Instruction for use: Gonal-F

ATX Code G03GA05 Foliotropin alfa

Active substance Follitropin alfa

Pharmacological group

Hormones of the hypothalamus, pituitary gland, gonadotropins and their antagonists

Composition

Solution for subcutaneous administration 1 pre-filled syringe pen

active substance:

Follicropin alfa 22 mcg (300 IU)

33 μg (450 IU)/ 66 μg (900 IU)

Auxiliary substances: poloxamer 188 - 0,05 / 0,075 / 0,15 mg; Sucrose - 30/45/90 mg; Methionine - 0.05 / 0.075 / 0.15 mg; Sodium dihydrogen phosphate monohydrate 0.225 mg / 0.3375 / 0.675 mg; Sodium hydrogen phosphate dihydrate - 0.555 / 0.8325 / 1.665 mg; M-cresol 1.5 / 2.25 / 4.5 mg; Phosphoric acid - q.s .; Sodium hydroxide - q.s .; Water for injection - up to 0.5 / 0.75 / 1.5 g

Description of dosage form

Clear colorless solution. Light opalescence is permissible.

Pharmacodynamics

GONAL-f® - recombinant human FSH (r-hFSH) - is a drug that stimulates the growth and development of follicles. The preparation is obtained by genetic engineering on the culture of Chinese hamster ovary cells. Has a gonadotropic effect: stimulates the growth and maturation of the follicle / follicles, promotes the development of several follicles during controlled ovarian hyperstimulation for assisted reproductive technology (ART) programs.

Comparative clinical studies of r-hFSH (follitropin alfa) and urinary FSH (y-FSH) for ART and induction of ovulation demonstrated the high efficacy of GONAL-f® to initiate follicular maturation in terms of both the cumulative dose reduction and the duration of treatment, compared with Y-FSH and, thus, a reduction in the risk of unwanted ovarian hyperstimulation.

For ART, the administration of GONAL-f® at a lower total dose with a shorter duration of treatment results in a greater number of oocytes recovered than y-FSH.

It has also been shown that in women with suppressed secretion of endogenous gonadotropins, follitropin alfa effectively stimulates the development of follicles and steroidogenesis, despite the inaccessibility of a small level of LH for measurement.

Pharmacokinetics

With n / k introduction, the absolute bioavailability is about 70%. After repeated injections of GONAL-f®, three-fold cumulation of follitropin alfa in the blood is observed compared to a single injection. Css in the blood is reached within 3-4 days. After intravenous administration of follitropin, alpha is distributed into extracellular fluids, with the initial T1 / 2 excreted from the body approximately 2 hours, whereas the final T1 / 2 is approximately 24 hours. The Vss value is 10 liters, the total clearance is 0.6 liters / h . 1/8 of the administered dose of follitropin alfa is excreted by the kidneys.

indications

Anovulation (including polycystic ovary syndrome) in women with clomiphene ineffective;

Controlled ovarian hyperstimulation in ART programs;

Ovarian stimulation in women with severe deficiency of FSH and LH (in combination with drugs LH);

Stimulation of spermatogenesis in hypogonadotropic hypogonadism in men (in combination with HG).

Contraindications

Hypersensitivity to the drug or excipients, hypothalamic-pituitary tumors;

In women - pregnancy, voluminous neoplasms or ovarian cysts (not caused by polycystic ovary syndrome), uterine bleeding of unclear etiology, ovarian cancer, uterine cancer, breast cancer;

The drug should not be prescribed in cases where a positive effect can not be obtained: in women - with abnormalities of genital organs and uterine fibroids, incompatible with pregnancy, primary ovarian failure, premature menopause; In men - with primary testicular failure.

pregnancy and lactation

During pregnancy and breastfeeding, GONAL-f® is not prescribed

Side effects

The use of the drug GONAL-f® may lead to the development of side effects, which, depending on the frequency of occurrence, are regarded as very frequent (≥1/10), frequent (≥1 / 100, <1/10), infrequent (≥1 / 1000, <1/100), rare (≥1 / 10000, <1/1000), very rare (<1/10000, including single messages). The frequency of side effects in each group is listed in descending order.

Application in Women

From the immune system: very rarely - from mild to moderate severity of systemic allergic reactions (eg, redness of the skin, rashes, swelling of the face, urticaria, shortness of breath), the development of severe allergic reactions, incl. Anaphylactic reactions and shock.

From the side of the central nervous system: very often - a headache.

From the vascular system: very rarely - thromboembolism, usually associated with a severe form of SWN.

On the part of the respiratory system: very rarely - in patients with bronchial asthma, worsening of the course or exacerbation of the disease.

From the gastrointestinal tract: often - abdominal pain, heaviness, discomfort in the abdomen, nausea, vomiting, diarrhea.

On the part of the reproductive system and mammary glands: very often - ovarian cysts; Often - HSH of mild or moderate severity (including the corresponding symptomatology); Infrequently - severe form of SWC (including the corresponding symptomatology); Rarely complication of OHSS (see "Special instructions"), ectopic pregnancy (in women who have a history of tubal ligation), multiple pregnancies.

Local reactions: very often - mild to moderate reactions at the injection site (pain, redness, bruising, swelling).

Use in men

On the part of the immune system: very rarely - from mild to moderate severity of systemic allergic reactions (eg, redness of the skin, rashes, swelling of the face, urticaria, shortness of breath), development of severe allergic reactions, incl. Anaphylactic reactions and shock.

On the part of the respiratory system: very rarely - in patients with bronchial asthma, worsening of the course or exacerbation of the disease.

Local reactions: very often a mild to moderate reaction at the injection site (pain, redness, bruising, swelling).

From the skin and subcutaneous tissue: often - the appearance of acne (acne).

On the part of the reproductive system and mammary glands: often - gynecomastia, varicocele.

Other: often - weight gain.

If serious side effects or effects occur that are not described above, you should tell your doctor.

Interaction

With the combination of GONAL-f® with other stimulant drugs (hCG, clomiphene), the response of the ovaries increases; Against the background of desensitization of the pituitary gland by an agonist or antagonist of GnRH - decreases (an increase in the dose of GONAL-f® is required). There is no data on the interaction of GONAL-f® with other drugs.

Dosing and Administration

Treatment with GONAL-f® should be started under the supervision of a specialist doctor who has experience in treating infertility.

The drug GONAL-f® is intended for administration.

The first injection of GONAL-f® should be performed under the supervision of the attending physician or qualified medical personnel. Self-introduction of GONAL-f® can only be carried out by patients who are well-motivated, trained and have the opportunity to receive expert advice.

It is recommended to change the injection site daily.

Women

Anovulation (including polycystic ovary syndrome) in women in case of ineffective clomiphene therapy. GONAL-f® should be administered daily in the form of daily injections. Treatment begins in the first 7 days of the cycle. The stimulation is carried out under the control of the ovary ultrasound (measure the size of the follicles) and / or the concentration of estrogens. The stimulation starts with a daily dose of 75-150 IU, increasing by 37.5-75 IU after 7-14 days until an adequate but not excessive response is received.

The maximum dose of a daily injection should not exceed 225 IU. In the absence of positive dynamics after 4 weeks treatment is stopped. In the next cycle, stimulation should begin with a higher dose than in the previous cycle.

After the optimal response is reached, after 24-48 hours after the last injection of GONAL-f®, 250 μg r-hHG or 5000-10000 IU hCG are administered once. On the day of injection of hCG and the next day, the patient is recommended to have sexual intercourse. As an alternative, intrauterine insemination can be performed.

In case of excessive ovarian response to stimulation, treatment with folbitropin alfa should stop and discontinue the administration of hCG. Stimulation is repeated in the next cycle, starting with a lower dose of GONAL-f® than in the previous cycle.

Controlled ovarian hyperstimulation in ART programs. GONAL-f® is prescribed daily for 150-225 IU starting from the 2-3rd day of the cycle. The daily dose may vary, but usually does not exceed 450 IU. Treatment is continued until the follicles reach adequate size according to ultrasound (5-20 days, on average, on the 10th day of treatment). 24-48 hours after the last injection of GONAL-f®, 250 μg of r-hCG or 5000-10000 IU hCG are injected once to induce the final maturation of the follicles.

To suppress the endogenous release of LH and maintain it at a low level, an agonist or antagonist of GnRH is used. In a conventional protocol, the administration of GONAL-f® commences approximately 2 weeks after initiation of treatment with an agonist, then the administration of both drugs is continued until the follicles are adequately sized. For example, after 2 weeks of treatment with an agonist, 150-225 IU of GONAL-f® is prescribed for 7 days. In the future, the dose is adjusted depending on the response of the ovaries. The existing experience of ART shows that in the main the probability of successful treatment is preserved during the first 4 attempts and then gradually decreases.

Ovarian stimulation in women with severe deficiency of FSH and LH (in combination with drugs LH). Dose and treatment scheme is selected by the doctor individually.

Usually, GONAL-f® is prescribed daily for 5 weeks at the same time as LH. Treatment with GONAL-f ® starts with a dose of 75-150 IU simultaneously with lutropin alfa in a dose of 75 IU. If necessary, the dose of GONAL-f® can be increased by 37.5-75 IU every 7-14 days.

In the absence of an adequate response to stimulation for 5 weeks, therapy should be discontinued and restarted in a new cycle at a higher dose.

After the optimal size of the follicle / follicles is reached, after 24-48 hours after the last injection of GONAL-f® and lutropin alfa, 250 μg of r-hCG or 5000-10000 IU hCG are administered once. On the day of injection of hCG and the next day, the patient is recommended to have sexual intercourse. As an alternative, intrauterine insemination can be performed.

In case of excessive ovarian response to stimulation, treatment with folbitropin alfa should be discontinued and the administration of hCG should be discontinued. Stimulation is repeated in the next cycle, starting with a lower dose of GONAL-f® than in the previous cycle.

The Men

Stimulation of spermatogenesis in hypogonadotropic hypogonadism in men (in combination with HG). Men are usually prescribed GONAL-f® at a dose of 150 IU 3 times a week for at least 4 months in combination with hCG. In the absence of a positive effect during this time, treatment can be continued up to 18 months.

Overdose

At present, overdoses of GONAL-f® have not been reported. Apparently, it is necessary to expect the appearance of the OHS, which is described in more detail in the section "Special instructions".

special instructions

Because the drug can cause various adverse reactions, GONAL-f® should only be prescribed by a specialist doctor directly dealing with infertility problems. The initiation of therapy should be preceded by examination of the infertile couple, in particular, examinations should be conducted to exclude hypothyroidism, adrenocortical insufficiency, hyperprolactinaemia, hypothalamic-pituitary tumors, and, if necessary, prescribe appropriate therapy.

It is necessary to assess the patency of the fallopian tubes in order to select the ART method. It is necessary to exclude obstruction of the fallopian tubes if the patient does not participate in the program of in vitro fertilization.

In patients with porphyria, as well as in the presence of porphyria in an anamnesis, during the therapy with GONAL-f®, careful monitoring is required. If the condition worsens or the first signs of this disease appear, it may be necessary to stop the therapy.

When treating with GONAL-f®, evaluation of the ovarian condition by ultrasound is required, either alone or in combination with the determination of estradiol in blood plasma.

The response to FSH administration may differ in different patients, so the minimum effective doses should be used in both women and men.

The drug GONAL-f® contains less than 1 mmol (23 mg) of sodium in 1 dose, i.e. Is not a significant source of sodium.

OCG must be differentiated from uncomplicated ovarian enlargement. The clinical symptoms of HNS can be manifested with increasing severity. A significant increase in the size of the ovaries, a high level of sex hormones, an increase in vascular permeability, leading to accumulation of fluid in the abdominal, pleural and, rarely, pericardial cavities.

For severe SWC, the following symptoms are most typical: pain and feeling of raspiraniya in the abdomen, a pronounced increase in the size of the ovaries, weight gain, shortness of breath, oliguria, gastrointestinal symptoms (nausea, vomiting, diarrhea); Hypovolaemia, hemoconcentration, electrolyte imbalance, ascites, hemoperitonium, pleural effusion, hydrothorax, acute respiratory distress syndrome may occur. In very rare cases, severe SWC may be complicated by ovarian torsion and cases of thromboembolism, such as pulmonary embolism, ischemic stroke, or myocardial infarction.

In order to minimize the risk of CHD and multiple pregnancies, it is recommended to regularly use ultrasound and evaluate the concentration of estradiol in the blood plasma for early identification of risk factors.

Independent risk factors for the development of OHSS are polycystic ovary or a high concentration of estradiol in the blood plasma. With anovulation, the risk of developing CHD increases with an estradiol concentration> 900 pg / ml (3300 pmol / L) and the presence of more than 3 follicles with a diameter of 14 mm or more. With ART, the risk of developing CHD increases with an estradiol concentration> 3000 pg / ml (11000 pmol / L) or the presence of 20 or more follicles with a diameter of 12 mm or more.

Strict adherence to the recommended dosage of GONAL-f®, as well as careful monitoring of therapy, minimize the risk of developing CHD and multiple pregnancies.

There is reason to believe that hCG plays a key role in the emergence of OHSS. At the onset of pregnancy, the severity of SWN may worsen, and its duration may increase. When the estradiol level> 5500 pg / ml (20200 pmol / L) or when 40 or more follicles are present, abstain from using hCG. The patient is recommended to abstain from coitus for 4 days or use barrier methods of contraception.

SHG can quickly progress (from days to several days) to a serious condition. Most often, CHD occurs after cessation of hormonal therapy and reaches its maximum after 7-10 days, therefore, after administration of hCG, it is necessary to observe for at least two weeks.

The probability of occurrence of OHSS in patients undergoing controlled ovarian hyperstimulation for ART is reduced by aspiration of all follicles.

HSH of mild or moderate severity passes spontaneously. In the development of severe HSH, gonadotropin therapy, if it continues, should be discontinued. The patient should be hospitalized and prescribed a specific therapy for CHD.

Multiple pregnancy

The frequency of multiple pregnancy and childbirth with induction of ovulation is higher in comparison with natural conception. The most common option for multiple pregnancies is twins. Multiple pregnancy, especially in the case of a large number of embryos, increases the risk of an adverse outcome for the mother and fetus. To minimize the risk of multiple pregnancies, careful monitoring of the ovarian response is necessary. In ART, the risk of multiple pregnancies is mainly related to the number of embryos transferred, their viability and the age of the patient.

Unintention of pregnancy

The incidence of miscarriage or spontaneous abortions (miscarriages) after induction of ovulation and ART programs is higher than in the general population.

Ectopic pregnancy

Patients with tubal diseases have a history of increased risk of ectopic pregnancy. The probability of ectopic pregnancy after the use of assisted reproductive technologies is higher than in the general population.

Neoplasms of the organs of the reproductive system

There are reports of benign and malignant neoplasms of the ovary and other reproductive organs in women after repeated induction of courses of infertility treatment with various medications. At present, the relationship between gonadotropin therapy and an increased risk of neoplasm with infertility has not been established.

Congenital malformations

The frequency of congenital anomalies after the application of ART programs can be slightly higher than with natural pregnancy and childbirth. Nevertheless, it is not known whether this is due to the peculiarities of the parents (for example, the age of the mother, the quality of the sperm) and the multiple pregnancy or directly with the ART procedures.

Thromboembolic complications

In patients with recent or current thromboembolic disease, and with a possible risk of their occurrence, the use of gonadotropins may increase this risk or complicate the course of these diseases. For patients in this group, the benefits of therapy should be correlated with the possible risk. It should be noted that pregnancy itself carries an increased risk of thromboembolic disorders.

Treatment of men

Elevated serum FSH concentration in men may indicate primary testicular failure. In this case, treatment with r-hFSH / xXG is ineffective and GONAL-f® should not be prescribed.

After 4-6 months after the start of the course of therapy, it is recommended to carry out a control of the spermogram. Patients should be aware of the risks listed above before starting therapy.

It is necessary to inform the doctor about all types of allergic reactions that are present in the patient, as well as about all drugs used before starting treatment with the drug GONAL-f®.

It is necessary to mark the date of the first application on the pen with the drug.

After first use, the drug can be stored for no longer than 28 days at a temperature of no higher than 25 ° C. Do not use the drug after this period. Within the shelf life of the drug can be stored at a temperature of no higher than 25 ° C to 3 months. After 3 months it should be destroyed, if it was not used. Re-placing in the refrigerator is not allowed.

Effect of the drug on driving and control of other mechanisms. The drug GONAL-f® does not affect the ability to drive a car and control other mechanisms.

Recommendations for self-administration of the drug

When using the drug alone, you must first read the instructions carefully. The doctor will give the patient a dose in IU. One package of the drug is intended for use by only one patient. The patient should prepare a pre-filled pen and inject. The next injection should be done the next day at the same time.

1. Wash your hands. It is very important that the hands and all the items that the patient uses are as clean as possible. Collect everything you need to complete the injection. On a clean surface, decompose everything that will be used: 2 alcohol impregnated swabs, pre-filled pen and needle for injection.

2. Prepare the pre-filled GONAL-f® handle for first use: remove the handle cap and insert the needle as described in step 3. Then refill the handle by setting the arrow-dose indicator opposite point 37.5 on the black dial to set the dose. Pull out the button for injection until it stops, remove the outer needle cap, then - the inner needle cap, while holding the handle with the needle vertically (the needle should point upwards). Carefully knock on the location of the cartridge so that possible air bubbles gather at the base of the needle. While directing the needle vertically upwards, press the button for injection. A drop should appear at the tip of the needle. This means that the pre-filled pen is ready for injection. If liquid does not appear at the tip of the needle, repeat the preparation process. Then set the dose as described in point 4. For the next injection, put on the needle and set the dose, as described in par. 3 and 4 respectively.

3. Attaching the needle

Take a new needle. If the needle packing is broken, do not use it, it is necessary to take a new one. Remove the protective membrane from the outer needle cap. While firmly holding the needle behind the outer cap, insert the needle into the handle on the threaded tip, turn clockwise until it clicks into place.

Caution: Use only the needles supplied with the handle or supplied separately for this handle.

4. Setting the dose

Set the required dose by turning the dial of the dose setting with a black scale until the dose value is in front of the arrow (the dose setting dial allows you to set the dose at an interval of 37.5 ME Minimum dose and maximum dose are in the intervals from 37.5 to 300 IU ). After setting the required dose, dial it, pulling the button for injection until it stops. Try to raise the button directly, and not rotate it, tk. This can change the established dose.

Caution: carefully monitor the set dose on the disc, as the After pulling the button for injection, you can no longer change the dose; She has already been recruited. If an error is found after pulling the injection button and dose set, do not inject. Remove the dialed dose and repeat the dialing again.

Check the red scale of the dose control dial in order to be sure that the correct dose was typed: when the injection button is extended, the digit on the red dial of the control disc, reflecting the dialed dose, is against the dose set on the black scale dial dial against the arrow. If the collected dose is less than the required dose, the dosing is not completed. In this case it is necessary to follow the instructions given in clause 2.

If the same dose is required each time, the arrow-dose indicator should remain at the same position.

5. Dosing Introduction

Choose the injection site in accordance with the doctor's recommendations. Wipe the injection site with an alcohol swab. Use the technique of administration recommended by a doctor or nurse. Insert the needle into the skin and press the button for injection. Make sure that the gray indicator of the full dose has become invisible. This position of the indicator indicates the delivery of the full dose. You must hold the needle in the skin and keep the button pressed for at least 10 seconds. When removing the needle from the skin, keep pressing the button.

6. Removing the needle

Remove the needle after each injection and discard it. Hold the handle firmly behind the drug tank. Carefully place the outer cap on the needle. Clamp the outer needle cap and unscrew the needle counter-clockwise. Discard the used needle. Put the cap on the handle.

7. Storing a pre-filled pen

After the injection, remove the used needles, as described in step 6. Attach the protective cap to the handle. Store the pen in a safe place, preferably in its original packaging. After the pen is empty, discard it.

Note. A scale that can be seen through the reservoir for the drug serves as an indicator of the volume of the drug remaining in the reservoir. It can not be used to set a dose.

8. The dose control dial with a red scale on the injection button serves to monitor whether the last dose was fully dialed or not. He changes his position, indicating the amount of the drug in the tank. If the dialed dose is not sufficient to complete the injection, there are two possibilities:

a. Enter the dose that remained in the handle, and then take a new pen, install the remaining part of the required dose on it and enter it.

B. Discard the old pen, take a new one and enter the required dose.

If more is entered than required, see "Side effect" and "Overdose".

When a dose is missed, a double dose should not be given.

Form of issue

A solution for subcutaneous administration was 22 μg / 0.5 ml, 33 μg / 0.75 ml, 66 μg / 1.5 ml. 0.5 ml (contains 22 μg of active substance, equivalent to 300 IU), 0.75 ml (contains 33 μg of active substance, equivalent to 450 IU) or 1.5 ml (contains 66 μg, equivalent to 900 IU ) In the syringe pen.

A syringe pen with 5 (for a dosage of 22 μg / 0.5 ml), 7 (for a dosage of 33 μg / 0.75 ml) or 14 (for dosing 66 μg / 1.5 ml) with disposable needles in a plastic container and a sticker To mark the first day of introduction placed in a cardboard box.

Terms of leave from pharmacies

On prescription.

Storage conditions

In the dark place at a temperature of 2-8 ° C (do not freeze). 3 years - solvent; After cooking - 28 days (at a temperature of no higher than 25 ° C).

Keep out of the reach of children.

Shelf life

2 years.

Do not use after the expiry date printed on the package.