hCG injection and the next day. Alternatively, intrauterine insemination or other medically assisted reproduction procedures may be performed at your doctor's discretion.

If your doctor does not observe the desired response after five weeks, that treatment cycle with GONAL-f should be interrupted. For the next cycle, your doctor will administer a higher initial dose of GONAL-f than the canceled cycle.

If an excessive response is obtained, treatment will be interrupted and hCG will not be administered (see section 2, "Ovarian Hyperstimulation Syndrome (OHSS)"). For the next cycle, your doctor will administer a lower dose of GONAL-f than the previous cycle.

If you need to develop multiple eggs for extraction prior to any assisted reproduction technique

• The initial dose of GONAL-f is usually individualized and may be adjusted in a stepwise manner up to a maximum of 450 IU per day.
• Treatment continues until the eggs have developed to the desired point. Your doctor will check this through blood tests and/or ultrasound.
• When the eggs are ready, a single injection of 250 micrograms of recombinant hCG (r-hCG, a hCG manufactured in a laboratory using a special DNA technique) or 5,000 to 10,000 IU of hCG will be administered 24 to 48 hours after the last injection of GONAL-f. This makes your eggs ready for extraction.

Men

• The usual dose of GONAL-f is 150 IU along with hCG.
• You will use these two medications three times a week for at least 4 months.
• If you have not responded to treatment after 4 months, your doctor may suggest that you continue using these two medications for at least 18 months.

If you use more GONAL-f than you should

The effects of using an excessive amount of GONAL-f are unknown. However, it is expected that Ovarian Hyperstimulation Syndrome (OHSS) will occur (see section 4). However, this syndrome will only occur if hCG is also administered (see section 2, "Ovarian Hyperstimulation Syndrome (OHSS)").

If you forgot to use GONAL-f

If you forgot to use GONAL-f, do not take a double dose to compensate for the missed doses. Consult your doctor as soon as you realize you have forgotten to take a dose.

If you have any other questions about the use of this medication, ask your doctor or pharmacist.

Like all medicines, this medicine may cause side effects, although not everyone will experience them.

Severe side effects in women

• Pelvic pain accompanied by nausea or vomiting may be symptoms of ovarian hyperstimulation syndrome (OHSS). This may indicate that the ovaries have reacted excessively to treatment and have developed large ovarian cysts (see section 2, "Ovarian Hyperstimulation Syndrome (OHSS)"). This side effect is common (may affect up to 1 in 10 people).
• Ovarian hyperstimulation syndrome may worsen with clearly enlarged ovaries, decreased urine production, weight gain, difficulty breathing, and/or possible fluid accumulation in the abdomen or chest. This side effect is rare (may affect up to 1 in 100 people).
• In rare cases, complications of ovarian hyperstimulation syndrome such as ovarian torsion or blood clotting may also occur (may affect up to 1 in 1,000 people).
• In very rare cases (may affect up to 1 in 10,000 people), severe complications of blood clotting (thromboembolic episodes) may occur, sometimes independent of ovarian hyperstimulation syndrome. This could cause chest pain, shortness of breath, stroke, or myocardial infarction (see also section 2, "Blood Clotting Problems").

Severe side effects in men and women

If you observe any of the side effects mentioned above, you should consult your doctor immediately, who may ask you to stop treatment with GONAL-f.

Other side effects in women

Very common(may affect more than 1 in 10 people):

• Fluid-filled sacs in the ovaries (ovarian cysts).
• Headache.
• Local reactions at the injection site, such as pain, redness, hematoma, swelling, and/or irritation.

Common(may affect up to 1 in 10 people):

• Abdominal pain.
• Nausea, vomiting, diarrhea, abdominal cramps, and flatulence.

Very rare(may affect up to 1 in 10,000 people):

• Allergic reactions, such as skin rash, skin redness, blisters, facial swelling with difficulty breathing. In some cases, these reactions may be severe.
• Asthma may worsen.

Other side effects in men

Very common(may affect more than 1 in 10 people):

• Local reactions at the injection site, such as pain, redness, hematoma, swelling, and/or irritation.

Common(may affect up to 1 in 10 people):

• Varicocele (swelling of the veins above and behind the testicles).
• Development of breasts, acne, or weight gain.

Very rare(may affect up to 1 in 10,000 people):

• Allergic reactions, such as skin rash, skin redness, blisters, facial swelling with difficulty breathing. In some cases, these reactions may be severe.
• Asthma may worsen.

Reporting of side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through thenational reporting system included in theAppendix V. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the cartridge label or on the box after CAD. The expiration date is the last day of the month indicated.

Store in refrigerator (between 2°C and 8°C). Do not freeze.

Before opening and within its validity period, the product may be stored outside the refrigerator at temperatures of up to a maximum of 25°C for a single maximum period of 3 months and must be discarded if not used within these 3 months.

Store the cap placed on the pen to protect it from light.

Do not use GONAL-f if you observe any visible sign of deterioration, if the liquid contains particles, or if it is not transparent.

Once opened, the pen must be stored between 2°C and 25°C for a maximum of 28 days.

Do not use the medication that remains in the pre-filled pen more than 28 days.

At the end of treatment, the unused solution must be discarded.

Medications should not be thrown away through drains or in the trash. Ask your pharmacist how to dispose of the containers and medications that you no longer need. This will help protect the environment.

Composition of GONAL-f

• The active principle is recombinant human follicle-stimulating hormone (r-hFSH).
• Each pre-filled pen with a multi-dose cartridge contains 900 IU (66 micrograms) of r-hFSH in 1.44 mL of solution.
• The other components are poloxamer 188, sucrose, methionine, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate dihydrate, and m-cresol, as well as concentrated phosphoric acid and sodium hydroxide for pH adjustment and water for injection.

Appearance of the product and contents of the package

• GONAL-f is presented as a transparent and colorless injectable solution in a pre-filled pen.
• It is supplied in a box with 1 pre-filled pen and 16 disposable needles.

Marketing Authorization Holder

Merck Europe B.V., Gustav Mahlerplein 102, 1082 MA Amsterdam, Netherlands

Responsible for manufacturing

Merck Serono S.p.A., Via delle Magnolie 15, 70026 Modugno (Bari), Italy

Last review date of this leaflet: {MM/AAAA}.

The detailed information on this medicinal product is available on the website of the European Medicines Agency:http://www.ema.europa.eu/.

Instructions for use

GONAL-f PRE-FILLED PEN 900 IU/1.44 mL

Injectable solution in a pre-filled pen

Recombinant human follicle-stimulating hormone (r-hFSH)

Important information about the GONAL-f pre-filled pen

• Read the instructions for use and the leaflet before using the GONAL-f pre-filled pen.
• Always follow all the instructions in these instructions for use and the training provided by the healthcare professional, as they may be different from those received previously. This information will help avoid errors in treatment or needlestick injuries or glass breakage.
• The GONAL-f pre-filled pen is only for subcutaneous injection.
• Only use the GONAL-f pre-filled pen if the healthcare professional teaches you how to use it correctly.
• The healthcare professional will tell you how many GONAL-f pre-filled pens you need to complete your treatment.
• Administer the injection at the same time every day.
• The numbers on thedose windowrepresent the number of international units (IU) and show the dose of r-hFSH. The healthcare professional will tell you how many IU of r-hFSH to inject each day.
• The numbers shown on thedose windowhelp you:

• Remove the needle from the pen immediately after each injection.

Do not re-use the needles.

Do not share the pen or needles with anyone else.

Do not use the GONAL-f pre-filled pen if it has fallen, or if the pen is cracked or damaged, as this may cause injuries.

How to use the treatment diary of the GONAL-f pre-filled pen

At the end of the instructions for usea treatment diary is included. Use the treatment diary to record the amount injected.

Injecting the wrong amount of medication may affect treatment.

• Record the day of treatment number (column 1), date (column 2), injection time (column 3), and pen volume (column 4).
• Record the prescribed dose (column 5).
• Check that you have selected the correct dose before administering the injection (column 6).
• After the injection, read the number indicated on thedose window.
• Confirm that you have received a complete injection (column 7) or record the number indicated on thedose windowif it is different from “0” (column 8).
• When necessary, administer another injection with a second pen, selecting the remaining dose that appears written in the “Amount to adjust for a second injection” section (column 8).
• Record this remaining dose in the “Adjusted amount for injection” section (column 6) on the next line.

The use of the treatment diary to record the daily injection(s) allows you to check that you have received the complete prescribed dose every day.

An example of a treatment diary:

Get familiar with the GONAL-f pre-filled pen

*For illustrative purposes only.The needles supplied may have a slightly different appearance.

**The numbers on thedose windowand the cartridge support represent the number of International Units (IU) of the medication.

Step 1 Gather materials

Step 2 Prepare for injection

Step 3 Attach the needle

If you do not see any liquid droplet on the needle tip or in its vicinity the first time you use a new pen:

1. Turn the dose adjustment button clockwise until it indicates “25” on thedose window(Figure 18).

• You can turn the dose adjustment button counterclockwise if you have turned it past “25”.

2. Hold the pen with the needle pointing upwards.

3. Gently tap the cartridge support (Figure 19).

4. Turn the dose adjustment button all the way down. A liquid droplet will appear on the needle tip (Figure 20).

5. Check that thedose windowindicates “0” (Figure 21).

6. Proceed with theStep 4 Select the dose.

If no liquid droplet appears, contact your healthcare professional.

Step 4 Select the dose

Note:The pen contains 450 IU of r-hFSH. The maximum single dose that can be adjusted on a 450 IU pen is 450 IU. The minimum single dose is 12.5 IU and the dose can be increased in increments of 12.5 IU.

4.1Turn the dose adjustment button until the desired dose appears on thedose window

• E.g., if the desired dose is “150” IU, confirm that thedose windowshows “150” (Figure 22). Injecting the wrong amount of medication may affect treatment.

4.2Check that thedose windowindicates theprescribed complete dosebefore proceeding to the next step.

Step 5 Administer the dose

Step 6 Remove the needle after each injection

Step 7 After the injection

Step 8 Store the GONAL-f pre-filled pen

Do not store the pen with the needle still attached, as this may cause an infection.

Do not re-use the GONAL-f pre-filled pen if it has fallen, or if the pen is cracked or damaged, as this may cause injuries.

Contact your healthcare professional if you have any questions.

Treatment diary of the GONAL-f pre-filled pen

Last review date of these instructions for use: {MM/AAAA}.