GONAL-F 1050 IU/1.75 ml POWDER AND SOLVENT FOR INJECTION

Introduction

Package Leaflet: Information for the User

GONAL-f 1050 UI/1.75 ml powder and solvent for solution for injection

follicle-stimulating hormone (follitropin alfa)

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• 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 only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What GONAL-f is and what it is used for
2. What you need to know before you use GONAL-f
3. How to use GONAL-f
4. Possible side effects
5. How to store GONAL-f
6. Contents of the pack and other information

How to prepare and use GONAL-f powder and solvent

1. What GONAL-f is and what it is used for

What is GONAL-f

GONAL-f contains a substance called ‘follitropin alfa’. Follitropin 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 GONAL-f is 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’.
• in combination 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 several follicles (each containing an egg) in women undergoing assisted reproduction techniques (techniques that can help you get pregnant), such as ‘in vitro fertilization’, ‘gamete intrafallopian transfer’, or ‘zygote intrafallopian transfer’.

In adult men, GONAL-f is used:

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

2. What you need to know before you use GONAL-f

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

Do not use GONAL-f

• if you are allergic to follicle-stimulating hormone or any of the other ingredients of this medicine (listed in section 6).
• if you have a tumor in the hypothalamus or pituitary gland (both are parts of the brain).
• if you are a woman:
• • with enlarged ovaries or fluid-filled sacs in the ovaries (ovarian cysts) of unknown origin.
  • with unexplained vaginal bleeding.
  • with cancer of the ovaries, uterus, or breast.
  • if you have a condition that normally makes pregnancy impossible, such as premature ovarian failure (early menopause) or a malformation of the reproductive organs.
• if you are a man:
• • with damaged testes that cannot be cured.

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

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting treatment with GONAL-f.

Porphyria

Tell your doctor before starting treatment if you or a family member has porphyria (a disorder that can be passed from parents to children).

Tell your doctor immediately if:

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

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

Ovarian Hyperstimulation Syndrome (OHSS)

If you are a woman, this medicine increases the risk of OHSS. 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 interrupt treatment (see section 4).

If you do not ovulate and the recommended dose and dosing schedule are respected, this syndrome is less likely to occur. Treatment with GONAL-f rarely causes severe OHSS, unless the medicine used for final follicular maturation (containing human chorionic gonadotropin, hCG) is administered. If you develop OHSS, your doctor may not prescribe hCG in this treatment cycle and advise you to abstain from intercourse or use barrier contraceptives 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 through natural conception. 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 inside you.

Miscarriage

If you undergo assisted reproduction techniques or ovarian stimulation to produce eggs, the likelihood of having a miscarriage is higher than in the average woman.

Blood Clotting Problems (Thromboembolic Events)

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

Men with High FSH Levels in the Blood

If you are a man, very high FSH levels in the blood can 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 Medicines and GONAL-f

Tell your doctor if you are taking, have recently taken, or might take any other medicines.

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

Pregnancy and Breast-feeding

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

Driving and Using Machines

GONAL-f is not expected to affect your ability to drive or use machines.

GONAL-f contains sodium and benzyl alcohol

This medicine contains less than 1 mmol of sodium (23 mg) per dose, which is essentially ‘sodium-free’.

When prepared with the supplied solvent, this medicine contains 1.23 mg of benzyl alcohol in each 75 UI dose, equivalent to 9.45 mg/ml. Benzyl alcohol may cause allergic reactions.

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

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

3. How to use GONAL-f

Follow the instructions for administration of this medicine exactly as told by your doctor. If you are unsure, consult your doctor or pharmacist.

Use of this medicine

• GONAL-f is designed to be administered by injection just under the skin (subcutaneously). The prepared solution can be used for several injections.
• The first injection of GONAL-f should 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, carefully read and follow the instructions at the end of this leaflet, section “How to prepare and use GONAL-f powder and solvent”.

How much to use

Your doctor will decide how much medicine 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 pack.

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

Women

If you are not ovulating and have irregular periods or no periods.

• GONAL-f is usually administered every day.
• If you have irregular periods, start using GONAL-f within the first 7 days of your menstrual cycle. If you do not have periods, you can start using the medicine any day you find convenient.
• The initial dose of GONAL-f is usually individualized and may be adjusted stepwise.
• The daily dose of GONAL-f should not exceed 225 IU.
• When the desired response is obtained, you will be given a single injection of 250 micrograms of ‘recombinant human chorionic gonadotropin’ (r-hCG), or 5,000 to 10,000 IU of hCG, 24 to 48 hours after the last injection of GONAL-f. The best time for intercourse is the same day as the hCG injection and the day after.

If your doctor does not observe the desired response after 4 weeks of treatment, that treatment cycle with GONAL-f should be discontinued. For the next cycle, your doctor will administer a higher initial dose of GONAL-f than before.

If an excessive response is obtained, treatment will be discontinued 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 in the previous cycle.

If you need to develop several eggs before any assisted reproduction technique

• The initial dose of GONAL-f is usually individualized stepwise 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 scans.
• When the eggs are ready, you will be given a single injection of 250 micrograms of ‘recombinant human chorionic gonadotropin’ (r-hCG), or 5,000 to 10,000 IU of hCG, 24 to 48 hours after the last injection of GONAL-f. This makes your eggs ready for retrieval.

In other cases, your doctor may first suppress ovulation using a GnRH agonist or antagonist. In such cases, administration of GONAL-f starts approximately 2 weeks after starting treatment with the agonist, with both treatments continuing 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.

Men

• The usual dose of GONAL-f is 150 IU, together with hCG.
• You will use these two medicines 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 medicines for at least 18 months.

If you use more GONAL-f than you should

The effects of using too much GONAL-f are not known. However, it can be expected that OHSS may 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 forget to use GONAL-f

If you forget to use GONAL-f, do not take a double dose to make up for forgotten doses. Consult your doctor as soon as you realize you have forgotten a dose.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

Severe Adverse Effects in Women

• Pelvic pain, accompanied by nausea or vomiting, can be symptoms of ovarian hyperstimulation syndrome (OHSS). This may indicate that the ovaries have overreacted to treatment and large ovarian cysts have developed (see section 2, "Ovarian Hyperstimulation Syndrome (OHSS)"). This adverse effect is frequent (it can affect up to 1 in 10 people).
• Ovarian hyperstimulation syndrome can worsen with clearly enlarged ovaries, decreased urine production, weight gain, difficulty breathing, and/or possible fluid accumulation in the abdomen or chest. This adverse effect is infrequent (it can affect up to 1 in 100 people).
• In rare cases, complications of ovarian hyperstimulation syndrome such as ovarian torsion or blood clotting can also occur (it can affect up to 1 in 1,000 people).

Severe Adverse Effects in Men and Women

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

If you notice any of the above adverse effects, you should consult your doctor immediately, who may ask you to interrupt treatment with GONAL-f.

Other Adverse Effects in Women

Very frequent (can affect more than 1 in 10 people):

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

Frequent (can affect up to 1 in 10 people):

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

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

• Allergic reactions, such as skin rash, skin redness, blisters, facial swelling with difficulty breathing, can occur. Sometimes, these reactions can be severe.
• Asthma can worsen.

Other Adverse Effects in Men

Very frequent (can affect more than 1 in 10 people):

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

Frequent (can affect up to 1 in 10 people):

• Swelling of the veins above and behind the testicles (varicocele).
• Development of breast tissue, acne, or weight gain.

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

• Allergic reactions, such as skin rash, skin redness, blisters, facial swelling with difficulty breathing, can occur. Sometimes, these reactions can be severe.
• Asthma can worsen.

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that is not listed in this prospectus. You can also report it directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of GONAL-f

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

Do not use this medicine after the expiration date stated on the label of the vial or on the carton after CAD. The expiration date is the last day of the month indicated.

Before reconstitution, do not store above 25°C.

Store in the original packaging to protect it from light.

Do not use GONAL-f if you notice any visible signs 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.

• Write the day you prepared the solution on the GONAL-f vial.
• Do not store above 25°C. Do not freeze.
• Store in the original container 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, the unused solution must be discarded.

Medicines should not be thrown away via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines you no longer need. This will help protect the environment.

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

GONAL-f 1050 UI/1.75 ml powder must not be mixed with other GONAL-f vials in the same syringe or needle.

6. Package Contents and Additional Information

Composition of GONAL-f

• The active ingredient is folitropin alfa.
• Each vial contains 1,200 UI of folitropin alfa.
• After reconstitution, there are 1,050 UI (77 micrograms) of folitropin alfa in 1.75 ml of solution, which means there are 600 UI (44 micrograms) per 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 injectable preparations and benzyl alcohol.

Appearance of the Product and Package Contents

• 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 clear, colorless liquid in a pre-filled syringe containing 2 ml.
• GONAL-f is presented in boxes of 1 powder vial along with 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

Manufacturer

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

Date of Last Revision of this Prospectus: {MM/YYYY}.

Detailed information about this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu/.

HOW TO PREPARE AND USE GONAL-f POWDER AND SOLVENT

• In this section, we explain how to prepare and use the GONAL-f powder and solvent.
• Before starting preparation, read these instructions thoroughly.
• Take 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 kitchen surface.

1. Gather and arrange everything you will need:

• 2 swabs soaked in alcohol.
• The pre-filled syringe containing the solvent (the clear liquid).
• The vial containing GONAL-f (the white powder).
• An empty syringe for injection (see the following figure).

1. Preparation of the solution

• Remove the protective caps from the powder vial and the pre-filled syringe.
• Take the pre-filled syringe, insert the needle into the powder vial, and slowly inject all the solvent into the vial containing the powder.
• Remove the syringe from the vial and discard it (put the protective cap back on to avoid injury).
• This vial contains several 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 injection

• Gently turn the prepared GONAL-f vial upside down without shaking. Check that the solution is transparent and does not contain any particles.
• Take the injection syringe and fill it with air by pulling the plunger to the correct dose in international units (IU of FSH).
• 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 by pulling the plunger until you reach the correct dose in IU of FSH.

1. Removal of air bubbles

• If you see air bubbles in the syringe, hold it with the needle facing upwards and tap the syringe until the air gathers 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 told you where to inject (e.g., in the abdomen, in the front of the thigh). To minimize skin irritation, choose a different injection site each day.
• Clean the selected skin area with an alcohol swab, using a circular motion.
• Firmly pinch the skin and insert the needle at an angle of 45° to 90°, with a motion similar to throwing darts.
• Inject under the skin, slowly pushing the plunger, according to the instructions received. Do not inject directly into a vein. Take all the time you need to inject the entire solution.
• Immediately remove the needle and clean the skin where you performed the injection with an alcohol swab, using a circular motion.

1. After the injection

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