Gonal-f 1050 IU/1.75 ml powder and solvent for solution for injection

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

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

folitropin alfa

Read this entire 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 questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only, and you should not give it to others, even if they have the same symptoms as you, because it may harm them.
• If you experience any side effects, talk to your doctor or pharmacist, even if the side effects are not listed in this leaflet. See section 4.

Contents of the leaflet

1. What GONAL-f is and what it is used for
2. What you need to know before using 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 the powder and solvent of GONAL-f

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

What GONAL-f is

GONAL-f contains a substance called "folitropin alfa". Folitropin alfa is a type of 'follicle-stimulating hormone' (FSH), which belongs to a family of hormones known as 'gonadotropins'. Gonadotropins play a role 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 are unable to 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 bodies produce very low levels of gonadotropins (FSH and LH).
• to help develop multiple follicles (each containing an egg) in women undergoing assisted reproductive techniques (procedures that may help them become 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 infertile men due to low levels of certain hormones.

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

Before starting treatment, your fertility and that of your partner should be evaluated by a physician experienced in the management of infertility disorders.

Do not use GONAL-f

• if you are allergic to follicle-stimulating hormone or to 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 ovarian, uterine, or breast cancer.
  • if you have a condition that normally makes pregnancy impossible, such as ovarian failure (premature menopause) or a malformation of the reproductive organs.
• if you are a man:
  • with irreversible testicular damage.

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 medicine.

Warnings and precautions

Talk to 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 disorder affecting the breakdown of porphyrins that can be inherited).

Inform your doctor immediately if:

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

In such cases, your doctor may recommend that you discontinue treatment.

Ovarian hyperstimulation syndrome (OHSS)

If you are a woman, this medicine increases the risk of developing OHSS. This occurs when your follicles develop excessively and become large cysts. If you experience pelvic pain, rapid weight gain, nausea or vomiting, or difficulty breathing, contact your doctor immediately, as they may discontinue treatment (see section 4).

If you do not ovulate and the recommended dose and dosing schedule are followed, this syndrome is less likely to occur. Treatment with GONAL-f rarely causes severe ovarian hyperstimulation syndrome unless the medication used to trigger final follicular maturation (containing human chorionic gonadotropin, hCG) is administered. If OHSS develops, your doctor may decide not to prescribe hCG in this treatment cycle and advise you to abstain from sexual intercourse or to use barrier contraception for at least 4 days.

Multiple pregnancy

If you use GONAL-f, you have a higher chance of becoming pregnant with more than one baby at a time (“multiple pregnancy,” usually twins) than if you become pregnant naturally. Multiple pregnancy may lead to 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 reproductive techniques, the risk of multiple pregnancy is related to your age and the quality and number of fertilized eggs or embryos transferred.

Miscarriage

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

Blood clotting problems (thromboembolic events)

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 an increased risk of developing these conditions or of them worsening during treatment with GONAL-f.

Men with high FSH levels in the blood

If you are a man, very high levels of FSH in the blood may indicate testicular damage. In such cases, GONAL-f is generally not effective.

If your doctor decides to attempt treatment with GONAL-f, they may request a semen analysis 4 to 6 months after starting treatment to monitor your response.

Children and adolescents

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

Other medicines and GONAL-f

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

• If you use GONAL-f together with other medications that promote ovulation (e.g., hCG or clomiphene citrate), your follicular response may be increased.
• If you use GONAL-f at the same time as a gonadotropin-releasing hormone (GnRH) agonist or antagonist (medications that reduce sex hormone levels and suppress ovulation), you may require 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 using machines

This medicine 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; i.e., it is essentially “sodium-free”.

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

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

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

3. How to use GONAL-f

Follow exactly the administration instructions for this medicine as given by your doctor. If in doubt, consult your doctor or pharmacist again.

Use of this medicine

• GONAL-f is intended for administration by injection just under the skin (subcutaneously). The prepared solution can be used for several 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 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 dose to use

Your doctor will decide how much medicine you should be given and how often. The doses described below are expressed in International Units (IU), which correspond to the scale on the administration syringes supplied in the package.

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

Dose to be injected (IU)	Volume to be injected (ml)
75	0.13
150	0.25
225	0.38
300	0.50
375	0.63
450	0.75

Women

If you are not ovulating and have irregular menstruation or no menstruation

• GONAL-f is usually administered every day.
• If you have irregular menstruation, start using GONAL-f within the first 7 days of your menstrual cycle. If you do not have menstruation, you may start taking the medication on any day convenient for you.
• The usual starting 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 achieved, you will receive a single injection of 250 micrograms of 'recombinant hCG' (r-hCG, a form of hCG produced in a laboratory using a special recombinant DNA technique), or 5,000 to 10,000 IU of hCG, 24 to 48 hours after the last injection of GONAL-f. The best time for sexual intercourse is on 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 cycle of treatment with GONAL-f should be discontinued. For the next cycle, your doctor will administer a higher starting dose of GONAL-f than in the previous cycle.

If an excessive response occurs, your treatment will be stopped and you will not receive hCG (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 have been diagnosed with very low levels of FSH and LH hormones

• The usual starting dose of GONAL-f is 75 to 150 IU, together with 75 IU of lutropin alfa.
• You will use these two medications every day for up to 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 achieved.
• When the desired response is achieved, you will receive a single injection of 250 micrograms of 'recombinant hCG' (r-hCG, a form of hCG produced in a laboratory using a special recombinant DNA technique), or 5,000 to 10,000 IU of hCG, 24 to 48 hours after the last injection of GONAL-f and lutropin alfa. The best time for sexual intercourse is on the same day as the hCG injection and the following day. Alternatively, intrauterine insemination or another medically assisted reproductive procedure may be performed, at your doctor's discretion.

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

If an excessive response occurs, your treatment will be stopped and you will not receive hCG (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 multiple eggs for retrieval prior to any assisted reproductive technique

• The starting dose of GONAL-f is usually individualized and may be increased stepwise up to a maximum of 450 IU per day.
• Treatment continues until the eggs have developed to the desired stage. Your doctor will monitor this through blood tests and/or ultrasound examinations.
• When the eggs are ready, you will receive a single injection of 250 micrograms of 'recombinant hCG' (r-hCG, a form of hCG produced in a laboratory using a special recombinant DNA technique), or 5,000 to 10,000 IU of hCG, 24 to 48 hours after the last injection of GONAL-f. This causes your eggs to become ready for retrieval.

In other cases, your doctor may first suppress ovulation using a gonadotropin-releasing hormone (GnRH) agonist or antagonist. In such cases, GONAL-f administration is started approximately 2 weeks after initiating treatment with the agonist, continuing both treatments until adequate follicular development is achieved. For example, after two 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 ovarian response.

Men

• The usual dose of GONAL-f is 150 IU together 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 continuing 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, ovarian hyperstimulation syndrome (OHSS), described in section 4, may be expected. 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 the missed doses. Consult your doctor as soon as you realize you have missed a dose.

If you have any further questions about 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 everybody will experience them.

Serious adverse 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 over-responded to treatment and large ovarian cysts have developed (see section 2, “Ovarian hyperstimulation syndrome (OHSS)”). This adverse effect is common (may affect up to 1 in 10 people).

• Ovarian hyperstimulation syndrome may worsen with clearly enlarged ovaries, reduced urine production, weight gain, difficulty breathing, and/or possible accumulation of fluid in the abdomen or chest. This adverse effect is uncommon (may affect up to 1 in 100 people).

• In rare cases, complications of ovarian hyperstimulation syndrome may also occur, 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), serious blood clotting complications (thromboembolic events) may occur, sometimes independent of ovarian hyperstimulation syndrome. This could cause chest pain, shortness of breath, stroke, or myocardial infarction (see also section 2, “Problems with blood clotting”).

Serious adverse effects in men and women

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

If you experience any of the above-mentioned adverse effects, you must consult your doctor immediately, who may instruct you to stop treatment with GONAL-f.

Other adverse 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, bruising, swelling, and/or irritation.

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

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

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

• Allergic reactions may occur, such as skin rash, redness of the skin, blisters, swelling of the face with difficulty breathing. Occasionally, these reactions may be severe.
• Asthma may worsen.

Other adverse effects in men

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

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

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

• Swelling of the veins above and behind the testicles (varicocele).
• Breast development, acne, or weight gain.

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

• Allergic reactions may occur, such as skin rash, redness of the skin, blisters, swelling of the face with difficulty breathing. Occasionally, these reactions may be severe.
• Asthma may worsen.

Reporting of adverse effects

If you experience any adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly through the national reporting system listed in Appendix V. By reporting adverse effects, you can help provide 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 expiry date stated on the vial label or on the carton after EXP. The expiry date refers to the last day of the month indicated.

Before reconstitution, do not store above 25°C.

Keep in the original packaging to protect 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 clear.

Once the solution has been prepared, it may be stored for up to 28 days.

• Mark on the GONAL-f vial the date on which the solution was prepared.
• Do not store above 25°C. Do not freeze.
• Keep in the original container to protect from light.
• Do not use the GONAL-f solution remaining in the vial after 28 days.

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

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and packaging 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 or containers in the same vial or syringe.

6. Contents of the pack and other information

Composition of GONAL-f

• The active substance is follitropin alfa.
• Each vial contains 1,200 IU of follitropin alfa.
• After reconstitution, there are 1,050 IU (77 micrograms) of follitropin alfa in 1.75 ml of solution, meaning that there are 600 IU (44 micrograms) per milliliter of solution.
• The other components are sucrose, monohydrate monosodium dihydrogen phosphate, 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 contents of the pack

• GONAL-f is presented as a powder and solvent for use in preparing 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 supplied in packs of 1 powder vial together with 1 pre-filled solvent syringe and 15 disposable syringes for administration, graduated in international units (FSH IU).

Marketing Authorization Holder

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

Manufacturer

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

Date of the most recent revision of this leaflet: {MM/YYYY}.

Detailed information on this medicine 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 beginning preparation, read these instructions completely.
• Administer your injection at the same time each day.

1. Wash your hands and find a clean place

• It is important that your hands and materials used are as clean as possible.
• A suitable place is a clean table or kitchen surface.

1. Gather and lay out everything you will need:

• 2 alcohol swabs.
• 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 of the solvent into the vial containing the powder.
• Remove the syringe from the vial and discard it (replace the protective cap to prevent injury).
• This vial contains multiple doses of GONAL-f. It must be stored for several days, and only the prescribed dose should be withdrawn each day.

1. Preparation of the syringe for injection

• Gently rotate the vial of reconstituted GONAL-f prepared in step 3, without shaking. Check that the solution is clear and free from particles.
• Take the injection syringe and fill it with air by pulling the plunger to the correct dose in international units (FSH IU).
• Insert the needle into the vial, turn the vial upside down, and inject the air into it.
• Withdraw the prescribed dose of GONAL-f into the administration syringe by pulling the plunger until it reaches the correct dose in FSH IU.

1. Removal of air bubbles

• If you see air bubbles in the syringe, hold the syringe with the needle pointing upward and tap it 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 instructed you where to administer the injection (e.g., in the abdomen or front of the thigh). To minimize skin irritation, select a different site each day.
• Clean the selected area of skin with an alcohol swab using a circular motion.
• Firmly pinch the skin and insert the needle at an angle of 45° to 90°, using a dart-like motion.
• Inject under the skin by slowly pushing the plunger, according to the instructions received. Do not inject directly into a vein. Take as much time as needed to fully inject the solution.
• Immediately withdraw the needle and clean the injection site with an alcohol swab using a circular motion.

1. After the injection

• After completing the injection, immediately and safely dispose of the used syringes, preferably in a sharps container.
• Store the glass vial containing 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.