Description
Composition, release form and packaging
Specialized imported drugs
For subcutaneous injection
【Raw materials and their quantity】 1 pre-filled pen (1.5 ml)
Active ingredient: Follitropin alpha (recombinant human follicle-stimulating hormone) (separately) 66.69 mcg (900 IU)
Additives (preservatives): m-cresol 4.5 mg
Additives (excipients): 90 mg white sugar.
Additive (stabilizer) Poloxamer 188 0.15 mg
Other additives: methionine, sodium hydroxide, 85% phosphoric acid, sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, water for injection.
Enclosure: 20 x Disposable Syringes
A pre-filled pen containing a colorless transparent liquid with adjustable dosage.
[Efficacy/action, dosage/dosage, precautions for use] Please refer to the attached document.
[Storage method] Store in a sealed container protected from light at a temperature of 2~8℃, and can be stored for 3 months at a room temperature below 25℃. If not used, it is mandatory.
If it is not refrigerated immediately after the first use, it can be stored at a room temperature below 25℃ for up to 28 days, and all the remaining liquid should be poured out.
Description of dosage form
Transparent colorless solution. Slight opalescence is allowed.
Pharmacotherapeutic group
Recombinant human follicle-stimulating hormone.
Pharmacokinetics
When administered subcutaneously, the absolute bioavailability value is approximately 70%. After repeated injections of GONAL-f®, a threefold accumulation of follitropin alpha in the blood is observed compared to a single injection. Css in the blood is achieved within 3-4 days. After intravenous administration, follitropin alpha is distributed into extracellular fluids, with the initial T1/2 from the body being approximately 2 hours, while the final T1/2 is approximately 24 hours. The Vss value is 10 l, the total clearance is 0.6 l/h. 1/8 of the administered dose of follitropin alpha is excreted by the kidneys.
Pharmacodynamics
GONAL-f® is a recombinant human FSH (r-hFSH) – a drug that stimulates the growth and development of follicles. The drug is obtained by genetic engineering on a culture of Chinese hamster ovary cells. It has a gonadotropic effect: it stimulates the growth and maturation of a 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 alpha) and urinary FSH (u-FSH) for ART and ovulation induction have demonstrated the greater effectiveness of GONAL-f® in initiating follicle maturation in terms of such indicators as a reduction in the cumulative dose and duration of treatment, compared to u-FSH and, thus, a reduced risk of unwanted ovarian hyperstimulation.
For ART, the administration of GONAL-f® in a lower total dose with a shorter duration of treatment leads to obtaining a greater number of retrieved oocytes compared to u-FSH.
It has also been shown that in women with suppressed secretion of endogenous gonadotropins, follitropin alpha effectively stimulates follicular development and steroidogenesis, despite the low level of LH that is inaccessible for measurement.
Indications for use
anovulation (including polycystic ovary syndrome) in women in case of ineffectiveness of clomiphene therapy;
controlled ovarian hyperstimulation in ART programs;
ovarian stimulation in women with severe deficiency of FSH and LH (in combination with LH preparations);
stimulation of spermatogenesis in hypogonadotropic hypogonadism in men (in combination with hCG).
Contraindications for use
hypersensitivity to the drug or excipients, hypothalamic-pituitary tumors;
in women – pregnancy, ovarian masses or cysts (not caused by polycystic ovary syndrome), uterine bleeding of unknown etiology, ovarian cancer, uterine cancer, breast cancer;
the drug should not be prescribed in cases where a positive effect cannot be achieved: in women – with developmental abnormalities of the genitals and uterine fibroids incompatible with pregnancy, primary ovarian insufficiency, premature menopause; in men – with primary testicular insufficiency.
Pregnancy and lactation
During pregnancy and breastfeeding, the drug GONAL-f® is not prescribed.
Side effects
When using the drug GONAL-f®, side effects may develop, which, depending on the frequency of occurrence, are assessed as very common (≥1/10), common (≥1/100,
Use in women
From the immune system: very rare – mild to moderate systemic allergic reactions (e.g. skin redness, rash, facial swelling, urticaria, difficulty breathing), development of severe allergic reactions, including anaphylactic reactions and shock.
From the central nervous system: very common – headache.
From the vasculary system: very rare – thromboembolism, usually associated with severe OHSS.
From the respiratory system: very rare – in patients with bronchial asthma, worsening or exacerbation of the disease.
From the gastrointestinal tract: common – abdominal pain, heaviness, discomfort in the abdomen, nausea, vomiting, diarrhea.
From the reproductive system and mammary glands: very common – ovarian cysts; common – mild or moderate OHSS (including the corresponding symptoms); uncommon – severe OHSS (including the corresponding symptoms); rare – complication of OHSS, ectopic pregnancy (in women with a history of fallopian tube disease), multiple pregnancy.
Local reactions: very common – mild/moderate reactions at the injection site (pain, redness, bruising, swelling).
Use in men
Immune system disorders: very rare – mild to moderate systemic allergic reactions (e.g. skin redness, rash, facial swelling, urticaria, difficulty breathing), development of severe allergic reactions, including anaphylactic reactions and shock.
Respiratory system disorders: very rare – worsening or exacerbation of the disease in patients with bronchial asthma.
Local reactions: very common – mild/moderate reaction at the injection site (pain, redness, bruising, swelling).
Skin and subcutaneous tissue disorders: common – acne.
Reproductive system and mammary gland disorders: common – gynecomastia, varicocele.
Other: common – weight gain.
If serious side effects or effects not described above occur, you must inform your doctor.
Interaction with medicinal products
When GONAL-f® is combined with other stimulating drugs (hCG, clomiphene), the ovarian response is enhanced; against the background of pituitary desensitization with a GnRH agonist or antagonist, it is reduced (an increase in the dose of GONAL-f® is required). There is no data on the interaction of GONAL-f® with other medicinal products.
Method of administration and dosage
Treatment with GONAL-f® should be initiated under the supervision of a specialist physician experienced in the treatment of infertility.
GONAL-f® is intended for subcutaneous administration.
The first injection of GONAL-f® should be carried out under the supervision of the attending physician or qualified medical personnel. Self-administration of GONAL-f® can only be carried out by well-motivated, trained patients who have the opportunity to receive specialist advice.
It is recommended to change the injection site daily.
Women
Anovulation (including polycystic ovary syndrome) in women in case of ineffective therapy with clomiphene. GONAL-f® should be prescribed as a course of daily injections. Treatment is started in the first 7 days of the cycle. Stimulation is carried out under the control of ovarian ultrasound (measuring the size of the follicles) and / or estrogen concentrations. Stimulation is started 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 obtained.
The maximum dose of daily injection should not exceed 225 IU. If there is no positive dynamics after 4 weeks, treatment is stopped. In the next cycle, stimulation should be started with a higher dose than in the previous cycle. After achieving an optimal response, 250 mcg r-hCG or 5000–10000 IU hCG are administered once 24–48 hours after the last injection of GONAL-f®. On the day of the hCG injection and the following day, the patient is advised to have sexual intercourse. Alternatively, intrauterine insemination can be performed.
In case of excessive ovarian response to stimulation, follitropin alfa treatment should be discontinued and hCG should be discontinued. Stimulation is repeated in the next cycle, starting with a lower dose of GONAL-f® compared to the previous cycle.
Controlled ovarian hyperstimulation in ART programs. GONAL-f® is administered daily at 150–225 IU, starting on day 2–3 of the cycle. The daily dose may vary, but usually does not exceed 450 IU. Treatment is continued until the follicles reach an adequate size according to ultrasound data (5–20 days, on average by the 10th day of treatment). 24–48 hours after the last injection of GONAL-f®, 250 μg r-hCG or 5,000–10,000 IU hCG are administered once to induce final maturation of the follicles. A GnRH agonist or antagonist is used to suppress the endogenous LH surge and maintain it at a low level. In the usual protocol, GONAL-f® administration begins approximately 2 weeks after the start of agonist treatment, then both drugs are administered until follicles reach an adequate size. For example, after 2 weeks of agonist treatment, 150–225 IU GONAL-f® is prescribed for 7 days. The dose is then adjusted depending on the ovarian response. The available experience of ART shows that the probability of successful treatment is generally maintained during the first 4 attempts and then gradually decreases.
Ovarian stimulation in women with severe deficiency of FSH and LH (in combination with LH preparations). Dose and treatment regimenthe doctor selects the treatment individually.
Usually GONAL-f® is prescribed daily subcutaneously for up to 5 weeks simultaneously with LH. Treatment with GONAL-f® is started with a dose of 75–150 IU simultaneously with lutropin alpha at a dose of 75 IU. If necessary, the dose of GONAL-f® can be increased by 37.5–75 IU every 7–14 days.
If there is no adequate response to stimulation within 5 weeks, therapy should be stopped and resumed in a new cycle at a higher dose.
After achieving the optimal size of the follicle/follicles, 24–48 hours after the last injection of GONAL-f® and lutropin alpha, 250 mcg r-hCG or 5,000–10,000 IU hCG are administered once. On the day of the hCG injection and the next day, the patient is advised to have sexual intercourse. Alternatively, intrauterine insemination may be performed.
In case of excessive ovarian response to stimulation, follitropin alfa treatment should be discontinued and hCG should be discontinued. Stimulation is repeated in the next cycle, starting with a lower dose of GONAL-f® compared to the previous cycle.
Men
Stimulation of spermatogenesis in hypogonadotropic hypogonadism in men (in combination with hCG). 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. If there is no positive effect during this time, treatment can be continued for up to 18 months.
Recommendations for self-administration of the drug
When self-administering the drug, you must first read the instructions carefully. The doctor will prescribe the patient doses in IU. One package of the drug is intended for use by one patient only. The patient should prepare a pre-filled pen and perform the injection. The next injection should be done the following day at the same time.
1. Wash your hands. It is very important that your hands and all items used by the patient are as clean as possible. Gather everything you need to perform the injection. Lay out everything you will use on a clean surface: 2 alcohol swabs, a pre-filled pen and an injection needle.
2. Prepare the pre-filled GONAL-f® pen for first use: remove the pen cap and attach the needle as described in point 3. Then prime the pen by aligning the dose pointer with point 37.5 on the black scale on the dose setting disk. Pull the injection button out as far as it will go, remove the outer needle cap, then the inner needle cap, while holding the pen and needle vertically (the needle should be pointing upwards). Gently tap the location of the cartridge so that any air bubbles collect at the base of the needle. Point the needle vertically upwards and press the injection button. A drop should appear at the tip of the needle. This means that the pre-filled pen is ready for injection. If no liquid appears 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 points 3 and 4, respectively.
3. Attaching the needle
Take a new needle. If the needle packaging is damaged, do not use it, take a new one. Remove the protective membrane from the outer cap of the needle. Firmly hold the needle by the outer cap, insert the needle into the pen onto the threaded tip, turn clockwise until it clicks into place.
Caution: Only use the needles supplied with the pen or sold separately for this pen.
4. Setting the dose
Set the required dose by turning the dose setting dial with the black scale until the dose value is opposite the arrow (the dose setting dial allows you to set the dose in 37.5 IU increments. The minimum and maximum doses are in the range from 37.5 to 300 IU). After setting the required dose, dial it by pulling the injection button out as far as it will go. Try to lift the button straight up and do not rotate it, as this may change the set dose.
Caution: carefully monitor the set dose on the dial, as after pulling out the injection button, it will no longer be possible to change the dose, as it has already been dialed. If an error is detected after pulling out the injection button and dialing the dose, do not give the injection. Remove the dialed dose and dial again.
Check the red scale of the dose control dial to be sure that the correct dose has been dialed: when the injection button is pulled out, the number on the red scale of the dose control dial, which reflects the dose dialed, is opposite the dose set on the black scale of the dose dial, opposite the arrow. If the dose dialed is less than the required dose, the dosing is not complete. In this case, follow the instructions in point 2.
If the same dose is required each time, the dose indicator arrow should remain in the same position.
5. Dosing
Choose the injection site according to the doctor’s recommendations. Wipe the injection site with an alcohol swab. Use the injection technique recommended by the doctor or nurse. Insert the needle into the skin and presson the injection button. Make sure that the grey full dose indicator is no longer visible. This indicates that the full dose has been delivered. You must keep the needle in the skin and press the injection button for at least 10 seconds. When removing the needle from the skin, you must continue to press the button.
6. Removing the needle
Remove the needle after each injection and discard it. Hold the pen firmly by the medication reservoir. Carefully place the outer cap on the needle. Squeeze the outer cap of the needle and unscrew the needle by turning it counterclockwise. Discard the used needle. Replace the cap on the pen.
7. Storing the pre-filled pen
After injection, remove used needles as described in step 6. Replace the protective cap on the pen. Store the pen in a safe place, preferably in the original packaging. Discard the pen when empty.
Note: The scale, visible through the medication reservoir, serves as an indicator of the amount of medication remaining in the reservoir. It cannot be used to set the dose.
8. The dose control dial with a red scale on the injection button serves to control whether the last dose has been completely drawn up or not. It changes its position, indicating the amount of the drug in the reservoir. If the dose drawn up is not enough to complete the injection, there are two options:
Inject the dose that remains in the pen, and then take a new pen, set the remaining part of the required dose on it and inject it.
Throw away the old pen, take a new one and inject the required dose.
If a dose is missed, do not inject a double dose.
Overdose
There are currently no reported cases of overdose with GONAL-f®.
Precautions and special instructions
Since the drug can cause various side effects, GONAL-f® should only be prescribed by a specialist doctor who is directly involved in infertility problems. The initiation of therapy should be preceded by an examination of the infertile couple, in particular, examinations should be performed to exclude hypothyroidism, adrenal cortex insufficiency, hyperprolactinemia, hypothalamic-pituitary neoplasms, and appropriate therapy should be prescribed if necessary.
It is necessary to assess the patency of the fallopian tubes in order to select the ART method. Obstruction of the fallopian tubes should be excluded if the patient is not participating in the in vitro fertilization program.
In patients with porphyria, as well as with a history of porphyria, careful monitoring is required during therapy with GONAL-f®. If the condition worsens or the first signs of this disease appear, it may be necessary to discontinue therapy.
When treating with GONAL-f®, it is necessary to assess the condition of the ovaries using ultrasound, both separately and in combination with the determination of estradiol in the blood plasma.
The response to the introduction of FSH may differ in different patients, therefore 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. it is not a significant source of sodium.
OHSS should be differentiated from uncomplicated ovarian enlargement. Clinical symptoms of OHSS may manifest with increasing severity. Characteristic features include significant increase in ovarian size, high level of sex hormones, increased vascular permeability leading to accumulation of fluid in the abdominal, pleural and, less commonly, pericardial cavities.
The following symptoms are most characteristic of severe OHSS: pain and a feeling of fullness in the abdomen, marked increase in ovarian size, weight gain, dyspnea, oliguria, gastrointestinal symptoms (nausea, vomiting, diarrhea); hypovolemia, hemoconcentration, electrolyte imbalance, ascites, hemoperitoneum, pleural effusion, hydrothorax, acute respiratory distress syndrome may occur. In very rare cases, severe OHSS may be complicated by ovarian torsion and thromboembolic events such as pulmonary embolism, ischemic stroke or myocardial infarction.
In order to minimize the risk of OHSS and multiple pregnancy, it is recommended to regularly use ultrasound and measure 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 syndrome or high concentration of estradiol in the blood plasma. In anovulation, the risk of developing OHSS increases with an estradiol concentration of >900 pg/mL (3300 pmol/L) and the presence of more than 3 follicles with a diameter of 14 mm or more. In ART, the risk of developing OHSS increases with an estradiol concentration of >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, minimizes the risk of developing OHSS and multiple pregnancies. There is reason to believe that hCG plays a key role in the development of OHSS. With the onset of pregnancy, the severity of OHSS may worsen, and its duration may be reduced.ь increase. When the estradiol level is >5500 pg/mL (20200 pmol/L) or when 40 or more follicles are present, hCG should be withheld. The patient should be advised to abstain from coitus for 4 days or to use barrier methods of contraception.
OHSS can progress rapidly (from one day to several days) to a severe condition. OHSS most often occurs after cessation of hormonal therapy and reaches its peak after 7-10 days, therefore, observation for at least two weeks after hCG administration is necessary.
The incidence of OHSS in patients undergoing controlled ovarian hyperstimulation for ART is reduced by aspiration of all follicles.
Mild to moderate OHSS resolves spontaneously. If severe OHSS develops, gonadotropin therapy, if still ongoing, should be discontinued. The patient should be hospitalized and treated specifically for OHSS.
Multiple Pregnancy
The incidence of multiple pregnancies and births with ovulation induction is higher than with natural conception. The most common variant of multiple pregnancies is twins. Multiple pregnancies, especially with a large number of embryos, increase the risk of adverse outcomes for the mother and fetus. Careful monitoring of the ovarian response is necessary to minimize the risk of multiple pregnancies. In ART, the risk of multiple pregnancies is mainly related to the number of embryos transferred, their viability, and the patient’s age.
Miscarriage
The incidence of miscarriage or spontaneous abortions (abortions) after ovulation induction and ART programs is higher than in the general population.
Ectopic Pregnancy
Patients with a history of fallopian tube disease have an increased risk of ectopic pregnancy. The likelihood of ectopic pregnancy after the use of assisted reproductive technologies is higher than in the general population.
Neoplasms of the reproductive system
There are reports of benign and malignant neoplasms of the ovary and other reproductive organs in women after multiple courses of infertility treatment with various drugs. At present, no association has been established between gonadotropin therapy and an increased risk of neoplasms in infertility.
Congenital anomalies
The incidence of congenital anomalies after the use of ART programs may be somewhat higher than in natural pregnancy and childbirth. However, it is unknown whether this is due to the characteristics of the parents (e.g., maternal age, sperm quality) and multiple pregnancies or directly to ART procedures.
Thromboembolic complications
In patients with recent or ongoing thromboembolic diseases, as well as with a probable 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 benefit 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 concentrations in men may indicate primary testicular failure. In this case, r-hFSH/hCG treatment is ineffective and GONAL-f® should not be prescribed.
It is recommended to have a spermogram monitored 4–6 months after the start of the therapy. Patients should be aware of the above risks before starting therapy.
It is necessary to inform the physician about all types of allergic reactions that the patient has, as well as about all medications used before starting treatment with GONAL-f®.
It is necessary to mark the date of first use on the pen with the drug.
After the first use, the drug can be stored for no more than 28 days at a temperature not exceeding 25 °C. Do not use the drug after this period. Within the expiration date, the drug can be stored at a temperature not exceeding 25 °C for up to 3 months. After 3 months, it should be destroyed if it has not been used. Re-placing in the refrigerator is not allowed.
The effect of the drug on driving a car and operating other mechanisms. The drug GONAL-f® does not affect the ability to drive a car and operate other mechanisms.
Storage conditions
In the refrigerator +2 +8 degrees
Conditions of dispensing from pharmacies
By prescription
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