Prospect: information for the user

GONAL-f 1050 UI/1.75 ml powder and solvent

for injectable solution

folitropin alfa

Read this prospect thoroughly before starting to use this medication, as it contains important information for you.

• Keep this prospect, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• This medication has been prescribed to you alone, and you must not give it to other people even if they 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 prospect. See section 4.

How to prepare and use the GONAL-f powder and solvent

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.

What is GONAL-f used for

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 hypothalamus or pituitary gland (both are parts of the brain).
• if you area woman:
• • with large ovaries or fluid-filled cysts 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 malformation of the reproductive organs.
• 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 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 discontinue 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 discontinue treatment (see section 4).

In the event that you do not ovulate and the recommended dose and treatment schedule are followed, this syndrome is less likely to occur. Treatment with GONAL-f rarely causes severe HSS, unless the medication used for final follicular maturation (which contains human chorionic gonadotropin, hCG) is administered. If you develop HSS, your doctor may not prescribe hCG for this treatment cycle and advise you to abstain from 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 child 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 correct times. 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 in your body.

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 conditions or worsening with GONAL-f treatment.

Males with high FSH levels in the blood

If you are a male, high FSH levels in the blood may be a sign of testicular damage. GONAL-f is generally 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), your follicle response 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 operate machinery.

GONAL-f contains sodium and benzyl alcohol

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

When prepared with the provided solvent, this medication contains 1.23 mg of benzyl alcohol per dose of 75 IU equivalent to 9.45 mg/ml. Benzyl alcohol may cause allergic reactions.

The needle guard of the pre-filled syringe that contains the solvent for reconstitution contains latex (dry natural rubber), which may cause severe allergic reactions.

A presentation (GONAL-f 75 IU powder and solvent for injectable solution) without benzyl alcohol or latex is available in case you are allergic to these components.

Follow exactly the administration instructions of this medication as indicated by your doctor. If in 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 prepared solution 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 inject GONAL-f before you can self-administer it.
• If you self-administer GONAL-f, read and carefully follow the instructions at the end of this leaflet, section “How to prepare and use the powder and solvent of GONAL-f”.

What amount should be used

Your doctor will decide what amount of medication to administer and how often. The doses described below are expressed in International Units (IU), which reflects the graduation of the administration syringes supplied in the package.

If you use another syringe, graduated in milliliters (ml) instead of IU, you can consult the correct amount for the injection in ml in the following table:

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 usual 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 following day.

If your doctor does not observe the desired response after 4 weeks of treatment, 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 previous one.

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 initial usual 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 up to 5 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 following 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 5 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 previous one.

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 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 the eggs ready for extraction.

In other cases, your doctor may first interrupt ovulation using a GnRH agonist or antagonist. In such cases, GONAL-f administration is initiated approximately 2 weeks after starting treatment with the agonist, continuing both treatments until adequate follicular development is achieved. For example, after 2 weeks of treatment with the GnRH agonist, 150 to 225 IU of GONAL-f are administered for 7 days. The dose is then adjusted according to the response of the ovaries.

Males

• 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, which is described in 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 can 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, in “Ovarian hyperstimulation syndrome (OHSS”). This side effect is frequent (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 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, in “Blood clotting problems”).

Severe side effects in men and women

• Allergic reactions, such as skin rash, skin redness, blisters, facial swelling with difficulty breathing, may be severe. This side effect is very rare (may affect up to 1 in 10,000 people).

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 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 prospectus. You can also report them directly through thenational notification 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 vial label or on the box after CAD. The expiration date is the last day of the month indicated.

Before reconstitution, do not store at a temperature above 25°C.

Store in the original packaging 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 the solution is prepared, it can be stored for a maximum of 28 days.

• Note the day you prepared the solution on the GONAL-f vial.
• Do not store at a temperature above 25°C. Do not freeze.
• Store in the original packaging to protect it from light.
• Do not use the GONAL-f solution that remains in the vial after 28 days.

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

Medicines should not be thrown away through drains or in the trash. Ask your pharmacist how to dispose of empty containers and unused medications. This will help protect the environment.

GONAL-f 1050 UI/1.75 ml powder should not be mixed with other medications in the same injection.

GONAL-f 1050 UI/1.75 ml powder should not be mixed with other GONAL-f containers in the same vial or syringe.

Composition of GONAL-f

• The active ingredient is recombinant human follicle-stimulating hormone (r-hFSH).
• Each vial contains 1,200 IU of r-hFSH.
• After reconstitution, there are 1,050 IU (77 micrograms) of r-hFSH in 1.75 ml of solution, which means there are 600 IU (44 micrograms) in each milliliter of solution.
• The other components are sucrose, sodium dihydrogen phosphate monohydrate, and disodium hydrogen phosphate dihydrate, as well as concentrated phosphoric acid and sodium hydroxide for pH adjustment.
• The solvent contains water for injection and benzyl alcohol.

Appearance of the product and contents of the pack

• GONAL-f is presented as a powder and solvent used to prepare an injectable solution.
• The powder is a white tablet in a multidose glass vial.
• The solvent is a transparent, colorless liquid in a pre-filled syringe containing 2 ml.
• GONAL-f is presented in a box containing 1 vial of powder, 1 pre-filled syringe of solvent, and 15 disposable syringes for administration, graduated in international units (IU of FSH).

Marketing Authorization Holder

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

Responsible Person

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

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

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

HOW TO PREPARE AND USE THE POWDER AND SOLVENT OF GONAL-f

• This section explains how to prepare and use the powder and solvent of GONAL-f.
• Before starting the preparation, read these instructions in full.
• Administer the injection at the same time every day.

1. Wash your hands and find a clean place

• It is essential that your hands and the materials you use are as clean as possible.
• A suitable place is a clean table or a kitchen surface.

1. Gather and arrange everything you will need:

• 2 alcohol-soaked swabs.
• The pre-filled syringe containing the solvent (the transparent liquid).
• The vial containing GONAL-f (the white powder).
• A syringe for the injection (see the next figure).

1. Preparation of the solution

• Remove the protective caps from the vial of powder and the pre-filled syringe.
• Take the pre-filled syringe, insert the needle into the vial of powder, and inject the solvent slowly into the vial containing the powder.
• Remove the syringe from the vial and discard it (place the protective cap to avoid injury).
• This vial contains multiple doses of GONAL-f. You will need to store it for several days and extract only the prescribed dose each day.

1. Preparation of the syringe for the injection

• Gently turn the vial of GONAL-f prepared in step 3, without shaking. Check that the solution is transparent and does not contain any particles.
• Take the syringe for the injection and fill it with air, pulling the plunger until the correct dose in international units (IU of FSH) is reached.
• Insert the needle into the vial, place the vial upside down, and inject the air.
• Extract the prescribed dose of GONAL-f with the administration syringe, pulling the plunger until the correct dose in IU of FSH is reached.

1. Removal of air bubbles

• If you see air bubbles in the syringe, hold it with the needle pointing upwards and tap the syringe gently until the air collects at the top. Push the plunger until the air bubbles disappear.

1. Injection of the dose

• Inject the solution immediately: your doctor or nurse will have indicated where to administer the injection (e.g., in the abdomen, in the front of the thigh). To minimize skin irritation, select a different place each day for injection.
• Clean the selected area of the skin with an alcohol-soaked swab, moving in a circular motion.
• Pinch the skin firmly and insert the needle at an angle of 45° to 90°, moving similarly to a dart.
• Inject under the skin, slowly pushing the plunger according to the instructions received. Do not inject directly into a vein. Use all the time you need to inject the entire solution.
• Remove the needle immediately and clean the skin where the injection was made with an alcohol-soaked swab, moving in a circular motion.

1. After the injection

• Once the injection is complete, discard the used syringes immediately and safely, preferably in a sharp object container.
• Store the glass vial with the prepared solution in a safe place, as you may need to use it again. The prepared solution is only for your use and should not be administered to other patients.
• For subsequent injections with the prepared solution of GONAL-f, repeat steps 4 to 7.