GONAL F - PACKAGE LEAFLET - LEAFLETS

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Gonal F - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Follitropin alfa

GONAL-f 75 IU (5.5 micrograms) powder and solvent for solution for injection

Why is Gonal F used? What is it for?

GONAL-f contains an active substance called "follitropin alfa". Follitropin alfa is a "follicle stimulating hormone" (FSH), belonging to the family of hormones called "gonadotropins". Gonadotropins are involved in reproduction and fertility.

In adult women, GONAL-f is used

to help release an egg from the ovary (ovulation) in women who are not ovulating and who have not responded to treatment with a medicine called 'clomiphene citrate'.
together with another medicine called "lutropin alfa" ("luteinizing hormone" or LH) to help release an egg from the ovary (ovulation) in women who are not ovulating because their body produces very few gonadotropins (FSH and LH ).
to encourage the development of several follicles (each containing an egg) in women undergoing assisted reproductive procedures (procedures that can help get pregnant), such as "in vitro fertilization", "intratubal gamete transfer" or " intratubal transfer of zygotes ".

In the adult man, GONAL-f is used

together with another medicine called 'human chorionic gonadotropin' (hCG) to help produce sperm in men who are infertile due to low levels of certain hormones.

Contraindications When Gonal F should not be used

Before starting treatment, the couple's fertility should be properly studied by a physician 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 of the hypothalamus or pituitary gland (both parts of the brain).
if you are a woman - with large ovaries or sacs of fluid in the ovary (ovarian cysts) of unknown origin - with vaginal bleeding of unknown origin - with cancer of the ovary, uterus or breast - with a condition that usually makes a normal pregnancy, such as ovarian failure (premature menopause) or malformations of the reproductive system, is impossible.
if it is a man - with irreversible damage to the testicles. Do not use GONAL-f if you suffer from any of these conditions. If you are unsure, ask your doctor before using this medicine.

Precautions for use What you need to know before you take Gonal F.

Porphyria

Tell your doctor before starting treatment if you or a family member have porphyria (an inability to break down porphyrins, which can be passed on from parents to children).

Tell your doctor immediately if:

the skin becomes fragile and blisters easily, particularly on areas that are frequently exposed to the sun, and / or
you have pain in your stomach, arms or legs.

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

Ovarian Hyperstimulation Syndrome (OHSS)

If you are a woman, this medicine increases the risk of OHSS. In this case, the follicles overdevelop and turn into large cysts. Tell your doctor immediately if you experience lower abdominal pain, rapid weight gain, nausea or vomiting or difficulty breathing; your doctor may ask you to stop taking the medicine (see section 4).

If you are anovulatory patient and if the recommended posology and administration schedule are well followed, the risk of OHSS is less likely.

Treatment with GONAL-f only in rare cases causes severe OHSS if you are not given a medicine (containing human chorionic gonadotropin - hCG) to induce ovulation. If you are developing OHSS, your doctor may not give you it. hCG in this course of treatment and recommend that you avoid sexual intercourse or use a barrier contraceptive for at least four days.

Multiple pregnancy

While using GONAL-f, you have a higher risk of having a multiple pregnancy, in most cases twins, than natural conception. Multiple pregnancy can cause complications for you and your children. It can reduce the risk of a multiple pregnancy by using the correct dose of GONAL-f at the correct times. In assisted reproductive procedures, the risk of a multiple pregnancy is related to the age, quality and number of fertilized ova or embryos transferred to it .

Abortion

If you undergo assisted reproductive or ovarian stimulation procedures for egg production, the risk of miscarriage is greater than in other women.

Blood clotting disorders (thromboembolic events)

If in the past or recently you have had clots in your legs or lungs, a heart attack or stroke, or if these events have occurred in your family, you may increase the risk of these problems occurring or worsening during treatment with GONAL-f.

Men with excessive FSH levels in their blood

If it's a man, excessive FSH levels in the blood can be a sign of testicular damage. In this case, GONAL-f generally has no effect. If your doctor decides to try treatment with GONAL-f, he may ask you to provide semen samples for control analysis 4-6 months after starting treatment.

Children

The use of GONAL-f is not indicated in children.

Interactions Which drugs or foods can modify the effect of 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 promote ovulation (such as hCG or clomiphene citrate), this may enhance the response of the follicles.
If you use GONAL-f at the same time as a "gonadotropin releasing hormone" (GnRH) agonist or antagonist (these medicines reduce the levels of sex hormones and stop ovulation), you may need a higher dose of GONAL-f to produce follicles.

Warnings It is important to know that:

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 the ability to drive or use machines.

Important information about some of the ingredients of GONAL-f

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, ie it is considered essentially "sodium-free".

Dosage and method of use How to use Gonal F: Dosage

Always use this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

How to use the medicine

GONAL-f is taken by injection just under the skin (subcutaneously).
The first injection of GONAL-f should be given under the supervision of your doctor.
Your doctor or nurse will show you how to inject GONAL-f before you can inject yourself.
If you administer GONAL-f alone, please carefully read and follow the instructions at the end of this leaflet "How to prepare and use the GONAL-f powder and solution".

Which dose to use

Your doctor will decide how much medicine you should use and how often. The doses given below are expressed in International Units (IU) and in milliliters (mL).

Women

If you are not ovulating and have irregular or absent menstrual cycles

GONAL-f is usually given every day.
If you have irregular periods, start using GONAL-f within the first 7 days of your cycle. If you do not have a period, you can start using the medicine any day.
The usual starting dose of GONAL-f is between 75 and 150 IU (0.12-0.24 mL) each day.
The dose of GONAL-f can be increased every 7 days or every 14 days by 37.5-75 IU until the desired response is achieved.
The maximum daily dose of GONAL-f generally does not exceed 225 IU (0.36 mL).
When you get the desired response, you will be given a single injection of 250 micrograms of "recombinant hCG" (r-hCG, a laboratory-made hCG using a particular DNA technique) or 5,000-10,000 IU of hCG, 24-48 hours later. the last injection of GONAL-f. The best days for sexual intercourse are the day of the hCG injection and the day after.

If the doctor does not see the desired response after 4 weeks, that course of treatment with GONAL-f should be stopped. In the next course of treatment, your doctor will give you a higher starting dose of GONAL-f.

If your body responds excessively, the treatment will be stopped and you will not be given hCG (see section 2, OHSS). In the next cycle, your doctor will give you a lower dose of GONAL-f.

If you are not ovulating, have no periods and have been diagnosed with very low levels of the hormones FSH and LH

The usual starting dose of GONAL-f is between 75 and 150 IU (0.12-0.24 mL) together with 75 IU (0.12 mL) of lutropin alfa.
You will need to use these two medicines every day for up to five weeks.
The dose of GONAL-f can be increased every 7 days or every 14 days by 37.5-75 IU until the desired response is achieved.
When you get the desired response, you will be given a single injection of 250 micrograms of "recombinant hCG" (r-hCG, a laboratory-made hCG using a particular DNA technique) or 5,000-10,000 IU of hCG, 24-48 hours later. the last injection of GONAL-f and lutropin alfa. The best days for sexual intercourse are the day of the hCG injection and the day after. Alternatively, intrauterine insemination can be performed, with sperm deposition directly into the uterus.

If the doctor does not see any response after 5 weeks, that course of treatment with GONAL-f should be stopped. In the next course of treatment, your doctor will give you a higher starting dose of GONAL-f.

If your body responds excessively, the treatment will be stopped and you will not be given hCG (see section 2, OHSS). In the next cycle, your doctor will give you a lower dose of GONAL-f.

If you have to develop several eggs to be collected for assisted reproductive techniques

The usual starting dose of GONAL-f is between 150 and 225 IU (0.24-0.36 mL) each day, starting on day 2 or 3 of your course on treatment.
The dose of GONAL-f can be increased, depending on the response. The maximum daily dose is 450 IU (0.72 mL).
The treatment continues until the eggs have reached a certain stage of development. This development typically lasts 10 days, but the duration can vary between 5 and 20 days. The doctor will determine the right time with a blood test and / or ultrasound.
When the eggs have developed, you will be given a single injection of 250 micrograms of "recombinant hCG" (r-hCG, an hCG produced in the laboratory with a particular recombinant DNA technique) or 5,000-10,000 IU of hCG, 24-48 hours after the last injection of GONAL-f. In this way, the eggs are prepared for collection.

In other cases, the doctor may first block ovulation with a gonadotropin releasing hormone (GnRH) agonist or antagonist. In this case, treatment with GONAL-f begins approximately two weeks after starting treatment with the agonist. Both GONAL-f and the GnRH agonist are administered until desired follicle development. For example, after two weeks of treatment with the GnRH agonist, 150-225 IU of GONAL-f are administered for 7 days. The dose is then adjusted based on the response of the ovary.

Men

The usual dose of GONAL-f is 150 IU (0.24 mL) together with hCG.
You will need to use these two medicines three times a week for at least 4 months.
If, after 4 months, you have not responded to the treatment, your doctor may suggest continuing to use the two medicines for at least 18 months.

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

This section describes the preparation and use of the GONAL-f powder and solvent.
Before starting the preparation, please read these instructions completely.
Practice self-injection at the same time each day.

1. Wash your hands and find a clean surface

It is important to make sure that your hands and accessories are well cleaned.
A clean table or kitchen worktop is suitable.

2. Prepare and arrange on a surface all the necessary:

1 vial containing the solvent (the clear liquid)
1 vial containing GONAL-f (the white powder)
1 needle for preparation
1 fine needle for subcutaneous injection

The following are not provided in the package:

2 alcohol-soaked cotton balls
1 empty syringe for injection
1 sharps waste container

3. Prepare the solution

Remove the protective cap from the solvent vial.
Attach the preparation needle to the empty injection syringe.
Draw some air into the syringe by pulling the plunger to the mark indicating approximately 1 mL.
Insert the needle into the vial containing the solvent and push the plunger to expel the air.
Invert the vial and slowly withdraw all the solvent.
Remove the syringe from the vial and store it carefully. Do not touch the needle and do not allow it to come into contact with any surface.
Prepare the solution for injection. Remove the protective cap from the vial containing the GONAL-f powder, take the syringe and slowly inject the solvent into the powder vial. Swirl gently without removing the syringe. Don't shake. After the powder has dissolved (which should happen immediately), check that the resulting solution is clear and free of particles. Turn the vial upside down and slowly draw the solution back into the syringe.

(If multiple vials of GONAL-f have been prescribed, slowly re-inject the resulting solution into another vial of powder until the prescribed number of vials dissolve in the solution. If you have been prescribed lutropin alfa in addition to GONAL-f, you can mix the two medicines together instead of injecting them separately. After dissolving the lutropin alfa powder, draw the solution back into the syringe and re-inject it into the vial containing GONAL-f. Once the powder has dissolved, draw the solution back into the syringe . Check for particles and do not use the solution if it is not clear. Up to 3 containers of powder can be dissolved in 1 mL of solvent).

4. Prepare the syringe for injection

Replace the needle with a thin needle for subcutaneous injections.
Eliminate any air bubbles: if there are air bubbles in the syringe, hold it vertical with the needle pointing upwards and tap lightly until the air bubbles collect at the top, then push the syringe plunger slightly to expel the air.

5. Inject the dose

Inject the solution immediately: Your doctor or nurse must have already advised you where to inject (eg tummy, front of thigh). To minimize skin irritation, choose a different injection site each day.
Clean the injection area with alcohol, in a circular motion.
Firmly hold the part where you intend to give the injection between your fingers and insert the needle at an angle between 45 ° and 90 ° with an arrow-like motion.
Inject the solution under the skin by slowly pressing the plunger, as instructed. Do not inject directly into a vein. Be sure to inject all of the solution.
Immediately remove the needle and clean the injection area with alcohol in a circular motion.

6. After the injection

Disposal of used objects: Once the injection is finished, immediately discard used needles and empty glasses in a safe condition, preferably in the sharps container. Any unused solution must be discarded.

Overdose What to do if you have taken too much Gonal F.

If you use more GONAL-f than you should

No effects from using too much GONAL-f have been described; however, ovarian hyperstimulation syndrome (OHSS) may occur as described in section 4. However, OHSS will only occur if hCG has also been administered (see paragraph 2, 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 a forgotten dose. Tell 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.

Side Effects What are the side effects of Gonal F

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects in women

Pelvic pain in combination with nausea or vomiting can be symptoms of ovarian hyperstimulation syndrome (OHSS). This may indicate that the ovaries overreact to treatment and that large ovarian cysts have developed (see also section 2 under "Ovarian hyperstimulation syndrome"). This side effect is common (may affect up to 1 in 10 people).
OHSS can become severe, with significantly enlarged ovaries, reduced urine production, weight gain, difficulty breathing and / or possible accumulation of fluid in the abdomen or chest. This side effect is uncommon (may affect up to 1 in 1 person). 100).
Complications of OHSS, such as ovarian torsion or blood clotting, may rarely occur (may affect up to 1 in 1,000 people).
Serious complications of blood clotting (thromboembolic events), independent of OHSS, may occur very rarely (may affect up to 1 in 10,000 people). This can cause chest pain, breathlessness, stroke or heart attack (see also section 2 under "Blood clotting disorders").

Serious side effects in men and women

Sometimes, allergic reactions such as skin reaction, redness, itching, swelling of the face with difficulty in breathing, can be serious. This side effect is very rare (may affect up to 1 in 10,000 people).

If you notice any of the side effects described, contact your doctor immediately, who may ask you to stop using GONAL-f.

Other side effects in women

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

Pockets of fluid in the ovary (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, diarrhea, abdominal cramps and bloating

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

Allergic reactions such as rash, redness of the skin, hives, swelling of the face with difficulty in breathing may occur. These reactions can be severe.
Asthma can get worse

Other side effects in man

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 gland enlargement, acne, or weight gain.

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

Allergic reactions such as rash, redness of the skin, hives, swelling of the face with difficulty in breathing may occur. These reactions can be severe.
Asthma can get worse.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

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

Do not use this medicine after the expiry date which is stated on the vial after EXP. The expiry date refers to the last day of that month.

Do not store above 25 ° C.

Store in the original package to protect the medicine from light.

Do not use GONAL-f if you notice visible signs of deterioration, if the liquid contains particles or if it is not clear.

The medicine should be administered immediately after preparation.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

GONAL-f must not be administered in mixture with other medicines in the same injectable preparation, with the exception of lutropin alfa. Studies have shown that these two medicines can be mixed and injected together, without either of them being altered in any way. .

Composition and pharmaceutical form

What GONAL-f

The active substance is follitropin alfa.
Each vial contains 5.5 micrograms of follitropin alfa.
After preparation of the final solution for injection, each milliliter of solution contains 75 IU (5.5 micrograms) of follitropin alfa.
The other ingredients are sucrose, monobasic sodium phosphate monohydrate, disodium phosphate dihydrate, methionine, polysorbate 20, concentrated phosphoric acid and sodium hydroxide.
The solvent is water for injections.

Description of what GONAL-f looks like and contents of the pack

GONAL-f is presented as a powder and solvent which are used to make a solution for injection.
The powder is a white pellet in a glass vial.
The solvent is a clear colorless liquid in a glass vial containing 1 mL.
GONAL-f is supplied in packs of 1 vial of powder with 1 vial of solvent.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Gonal F can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER O 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

GONAL-F 75 IU

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains 75 IU of follitropin alfa, recombinant human follicle stimulating hormone (FSH). The reconstituted solution contains 75 IU / ml. Follitropin alfa is produced by genetically engineered Chinese Hamster Ovary (CHO) cells.

Excipients: sucrose 30 mg, disodium phosphate dihydrate 1.11 mg, monobasic sodium phosphate monohydrate 0.45 mg.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Appearance of the powder: white lyophilisate pellets

Appearance of the solvent: clear colorless solution

The pH of the reconstituted solution is 6.5 - 7.5.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Anovulation (including PCOD Polycystic Ovary Syndrome) in women who do not respond to treatment with clomiphene citrate.

Stimulation of multiple follicular development in women undergoing assisted reproductive techniques (ART), such as fertilization in vitro (IVF), transfer of gametes within the fallopian tubes (GIFT) or transfer of zygotes within the fallopian tubes (ZIFT).

GONAL-f, in combination with a luteinizing hormone (LH) -based preparation, is recommended for the stimulation of follicular development and ovulation in women with severe LH and FSH insufficiency. In clinical trials these patients were identified on the basis of serum levels of endogenous LH

GONAL-f is indicated in the induction of spermatogenesis in men with congenital or acquired hypogonadotropic hypogonadism, in association with human Chorionic Gonadotropin (hCG).

04.2 Posology and method of administration

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

GONAL-f must be administered subcutaneously.

The powder must be reconstituted immediately before use with the solvent provided. To avoid injection of excessive volumes, up to 3 containers of product can be dissolved in 1 ml of solvent.

The recommended dosages for GONAL-f are those used for urinary FSH. Clinical evidence of GONAL-f indicates that its daily doses, administration regimens and treatment monitoring methods should not differ from those normally used for preparations containing urinary FSH. However, when these doses were used in a comparative clinical study between GONAL-f and urinary FSH, GONAL-f was more effective than urinary FSH in terms of lower total dose and longer treatment period. short necessary to obtain pre-ovulatory conditions. It is advisable to follow the recommended starting doses indicated below.

Women with anovulation (including PCOD Polycystic Ovary Syndrome):

The goal of treatment with GONAL-f is to stimulate the maturation of a single Graafian follicle that will ovulate after administration of hCG. Treatment with GONAL-f can be performed with daily injections and therapy should begin within first 7 days of the menstrual cycle.

The posology should be adapted according to the individual response which should be assessed by ultrasound monitoring of the follicle size and / or by measuring estrogen. The most common dosing schedule involves daily injections of 75-150 IU of FSH which can be increased, if necessary, by 37.5 IU or 75 IU at intervals of 7 or 14 days to obtain an adequate but not excessive response. The maximum daily dose generally does not exceed 225 IU of FSH. If the patient does not respond adequately after 4 weeks of treatment, the course of therapy should be interrupted; the following therapeutic cycle must start with a higher dose than the one previously interrupted.

Once the optimal response has been obtained, 5,000 to 10,000 IU of HCG should be administered in a single dose 24-48 hours after the last injection of GONAL-f. It is preferable that the patient has sexual intercourse for procreative purposes both on the day of administration. HCG than the next. Alternatively, intrauterine insemination (IUI) may be performed. If an excessive response is obtained, treatment with GONAL-f should be stopped and the administration of HCG abandoned (see section 4.4). In the next cycle treatment should be resumed at a lower dose.

Women undergoing ovarian stimulation for multiple follicular development that precedes fertilization in vitro or other assisted reproductive techniques:

The regimen commonly adopted in superovulation involves the administration of 150-225 IU of GONAL-f per day starting on the 2nd or 3rd day of the cycle.

Treatment is continued until adequate follicular development is achieved (assessed by estrogen concentration monitoring and / or ultrasound monitoring) adjusting the dose based on the patient's response up to a maximum generally of 450 IU per day. Generally, adequate follicular development is achieved around the 10th day of treatment (range between 5 and 20 days).

To induce final follicular maturation, up to 10,000 IU of chorionic gonadotropin (hCG) should be administered, in a single dose, 24-48 hours after the last administration of GONAL-f.

Commonly down-regulation is caused with a gonadotropin-releasing hormone (GnRH) agonist in order to suppress the endogenous LH surge and control its tonic secretion.

The most common treatment regimen involves the use of GONAL-f approximately 2 weeks after the initiation of agonist therapy, both treatments are continued until adequate follicular development is achieved.

For example, after 2 weeks of agonist treatment, administer 150-225 IU of GONAL-f for the first 7 days. The dose is then adjusted according to the ovarian response. The experience gained in IVF generally indicates that the percentage of successes remains stable during the first four attempts, and then gradually decreases thereafter.

Women with anovulation due to severe LH and FSH insufficiency:

In women deficient in LH and FSH (hypogonadotropic hypogonadism), the goal of therapy with GONAL-f in combination with lutropin alfa is the development of a single mature Graafian follicle from which the oocyte will be released after administration of human chorionic gonadotropin. (hCG). GONAL-f should be administered as daily injections at the same time as lutropin alfa. Since these patients are amenorrhoeic and have low endogenous estrogen secretion, treatment can be started on any day.

Treatment should be tailored to the patient's individual response which should be assessed by ultrasound follicle size monitoring and estrogen measurement. A recommended dosing schedule starts with 75 IU of lutropin alfa per day and 75 - 150 IU of FSH.

If an increase in FSH dose is deemed appropriate, dosage adjustment should preferably be made in increments of 37.5 IU-75 IU at intervals of 7-14 days. The stimulation duration of a cycle can be extended up to 5 weeks Once optimal response is achieved, 24-48 hours after the last injection of GONAL-f and lutropin alfa, 5,000 to 10,000 IU of hCG should be administered in a single dose. The patient is recommended to have sexual intercourse for procreative purposes on the day of hCG administration and the day after.

Alternatively, intrauterine insemination (IUI) may be performed. In order to avoid an early insufficiency of the corpus luteum after ovulation, due to the deficiency of substances with luteotropic activity (LH / hCG), the appropriateness of a support of the luteal phase must be evaluated.

In the event of an excessive response, treatment should be stopped and hCG should not be administered. In the next cycle, treatment should be resumed with lower FSH dosages than in the previous cycle.

Men with hypogonadotropic hypogonadism:

GONAL-f should be administered at a dosage of 150 IU three times a week, in combination with hCG, for at least 4 months.

If after this period the patient does not respond, the combined treatment can continue further; Current clinical experience indicates that treatment for at least 18 months may be needed to induce spermatogenesis.

04.3 Contraindications

GONAL-f must not be used in case of:

hypersensitivity to the active substance follitropin alfa, to FSH or to any of the excipients;

tumors of the hypothalamus or pituitary gland;

and in women:

ovarian enlargement or cyst not due to polycystic ovary syndrome;

gynecological haemorrhages of unknown etiology;

carcinoma of the ovary, uterus or breast.

GONAL-f should also not be used when an effective response cannot be obtained due to: in women:

primary ovarian failure;

malformations of the sexual organs incompatible with pregnancy;

fibroids of the uterus incompatible with pregnancy.

In men:

in case of primary testicular insufficiency.

04.4 Special warnings and appropriate precautions for use

GONAL-f is a potent gonadotropin capable of causing mild to severe adverse reactions and should only be used by physicians experienced in infertility problems and their treatment. Gonadotropin therapy requires some commitment from the physician, the support of nurses and the availability of adequate monitoring equipment. In women, the safe and effective use of GONAL-f involves monitoring the ovarian response by ultrasound, preferably associated with regular serum estradiol measurement. Some degree of individual variability may occur in FSH response, and in some patients the response may be poor. In both women and men the lowest effective dose should be used in relation to the treatment goals.

Self-administration of GONAL-f should only be performed by patients who are well motivated, properly trained and who can consult with an expert. The first injection of GONAL-f should be performed under direct medical supervision. Patients with porphyria or familiar for porphyria should be carefully monitored during treatment with GONAL-f. Worsening or onset of this condition may require discontinuation of therapy.

GONAL-f contains less than 1 mmol sodium (23 mg) per dose, and is therefore virtually "sodium free".

Treatment in women:

Before starting treatment, the couple's infertility should be adequately verified and any contraindications for pregnancy should be evaluated. In particular, patients should be examined for the presence of hypothyroidism, adrenocortical insufficiency, hyperprolactinaemia, hypothalamic or pituitary tumors and carry out appropriate therapy. Patients undergoing follicular growth stimulation as part of anovulatory infertility treatment or assisted reproductive techniques may develop ovarian enlargement or overstimulation. Adherence to recommended GONAL-f dosages, administration methods and careful monitoring of therapy will minimize the incidence of such events. The exact interpretation of the indices of follicular development and maturation requires the experience of a physician specialized in their interpretation.

In clinical studies, there was an increase in ovarian sensitivity to GONAL-f when administered in combination with lutropin alfa. If an increase in FSH dose is deemed appropriate, dosage adjustment should preferably be made in increments of 37.5-75 IU at intervals of 7-14 days.

A direct comparison between GONAL-f / LH and human menopausal gonadotropin (hMG) was not performed. A comparison performed on historical data indicates that the ovulation rate obtained with GONALf / LH is similar to that obtained with hMG.

Ovarian Hyperstimulation Syndrome (OHSS):

OHSS is a distinct medical event from uncomplicated ovarian enlargement. OHSS is a syndrome that can occur with varying degrees of severity. It includes marked ovarian enlargement, high serum steroid hormone levels, and an increase in vascular permeability which can develop into an accumulation of fluid in the peritoneum, pleura and, rarely, in the pericardial cavities. In severe cases of OHSS the following symptoms may be observed: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and symptoms gastrointestinal disorders such as nausea, vomiting and diarrhea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalance, ascites, haemoperitoneum, pleural effusions, hydrothorax, acute pulmonary failure and thromboembolic events. Very rarely, severe OHSS may be complicated by pulmonary embolism, stroke ischemic and myocardial infarction. An "excessive ovar response." ica rarely results in OHSS if administration of hCG to induce ovulation is avoided. Therefore in cases of ovarian hyperstimulation it is prudent not to administer hCG and to advise the patient to refrain from sexual intercourse or to use barrier methods of contraception for at least 4 days. OHSS can evolve rapidly (over 24 hours and over several days) and become a serious clinical event, therefore patients should be monitored for at least two weeks after hCG administration.

Pelvic ultrasound scans and measurement of serum estradiol levels are recommended in order to reduce the risk of OHSS or multiple pregnancies. The main risk factors for OHSS and multiple pregnancy in anovulatory patients are represented by higher estradiol levels of 900 pg / ml (3,300 pmol / l) and the presence of more than three follicles with a diameter equal to or greater than 14 mm. In assisted reproduction techniques (ART) the main risk factors are represented by estradiol levels greater than 3,000 pg / ml (11,000 pmol / l) and by the presence of 20 or more follicles with a diameter equal to or greater than 12 mm. When estradiol levels exceed 5,500 pg / ml (20,200 pmol / l) and in the presence of 40 or more follicles , it is advisable to avoid the administration of hCG. Adherence to recommended dosages, methods of administration and careful monitoring of therapy can minimize the incidence of ovarian hyperstimulation and multiple pregnancies. tiple (see sections 4.2 and 4.8).

In ART, aspiration of all follicles prior to ovulation can prevent hyperstimulation from occurring.

OHSS may become more severe and more protracted if pregnancy occurs. Most often, OHSS occurs after discontinuation of treatment and reaches its maximum levels approximately seven to ten days after treatment. It generally resolves spontaneously with the onset of menstruation.

If severe OHSS occurs, gonadotropin treatment, if still ongoing, should be stopped, the patient hospitalized, and specific therapy for OHSS initiated. This syndrome occurs with a higher incidence in patients with polycystic ovary.

Multiple pregnancy:

Multiple pregnancy, especially multiple pregnancies, leads to an increased risk of adverse maternal and perinatal outcomes.

In patients undergoing induction of ovulation with GONAL-f, the incidence of multiple pregnancies is increased compared to natural conception. The majority of multiple conceptions are twins. To minimize the risk of multiple pregnancies, careful monitoring of the ovarian response is recommended.

In patients undergoing assisted reproductive techniques, the risk of multiple pregnancies is mainly related to the number of embryos transferred, their quality and the patient's age. Before starting treatment, patients should be informed of the potential risk of multiple births.

Termination of pregnancy:

The incidence of miscarriage due to miscarriage before or after the first trimester is higher in patients undergoing follicular developmental stimulation to induce ovulation or ART than in the normal population.

Ectopic pregnancies:

Women with a history of previous tubal disorders are at risk of ectopic pregnancies, whether pregnancy is achieved through spontaneous conception or infertility treatments. A 2-5% prevalence of ectopic pregnancies has been reported after IVF. to 1-1.5% of the general population.

Neoplasms of the reproductive system:

Cases of both benign and malignant neoplasms of the ovary or other neoplasms of the reproductive system have been reported in women undergoing repeated courses of therapy for the treatment of infertility. It has not yet been established whether treatment with gonadotropins increases or not. the baseline risk of these cancers in infertile women.

Congenital malformations:

The prevalence of congenital malformations following ART may be slightly higher than in natural conception. This is thought to be due to different parental characteristics (eg maternal age, semen characteristics) and multiple pregnancies.

Thromboembolic events:

In women with generally recognized risk factors for thromboembolic events, both personal and familial, treatment with gonadotropins may further increase this risk. In such patients the benefit of gonadotropin administration should be weighed against the risk. However, it should be noted that pregnancy itself leads to an increased risk of thromboembolic events.

Treatment in men

Elevated endogenous rates of FSH are indicative of primary testicular failure. Such patients are unresponsive to GONAL-f / hCG therapy.

To assess response, semen analysis is recommended 4-6 months after starting treatment.

04.5 Interactions with other medicinal products and other forms of interaction

The concomitant use of GONAL-f with other ovulation stimulating drugs (eg hCG, clomiphene citrate) can lead to an enhancement of the follicular response, while the concomitant use of a GnRH agonist drug, resulting in pituitary desensitization, may require an increase of the dosage of GONAL-f necessary to achieve an adequate ovarian response. No other clinically significant interactions with other drugs have been reported during therapy with GONAL-f. GONAL-f should not be administered mixed with other drugs in the same syringe, except of lutropin alfa for which studies have been carried out which have shown that the joint administration of the two drugs does not significantly alter the activity, stability, pharmacokinetic and pharmacodynamic properties of the active ingredients.

04.6 Pregnancy and lactation

Use during pregnancy:

There is no indication for the use of GONAL-f during pregnancy. No teratogenic risk has been reported following controlled ovarian hyperstimulation in clinical use with gonadotropins. In case of exposure during pregnancy, clinical data are insufficient to exclude a teratogenic effect of r-hFSH. However, to date, no malformative effects have been reported. No teratogenic effects were observed in animal studies.

Use while breastfeeding:

GONAL-f is not indicated during lactation. Prolactin secretion during lactation may result in a poor response to ovarian stimulation.

04.7 Effects on ability to drive and use machines

No studies on the ability to drive and use machines have been performed.

04.8 Undesirable effects

Within each frequency class, undesirable effects are reported in descending order of severity.

Treatment in women Alterations of the immune system Very rare ( Moderate systemic allergic reactions (e.g. mild forms of erythema, rash, facial swelling, hives, edema, difficulty in breathing). Cases of severe allergic reactions, including anaphylactic reactions, have also been reported Alterations of the nervous system Very common (> 1/10) Headache Alterations of the vascular system Very rare ( Thromboembolism, usually associated with severe OHSS Alterations of the respiratory system, thorax and mediastinum Very rare ( Exacerbation or worsening of asthma Alterations of the gastrointestinal system Municipalities (> 1/100, Abdominal pain and gastrointestinal symptoms such as nausea, vomiting, diarrhea, cramps and abdominal distension. Disorders of the reproductive system and breast Very common (> 1/10) Ovarian cysts Municipalities (> 1/100, Mild or moderate OHSS (see section 4.4) Uncommon (> 1 / 1,000, Severe OHSS (see section 4.4) Rare (> 1 / 10,000, Ovarian torsion as a complication of OHSS General disorders and changes in the administration site Very common (> 1/10) Mild or moderate injection site reactions (pain, redness, bruising, swelling and / or irritation at the injection site)
Treatment in man Alterations of the skin and subcutaneous tissue Municipalities (> 1/100, Acne Disorders of the reproductive system and breast Municipalities (> 1/100, Varicocele gynecomastia General disorders and changes in the administration site Very common (> 1/10) Mild or moderate injection site reactions (pain, redness, bruising, swelling and / or irritation at the injection site) Diagnostic investigations Municipalities (> 1/100, Weight gain

04.9 Overdose

There have been no reported cases of overdose due to GONAL-f, however hyperstimulation syndrome may occur as described in section 4.4.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: gonadotropins, ATC code: G03GA05

GONAL-f is a genetically engineered human follicle-stimulating hormone in Chinese Hamster Ovary (CHO) mammalian cells.

The main effect of parenteral administration of FSH in women is the development of mature Graafian follicles.

In clinical studies, patients with severe LH and FSH deficiency were identified based on serum levels of endogenous LH

05.2 Pharmacokinetic properties

After intravenous administration, GONAL-f distributes into the extracellular fluid space with an initial half-life of approximately 2 hours and is eliminated with a terminal half-life of approximately 1 day.

The steady-state volume of distribution is 10 liters and the total clearance is 0.6 l / hour. One eighth of the administered dose is excreted in the urine.

After subcutaneous administration, the absolute bioavailability is approximately 70%. After repeated administration the accumulation of GONAL-f is 3 times greater reaching the equilibrium phase within 3-4 days.

GONAL-f effectively stimulates follicular development and steroidogenesis even in women with suppressed secretion of endogenous gonadotropins, despite unmeasurable levels of LH.

05.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity other than those already mentioned in other sections of this summary of product characteristics.

Impaired fertility with reduced fecundity was observed in rats exposed to pharmacological doses of follitropin alfa (> = 40 IU / kg / day) for prolonged periods. Given at high doses (> = 5 IU / kg / day) follitropin alfa caused a decrease in the number of live fetuses, without being teratogenic, and dystocia similar to that observed with urinary hMG. However, as GONAL-f is not indicated in pregnancy, these data are of little clinical relevance.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Dust:

sucrose;

monobasic sodium phosphate monohydrate;

disodium phosphate dihydrate;

concentrated phosphoric acid;

sodium hydroxide.

Solvent:

water for injections.

06.2 Incompatibility

The medicinal product must not be mixed with other products except those mentioned in section 6.6.

06.3 Period of validity

2 years.

For single use, for use immediately after opening and reconstitution.

06.4 Special precautions for storage

Do not store above 25 ° C.

Store in the original packaging.

06.5 Nature of the immediate packaging and contents of the package

The powder is packaged in 3 ml ampoules in colorless neutral glass (type I). The solvent is packaged in 3 ml ampoules in type I colorless neutral glass.

The product is supplied in packs of 1, 5, 10 ampoules with the corresponding number of solvent ampoules.

06.6 Instructions for use and handling

For single use only.

GONAL-f must be reconstituted with the solvent before use. GONAL-f can be reconstituted together with lutropin alfa and administered together in a single injection. In this case the lutropin alfa must be reconstituted first and then used to reconstitute the powder by GONAL-f.

The reconstituted solution should not be administered if it contains particles or is not clear. Unused product and waste derived from this medicine must be disposed of in accordance with local legal requirements.