Instruction for use: Pergoveris

ATX Code G03GA05 Foliotropin alfa

Pharmacological group

Follicle-stimulating and luteinizing agent [Hormones of hypothalamus, pituitary gland, gonadotropins and their antagonists]

Nosological classification (ICD-10)

Z31.1 Artificial insemination

Fence of egg, ICSI (Intra Cytoplasmic Sperm Injection), Controlled ovarian stimulation, Controlled superovulation, Controlled superovulation in artificial insemination, Treatment of insemination, Fertilization artificial, Premature ovulation, The IVF program, The program of in vitro fertilization, Superovulation

Z31.2 In Vitro Fertilization

Support of the luteal phase in the spontaneous or induced menstrual cycle, Support of the luteal phase during preparation for in vitro fertilization, Reproductive technologies, Superovulation, ECO, In Vitro Fertilization, Controlled superovulation in in vitro fertilization

Composition

Lyophilizate for the preparation of a solution for subcutaneous administration 1 vial.

active substance:

Follicotropin alfa 150 IU (11 μg)

Lutropin alfa 75 IU (3 μg)

Auxiliary substances: sucrose - 30 mg, sodium hydrogen phosphate dihydrate - 1.11 mg, sodium dihydrogen phosphate monohydrate 0.45 mg, methionine 0.1 mg, polysorbate 20-0.05 mg, phosphoric acid concentrated to pH 6.5 -7.5, sodium hydroxide - up to pH 6.5-7.5

1 fl. With solvent contains: water for injection - 1 ml

The reconstituted solution contains 150 IU of foliotropin alfa and 75 IU of lutropin alfa in 1 ml

Description of dosage form

Lyophilizate: white or almost white lyophilized powder or porous mass.

Reconstituted solution: a clear or slightly opalescent colorless or pale yellow solution.

Solvent: clear, colorless liquid.

pharmachologic effect

Pharmacological action - luteinizing, follicle-stimulating.

Pharmacodynamics

Pergoversion® is a combined drug containing recombinant human FSH (follicotropin alfa, p-FSHh) and recombinant human LH (lutropin alfa, p-LHh). The preparation is obtained by genetically engineered method on the culture of Chinese hamster ovary cells.

The main role of FSH is to initiate folliculogenesis by acting on granulosa cells of the developing follicle, whereas LH plays an important role in enhancing the production of estradiol by the mature follicle, induces follicle maturation and ovulation at the peak of its activity. LH supports the functioning of the yellow body and, thus, ensures the onset and development of pregnancy in the early stages.

In the process of follicle development, FSH together with estradiol induces LH receptors on the membrane of granulosa cells.

The effect of LH on the cells of the current generates androgen production for granulosa cells, where the transformation of androgens into estrogens through the aromatase system takes place. Thus, in the absence of LH, FSH can induce follicle growth, but the synthesis of estradiol is reduced. Without a sufficient amount of estradiol, the conditions for the onset of pregnancy are violated, as well as the secretion of cervical mucus, the growth of the endometrium, and the maturation of a full-blown yellow body in response to the introduction of human HG (hCG).

In clinical studies, the efficacy of the combination of follitropin alfa and lutropin alfa has been shown in hypogonadotropic hypogonadism in women.

When stimulating the development of follicles in women with anovulation with a deficiency of LH and FSH, the main effect of lutropin alfa is an increase in the secretion of estradiol follicles, the growth of which, in turn, is stimulated by FSH.

It was shown that in women with hypogonadotropic hypogonadism and serum LH concentration below 1.2 IU / L, the daily use of a combination of lutropin-alpha in a dose of 75 IU and foliotropin-alpha in a dose of 150 IU leads to the adequate development of follicles and an increase in the synthesis of estradiol, while As a combination of lutropin alpha 25 IU and follicropin alpha 150 IU does not provide such an effect.

Thus, with the appointment of less than one vial pergoversion® per day, the activity of LH may be insufficient for the full development of follicles.

Although the efficacy of p-FSHH monotherapy with the use of assisted reproductive technologies (ART) has been proven, the published results of clinical studies indicate the benefits of the additional p-LHh administration in patients with insufficient (suboptimal) efficacy of p-FSHh monotherapy.

The addition of p-LHh is intended to increase ovarian sensitivity to p-FSHh, to stimulate the secretion of estradiol by the preovulatory follicle that causes endometrial growth, and to provide later luteinization of the follicles, which leads to normalization of the level of progesterone in the luteal phase.

Pharmacokinetics

Folitropin-alpha and lutropin-alpha, administered in combination, retain the same pharmacokinetic characteristics as separately.

Foliotropin alfa

After intravenous administration of follitropin, alpha is distributed in extracellular fluids, with the initial T1 / 2 of the body being about 2 hours, while the final T1 / 2 is about 24 hours. The Vss value is 10 liters, the total clearance is 0.6 liters / H. One eighth of the administered dose of follitropin alfa is excreted by the kidneys.

With n / k introduction, absolute bioavailability is about 70%. After repeated injections, there is a triple cumulation of the drug in the blood compared to a single injection. Stationary Css in the blood is reached within 3-4 days. It has also been shown that in women with inhibited secretion of endogenous gonadotropins, follitropin alpha effectively stimulates the development of follicles and steroidogenesis, despite the inaccessibility of a small amount of LH for quantitative measurement.

Lutropin alfa

After intravenous administration of lutropin, alpha is rapidly distributed with an initial T1 / 2 of about 1 hour, and is excreted from the body with a finite T1 / 2 of about 10-12 hours. Vss is 10 to 14 liters. Lutropin alfa shows a linear pharmacokinetic profile, which is confirmed by the direct proportional dependence of AUC on the administered dose. The total clearance is about 2 l / h, less than 5% of the dose is excreted by the kidneys.

The average retention time in the body is 5 hours.

After sc administration, lutropin alfa is rapidly distributed in organs and tissues, absolute bioavailability is about 60%; The finite T1 / 2 is somewhat elongated. The pharmacokinetics of lutropin alfa when administered once is comparable to that of multiple, the degree of cumulation is minimal. With the simultaneous administration of lutropin-alpha and foliotropin, no pharmacokinetic interaction was observed.

Indications

Stimulation of growth and maturation of follicles in women - with marked deficiency of LH and FSH.

Suboptimal response in patients with previously conducted controlled ovarian stimulation (CBS), which was characterized by either a small number of preovulatory follicles / oocytes obtained (less than 7), or by using high doses of FSH (3000 IU and more / per cycle) or the patient's age (35 Years and older), either individually or in combination, during an assisted reproductive technology (ART) program: in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), gamete / si transplantation Goth into the fallopian tubes (GIFT / ZIFT).

Contraindications

Hypersensitivity to any of the active or auxiliary substances or a combination thereof;

Tumors of the hypothalamus and / or pituitary gland;

Volumetric neoplasms or ovarian cysts not caused by the syndrome of polycystic ovaries;

Uterine and / or other gynecological bleeding of unclear etiology;

Ovarian cancer, uterine cancer, breast cancer;

Pregnancy and lactation;

Primary ovarian failure;

Abnormalities of development of female genitalia, incompatible with pregnancy;

Fibroid tumors of the uterus, incompatible with pregnancy.

pregnancy and lactation

The drug Pergoveris® is contraindicated for use during pregnancy and breastfeeding.

Side effects

With the use of the drug Pergoveris, it is possible to develop side effects that, depending on the incidence, are divided into very rare (<1/10000 applications), rare (≥1 / 10000 and <1/1000), infrequent (≥1 / 1000 and < 1/100), frequent (≥1 / 100 and <1/10) and very frequent (≥1 / 10).

From the side of the central nervous system: very often - headache; Often - drowsiness.

From the genitals and the breast: very often - ovarian cysts; Often - a syndrome of hyperstimulation of the ovaries (SWS) of mild severity (accompanied by pain in the abdomen, nausea, vomiting, weight gain, increased ovaries, including due to the formation of cysts); Often - HSH of moderate severity (except for abdominal pain, nausea, vomiting, weight gain and ovaries, dyspnoea, oliguria, ascites, pleural effusion, accumulation of fluid in the pericardial cavity). For more information, see "Special instructions"; Often - pain in the area of the mammary glands; Pelvic pain; Infrequently, a severe form of HSH (can be accompanied by severe forms of ascites, pleural effusion, accumulation of fluid in the pericardial cavity, oliguria, acute respiratory distress syndrome and pulmonary embolism (very rare).) For details, see "Special instructions" Ovarian cysts (as a complication of HHV).

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

From the heart and blood vessels: very rarely - thromboembolism, usually associated with a severe form of SWC.

From the respiratory system: very rarely - worsening of the course or exacerbation of asthma in patients with bronchial asthma.

On the part of the immune system: very rarely - systemic allergic reactions of varying severity (redness of skin, urticaria, rash, face swelling, difficulty breathing, generalized edema, anaphylaxis, fever, arthralgia)

Local reactions: very often - reactions of varying severity at the injection site (pain, redness, bruise, swelling).

When follitropin alfa (p-FSHCH) is used, the following undesirable effects are possible: rarely - ovarian apoplexy, ectopic pregnancy (in women who have a history of fallopian tube disease), multiple pregnancies.

All the undesirable phenomena that occur when using Pergoveris® should be reported immediately to the treating physician.

Interaction

The incompatibility of the drug Pergoveris ® with other medications has not been reported. Do not mix Perergovery® with any other drug in one syringe, except for foliotropin alfa.

Dosing and Administration

The preparation Pergoversion® is intended for the administration of p / to!

Treatment with Pergoveris® should be started and carried out only under the supervision of a doctor who has the appropriate specialization and experience in treating infertility.

The lyophilizate is dissolved with the applied solvent just before administration, and the resulting solution for s.c. injection is used once.

The rest of the unused solution, as well as used syringes and empty vials should be disposed of immediately after the injection.

Stimulation of growth and maturation of follicles in women with severe LH and FSH deficiency

The recommended initial dose of Pergoveris® is 1 f. (150 IU p-FGGh + 75 IU p-LHh) per day. Since this group of patients is characterized by amenorrhea and a low endogenous level of estrogen secretion, a course of therapy can be started any day.

The duration of the course is selected individually, in accordance with the growth / size of the follicle, determined during ultrasound monitoring, and based on the concentration of estrogen in the blood serum.

If a decision is made to increase the dose of p-FSHh, it is recommended to increase it after 7-14 days, preferably at 37.5-75 IU of foliotropin alfa.

The solution of Pergoveris ® can be mixed with follitropin alfa and administered in one injection. It is possible to increase the duration of stimulation within one of the cycles up to 5 weeks. Once the optimal response is reached, 5,000 to 10,000 IU of hCG or 250 μg of r-hCG is administered once in the 24-48 hour interval after the last injection of Pergoveris®. Sexual contact is recommended on the same day and the day after the introduction of hCG, as an alternative, the intrauterine insemination (IUD) method can be used.

Luteal phase support may be required, since a lack of luteotropic activity (LH / hCG) after ovulation can lead to premature malnutrition of the yellow body.

With excessive ovarian response to stimulation, therapy should be suspended, and the introduction of hCG - postponed. The course of therapy can be resumed in the next cycle using a dose of p-FSHh lower than in the previous cycle.

Suboptimal response in patients with previous CBS in ART programs

The recommended treatment regimen begins with IU p-FSHCH once a day for 5-7 days. Starting from the 6th-8th day of controlled ovarian stimulation (CBS), p-FSHCH is replaced by 2 fl. Of the preparation Pergoveris® (300 IU p-FSHCH and 150 IU p-LHh). An alternative treatment regimen may be the administration of 2 vials of Pergoveris® (300 IU p-FSHh and 150 IU p-LHh) per day starting from the first day of CBS following the desensitisation of the pituitary.

Treatment continues to an adequate level of development of the follicle, determined by the concentration of estrogens in the blood serum and the results of ultrasound, with the selection of a dose of p-FSHh, depending on the severity of the effect. When increasing the dose of p-FSHCH it should be borne in mind that the daily dose of p-FSHCH should not exceed 450 IU.

When an adequate level of follicular development is reached, HCG should be introduced to induce the final maturation of the follicles and prepare for a puncture to extract the oocyte. It should refrain from the introduction of hCG in the case of a significant increase in ovaries on the last day of treatment in order to reduce the likelihood of developing CHD. When receiving an excessive response, treatment should be stopped, and the administration of hCG should be canceled. Treatment can be resumed starting from the next cycle with a lower dose of the drug than in the previous cycle.

Recommendations for patients with self-administration of the drug

Self-administration of Pergoveris® is permissible only in highly motivated and trained patients who are under constant supervision of a doctor who has appropriate training and experience in treating infertility. The first injection of Pergoversion® must be performed under direct medical supervision.

Before starting the manipulation, you should:

1. Wash your hands. It is very important that the hands and all the items you need to use are as clean as possible.

2. Prepare a clean surface and spread out on it:

- the vial with the drug;

- a bottle with a solvent;

- 2 antiseptic soaked tampons;

- a syringe;

- a needle for the preparation of solution and a needle for p / c injection;

- container for disposal.

3. Connect the needle to prepare the solution with the syringe. Remove the cap from the needle and draw the air into the syringe to a mark of 1 ml. Insert the needle into the vial with the solvent, piercing the rubber cover, push the syringe plunger so that all air from the syringe leaves the vial, turn the bottle upside down and slowly collect all volume of the solvent into the syringe. Without touching the needle, gently place the solvent filled syringe on a clean work surface.

4. Preparation of solution for injection: remove the latching cover from the bottle with lyophilizate Pergoveris®. Insert the needle of the syringe with the solvent into the vial, piercing the rubber cap of the vial. Slowly insert the entire contents of the syringe into the vial. Rotate the vial for better dissolution, but do not shake it. After dissolving the lyophilizate (which usually occurs immediately), check the purity and transparency of the resulting solution. Make sure that the solution does not contain any particles. Turn the bottle upside down and slowly pour the solution back into the syringe. Remove the needle from the vial.

5. Change the needle to prepare the solution for the needle for the syringe and remove all the air bubbles: if the air bubbles are visible in the syringe, rotate it with the needle upwards and tap gently on the syringe so that all the bubbles gather at the top of the syringe. Push the plunger until all the bubbles disappear.

6. Immediately after this, add the solution. The doctor should instruct the patient which part of the body is best injected (abdomen or anterior thigh). For the injection, it is necessary: to collect the skin in a small crease and in one movement of the brush to insert the needle into the formed fold at an angle of 45-90 °. When injecting, slowly push the plunger until the entire dose is administered. After this, immediately remove the needle and in a circular motion, wipe the injection site with a tampon with an antiseptic.

Dispose of all used items and unused residue immediately after the injection.

8. If a greater dose of Pergoveris® is accidentally injected than it should be, consult a physician. Cases of overdose are unknown, but it is possible to develop HHV, described in detail in the sections "Side effect" and "Special instructions". It should be noted that HSH often develops only with the use of hCG.

9. If the patient misses the injection of Pergoveris®, do not administer a double dose, consult a physician.

Overdose

Cases of drug overdose are unknown. Possible development of HNS and other adverse reactions described in the sections "Side effect" and "Special instructions".

special instructions

The preparation Pergoveris® contains active substances of gonadotropins, which can cause adverse reactions of varying severity, therefore the drug should be prescribed only by a doctor having appropriate specialization and experience in the treatment of infertility. Initiation of therapy should be preceded by examination of a barren couple, in particular, studies should be conducted to exclude hypothyroidism , Insufficiency of the adrenal cortex, hyperprolactinaemia, hypothalamic-pituitary tumors.

For gonadotropin therapy, the attending physician must have the necessary equipment and sufficient time to observe the patient.

Safe and effective therapy with Pergoveris® requires regular monitoring of the development of follicles with the help of ultrasound, and, if possible, monitoring the concentration of estradiol in the serum.

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

The preparation Pergoveris ® contains less than 1 mmol (23 mg) of sodium in 1 dose, that is, it is not a significant source of sodium.

The preparation Pergoveris ® contains 30 mg of sucrose in a single dose, which should be taken into account when prescribing the drug to patients with concomitant diabetes.

Ovarian stimulation increases the risk of ovarian hyperstimulation due to the possibility of excessive estrogenic response and multiple development of follicles.

Minimum effective doses should be used.

It is known about the existence of an individual variability in the response in the treatment of p-FSHh / p-LGH, incl. Insufficient response in some patients. In clinical studies, the use of a combination of lutropin alpha and follitropin alfa resulted in an increase in ovarian sensitivity to gonadotropins. If it is necessary to increase the dose of p-FSHh, it is recommended to increase it by 37.5-75 IU of foliotropin alfa every 7-14 days.

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, acute respiratory distress syndrome, thromboembolic disorders occur.

In very rare cases, severe SWC may be complicated by ovarian torsion, pulmonary embolism, ischemic stroke, or myocardial infarction.

If hCG was not prescribed to induce ovulation, an excessive ovarian response causes the development of significant hyperstimulation in rare cases.

Therefore, with excessive ovarian response to stimulation, hCG is not prescribed, and patients are advised to refrain from coitus or use barrier methods of contraception for at least 4 days.

OCS can rapidly progress (from days to several days) to a serious condition, so after the administration of HCG it is necessary to observe for at least two weeks.

To minimize the risk of CHD and multiple pregnancy, ultrasound and estradiol concentration in serum are regularly used. With anovulation, the risk of developing CHD increases with an estradiol concentration> 900 pg / ml (3300 pmol / ml) and the presence of more than 3 follicles with a diameter of at least 14 mm.

Strict adherence to the recommended dosage of Pergoveris ® and follitropin alfa, as well as careful monitoring of therapy, minimizes the risk of developing CHD and multiple pregnancies.

At the onset of pregnancy, the severity of SWS may worsen, and its duration may increase. Most often, CHD occurs after the cessation of hormonal therapy and reaches its maximum after 7-10 days thereafter. As a rule, CHD spontaneously disappears with the onset of menstruation.

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.

In patients with polycystic ovary syndrome, the risk of developing CHD is higher.

Multiple pregnancy

The frequency of multiple pregnancy and childbirth with induction of ovulation is higher, compared with natural conception, the most common option for multiple pregnancy is twins. 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 frequency of miscarriage after ovulation induction and ART programs is higher than in the 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 from 2 to 5%, compared with 1-1.5% 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 numerous and varied courses of infertility treatment. 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 assisted reproductive technologies may be slightly higher than with natural pregnancy and childbirth. Nevertheless, it is not known whether this is due to factors that cause infertility of the couple or directly to ART procedures.

Based on the data of clinical trials and post-registration monitoring, there are no signs that the use of gonadotropins infertility treatment increases the risk of congenital anomalies in the offspring of patients.

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.

Patients should be aware of the above risks before starting therapy. With the immediate occurrence of CHD or multiple pregnancies, a decision to discontinue therapy should be considered.

The patient should be informed of the doctor about all types of allergic reactions, as well as about all drugs used before the start of treatment with Pergoversion®.

Impact on the ability to drive and work with machinery. Studies of the effect of the drug on the ability to drive and other mechanisms have not been carried out.

Form of issue

Lyophilizate for the preparation of a solution for subcutaneous administration of 150 IU r-hFSH + 75 IU r-hLG. For 150 IU of foliotropin alfa and 75 IU of lutropin alfa in bottles of colorless clear glass type I (Hev. F.) with a capacity of 3 ml, sealed with a bromobutyl rubber stopper, sealed on top by an aluminum cap with a detachable plastic cap of the "Flip off" type.

1 ml of solvent (water for injection) in bottles of colorless transparent glass type I (Hev. F.) with a capacity of 3 ml, sealed with a rubber stopper with Teflon coating, sealed on top with an aluminum cap with a detachable plastic cap of the type "Flip off".

1 bottle with lyophilizate and 1 vial of solvent (kit) in a plastic container, closed with shrinkable polymer film.

By 1, 3 or 10 (2 × 5) sets are placed in a cardboard box with the control of the first opening.

Terms of leave from pharmacies

On prescription.

Storage conditions

At temperatures not higher than 25 ° C, in the original packaging.

Keep out of the reach of children.

Shelf life

Lyophilizate for the preparation of a solution for subcutaneous administration of 150 IU + 75 IU 150 IU + 75 - 3 years. Solvent 3 years.

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