Pergoveris lyophilisate d / pr-ra d / p / k / v. 150ME + 75ME, No. 1

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

• suboptimal response in patients with previous controlled ovarian stimulation (CBS), which was characterized by either a small number of preovulatory follicles / oocytes obtained (less than 7), or the use of high doses of FSH (3000 IU and more / per cycle), or the patient's age (35 years and older), both individually and in combination, - during the program of assisted reproductive technologies (ART): in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), gamete / zygote transplantation into the fallopian tubes (GIFT / ZIFT).

The drug PergoverisЃ is intended for subcutaneous administration!

Treatment with PergoverisЃ should be started and carried out only under the supervision of a physician with the appropriate specialization and experience in infertility treatment.

The lyophilisate is dissolved with the supplied solvent immediately before administration, the resulting solution for SC administration 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 follicle growth and maturation in women with severe LH and FSH deficiency

The recommended initial dose of PergoverisЃ is 1 vial. (150 IU r-FSHh + 75 IU r-LHh) per day. Since this group of patients is characterized by amenorrhea and a low endogenous level of estrogen secretion, the 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 values ??of the concentration of estrogen in the blood serum.

If a decision is made to increase the dose of r-FSHH, it is recommended to increase it after 7-14 days, preferably by 37.5-75 IU of follitropin alfa.

A solution of the drug PergoverisЃ can be mixed with follitropin alfa and inject these drugs in one injection. It is possible to increase the duration of stimulation within one of the cycles up to 5 weeks. Upon reaching the optimal response, 5000 to 10000 IU of hCG or 250 ?g of r-hCG is injected once in the interval 24Ц48 hours after the last injection of PergoverisЃ. Sexual intercourse is recommended on the same day and the next day after the administration of hCG; as an alternative, the method of intrauterine insemination (IUI) can be used.

Support of the luteal phase may be required, since a deficiency of luteotropic activity (LH / hCG) after ovulation can lead to premature corpus luteum failure.

If the ovaries respond excessively to stimulation, therapy should be suspended, and the administration of hCG should be postponed. The course of therapy can be resumed in the next cycle using a dose of r-FSHH lower than in the previous cycle.

Suboptimal response in patients with previous CBS in ART programs

The recommended treatment regimen starts with IU r-FSHh 1 time per day for 5Ц7 days. Starting from the 6-8th day of controlled ovarian stimulation (COS), r-FSHCH is replaced by 2 vials. the drug PergoverisЃ (300 IU r-FSHch and 150 IU r-LHh). An alternative treatment regimen may be the appointment of 2 vials of the drug PergoverisЃ (300 IU r-FSHh and 150 IU r-LHh) per day, starting from the first day of CBS, following the desensitization of the pituitary gland.

Treatment continues until an adequate level of follicular development, determined by the concentration of estrogen in the blood serum and the results of ultrasound, with the selection of the dose of r-FSHC depending on the severity of the effect. When increasing the dose of r-FSHch, it should be borne in mind that the daily dose of r-FSHch should not exceed 450 IU.

When an adequate level of follicle development is achieved, hCG should be administered to induce the final maturation of the follicles and prepare for a puncture for oocyte retrieval. You should refrain from the introduction of hCG in the case of a significant increase in the ovaries on the last day of treatment in order to reduce the likelihood of developing OHSS. If an excessive response is received, treatment should be suspended 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 the drug PergoverisЃ is permissible only in highly motivated and trained patients who are under constant supervision of the attending physician who has appropriate training and experience in infertility treatment. The first injection of PergoverisЃ should be carried out under direct medical supervision.

Before starting the manipulation, you should:

1. Wash your hands. It is very important that hands and all objects that need to be used are as clean as possible.

2. Prepare a clean surface and lay on it:

- a bottle with the drug;

- a bottle with a solvent;

- 2 tampons soaked in antiseptic;

- syringe;

- a needle for solution preparation and a needle for subcutaneous injection;

- container for disposal.

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

4. Preparation of solution for injection: remove the snap-on cap from the vial with PergoverisЃ lyophilisate. Insert the needle of the syringe with the solvent into the vial by piercing the rubber cap of the vial. Slowly introduce the entire contents of the syringe into the vial. Rotate the bottle for better dissolution, but do not shake it. After dissolving the lyophilisate (which usually occurs immediately), check the purity and transparency of the resulting solution. Make sure the solution does not contain any particles. Turn the bottle upside down and slowly draw the solution back into the syringe. Remove the needle from the bottle.

5. Change the needle for preparation of the solution to the needle for subcutaneous injection and remove all air bubbles: if air bubbles are visible in the syringe, turn it with the needle up and tap the syringe gently so that all bubbles are collected in the upper part of the syringe. Press down on the plunger until all bubbles disappear.

6. Immediately then add the solution. The physician should instruct the patient in which part of the body it is best to inject (abdomen or front of the thigh). To carry out the injection, it is necessary: ??to collect the skin in a small fold and with one movement of the hand, insert the needle into the formed fold at an angle of 45-90 ?. When injecting, slowly push the plunger until the entire dose has been injected. After that, immediately remove the needle and wipe the injection site with an antiseptic swab in a circular motion.

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

8. If you accidentally injected a larger dose of PergoverisЃ than necessary, you should consult your doctor. Overdose cases are unknown, however, the development of OHSS is possible, described in detail in the 'Side effects' and 'Special instructions' sections. It should be noted that OHSS often develops only with the use of hCG.

9. If a patient missed an injection of PergoverisЃ, a double dose should not be administered, it is necessary to consult a doctor.

Lyophilisate for preparation of a solution for subcutaneous administration of white or almost white color in the form of a powder or a porous mass; reconstituted solution - transparent or slightly opalescent, colorless or light yellow.

1 fl.

follitropin alpha 150 IU (11 ?g) lutropin alpha 75 IU (3 ?g)

Excipients: 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, concentrated phosphoric acid - up to pH 6.5-7.5, sodium hydroxide - up to pH 6.5- 7.5.

• Hypersensitivity to any of the active or excipients or their combination;

• tumors of the hypothalamus and / or pituitary gland;

• bulky neoplasms or ovarian cysts not caused by polycystic ovary syndrome;

• uterine and / or other gynecological bleeding of unknown etiology;

• ovarian cancer, uterine cancer, breast cancer;

• pregnancy and lactation;

• primary ovarian insufficiency;

• anomalies in the development of female genital organs incompatible with pregnancy;

• fibroid tumors of the uterus, incompatible with pregnancy.

pharmachologic effect

A combined preparation containing recombinant human follicle-stimulating hormone (FSH) (follitropin alpha, r-FSHh) and recombinant human luteinizing hormone (LH) (lutropin alpha, r-LHh). The drug is obtained by genetic engineering on a Chinese hamster ovary cell culture.

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

In the process of follicle development, FSH, together with estradiol, induces LH receptors on the granulosa cell membrane. The effect of LH on theca cells ensures the production of androgens for granulosa cells, where the transformation of androgens into estrogens occurs through the aromatase system. Thus, in the absence of LH, FSH can induce follicular growth, but estradiol synthesis is reduced. Without a sufficient amount of estradiol, the conditions for the onset of pregnancy are disrupted, as well as the secretion of cervical mucus, the growth of the endometrium and the maturation of a full-fledged corpus luteum in response to the introduction of human chorionic gonadotropin (hCG).

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

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

It has been shown that in women with hypogonadotropic hypogonadism and serum LH concentration below 1.2 IU / L, the daily use of a combination of lutropin alfa at a dose of 75 IU and follitropin alfa at a dose of 150 IU leads to adequate follicular development and an increase in estradiol synthesis, while the combination lutropin alpha 25 IU and follitropin alpha 150 IU do not provide such an effect. Thus, if less than one bottle of PergoverisЃ is prescribed per day, LH activity may be insufficient for the full development of follicles.

Although the efficacy of r-FSHH monotherapy with the use of assisted reproductive technologies (ART) has been proven, the published results of clinical studies indicate the advantages of additional r-LHH administration in patients with insufficient (suboptimal) efficacy of r-FSH monotherapy. The addition of r-LHh is intended to increase the sensitivity of the ovaries to r-FSHh, to stimulate the secretion of estradiol by the preovulatory follicle, which causes the growth of the endometrium, and also to ensure later luteinization of the follicles, leading to the normalization of progesterone levels in the luteal phase.

Pharmacokinetics

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

Follitropin alpha

After intravenous administration, follitropin alfa is distributed in extracellular fluids, and its initial T1 / 2 is about 2 hours, while the final T1 / 2 is about 24 hours. The value of the equilibrium Vd is 10 l, the total clearance is 0.6 l / h. One-eighth of the administered dose of follitropin alfa is excreted by the kidneys.

With subcutaneous administration, the absolute bioavailability is about 70%. After repeated injections, there is a threefold cumulation of the drug in the blood, but compared with a single injection. Stationary Css in the blood is reached within 3-4 days. It has also been shown that in women with suppressed secretion of endogenous gonadotropins, follitropin alfa effectively stimulates follicular development and steroidogenesis, despite the inaccessibly low level of quantitative measurement of LH.

Lutropin alpha

After intravenous administration, lutropin alfa is rapidly distributed with an initial T1 / 2 of about 1 hour, and is excreted from the body with a final T1 / 2 of about 10-12 hours. In an equilibrium state, Vd is from 10 to 14 liters. Lutropin alfa demonstrates a linear pharmacokinetic profile, as evidenced by the direct proportional dependence of the 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 of the drug in the body is 5 hours.

After subcutaneous administration, lutropin alfa is rapidly distributed in organs and tissues, the absolute bioavailability is about 60%; the final T1 / 2 is slightly lengthened. The pharmacokinetics of lutropin alfa with a single administration is comparable to that with multiple doses, the degree of cumulation is minimal. With the simultaneous administration of lutropin alfa with follitropin alfa, no pharmacokinetic interaction was observed.

Side effect

From the nervous system: very often - headache; often - drowsiness.

From the genital organs: very often - ovarian cysts; often - mild OHSS (accompanied by lower abdominal pain, nausea, vomiting, weight gain, ovarian enlargement, including due to the formation of cysts), moderate OHSS (except for lower abdominal pain, nausea, vomiting, weight gain body and ovaries, there may be shortness of breath, oliguria, ascites, pleural effusion, accumulation of fluid in the pericardial cavity), pain in the mammary glands, pelvic pain; infrequently - severe OHSS (may be accompanied by severe forms of ascites, pleural effusion, fluid accumulation in the pericardial cavity, oliguria, acute respiratory distress syndrome and pulmonary embolism (very rare)); rarely - torsion of the ovarian cyst (as a complication of OHSS).

From the digestive system: often - abdominal pain, nausea, vomiting, diarrhea, abdominal colic, flatulence.

From the side of the cardiovascular system: very rarely - thromboembolism, usually associated with a severe form of OHSS.

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

From the immune system: very rarely - systemic allergic reactions of varying severity (skin redness, urticaria, rash, facial edema, difficulty breathing, generalized edema, anaphylaxis, fever, arthralgia).

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

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

The patient should be warned that all undesirable phenomena arising from the use of PergoverisЃ should be immediately reported to the attending physician.

Application during pregnancy and lactation

The drug PergoverisЃ is contraindicated for use during pregnancy and breastfeeding.

Use in elderly patients

Not applicable.

special instructions

The drug PergoverisЃ contains the active substances of gonadotropins, which can cause side reactions of varying severity, therefore, the drug should be prescribed only by a doctor with the appropriate specialization and experience in the treatment of infertility.

The beginning of therapy should be preceded by examination of the infertile couple, in particular, studies should be carried out to exclude hypothyroidism, adrenal insufficiency, hyperprolactinemia, hypothalamic-pituitary neoplasms.

To carry out gonadotropin therapy, the attending physician must have the necessary equipment and sufficient time to monitor the patient.

Safe and effective therapy with PergoverisЃ requires regular monitoring of follicular development using ultrasound, and, if possible, monitoring the concentration of estradiol in the blood serum.

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

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

The drug PergoverisЃ contains 30 mg of sucrose in 1 dose, which should be taken into account when prescribing the drug to patients with concomitant diabetes mellitus.

With ovarian stimulation, the risk of ovarian hyperstimulation increases due to the possibility of an excessive estrogenic response and multiple follicular development.

The minimum effective dose should be used.

It is known about the existence of individual variability of response in the treatment of r-FSHh / r-LHh, incl. insufficient response in some patients.

In clinical studies, the use of a combination of lutropin alfa and follitropin alfa led to an increase in ovarian sensitivity to gonadotropins. If it is necessary to increase the dose of r-FSHch, it is recommended to increase it by 37.5-75 IU of follitropin alfa every 7-14 days.

Ovarian hyperstimulation syndrome

OHSS must be differentiated from uncomplicated ovarian enlargement.

The clinical symptoms of OHSS can become progressively more pronounced. Characterized by a significant increase in the size of the ovaries, a high level of sex hormones, an increase in vascular permeability, leading to the accumulation of fluid in the abdominal, pleural and, less often, pericardial cavities.

For severe OHSS, the following symptoms are most characteristic: pain and a feeling of fullness in the abdomen, a pronounced increase in the size of the ovaries, increased body weight, shortness of breath, oliguria, gastrointestinal symptoms (nausea, vomiting, diarrhea); hypovolemia, hemoconcentration, electrolyte imbalance, ascites, hemoperitoneum, pleural effusion, acute respiratory distress syndrome, thromboembolic disorders occur.

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

?сли дл¤ индуцировани¤ овул¤ции не назначалс¤ ’vч, то избыточный ответ ¤ичников вызывает развитие существенной гиперстимул¤ции в редких случа¤х. ѕоэтому, при чрезмерном ответе ¤ичников на стимул¤цию, ’vч не назначают, а пациенткам рекомендуют воздержатьс¤ от коитуса или использовать барьерные методы контрацепции не менее 4-х дней.

—vя может быстро прогрессировать (от суток до нескольких дней) до т¤желого состо¤ни¤, поэтому после введени¤ ’vч необходимо наблюдение в течение как минимум двух недель.

?л¤ минимизации риска —vя и многоплодной беременности, регул¤рно используют ”«» и оценку концентрации эстрадиола в сыворотке крови. ѕри ановул¤ции риск развити¤ —vя увеличиваетс¤ при концентрации эстрадиола > 900 пг/мл (3300 пмоль/мл) и наличии более 3 фолликулов диаметром не менее 14 мм.

—трогое соблюдение рекомендованной дозировки препарата ѕерговерисЃ и фоллитропина альфа, а также тщательный мониторинг терапии, минимизирует риск развити¤ —vя и многоплодной беременности.

ѕри наступлении беременности степень т¤жести —vя может усугубитьс¤, а его длительность - увеличитьс¤. Ќаиболее часто —vя возникает после прекращени¤ гормональной терапии и достигает своего максимума через 7-10 дней после этого.  ак правило, —vя самопроизвольно исчезает с наступлением менструации.

ѕри развитии т¤желой формы —vя терапи¤ гонадотропинами, если она еще продолжаетс¤, должна быть прекращена. ѕациентку следует госпитализировать и назначить специфическую дл¤ —vя терапию.

” пациенток с синдромом поликистозных ¤ичников риск развити¤ —vя выше.

ћногоплодна¤ беременность

„астота многоплодной беременности и родов при индукции овул¤ции выше, по сравнению с естественным зачатием, наиболее частым вариантом при многоплодии ¤вл¤етс¤ двойн¤.

?л¤ минимизации риска многоплодной беременности, необходим тщательный мониторинг овариального ответа.

ѕри ¬–“ риск многоплодной беременности св¤зан, главным образом, с количеством перенесенных эмбрионов, их жизнеспособностью и возрастом пациентки.

Ќевынашивание беременности

„астота невынашивани¤ беременности после индукции овул¤ции и программ ¬–“ выше, чем в попул¤ции.

Ёктопическа¤ беременность

” пациенток с заболевани¤ми маточных труб в анамнезе повышен риск внематочной беременности. ¬еро¤тность внематочной беременности после применени¤ вспомогательных репродуктивных технологий составл¤ет от 2 до 5%, по сравнению с 1-1.5% в общей попул¤ции.

Ќовообразовани¤ органов репродуктивной системы

»меютс¤ сообщени¤ о доброкачественных и злокачественных новообразовани¤х ¤ичника и других репродуктивных органов у женщин после проведени¤ многочисленных и разнообразных курсов лечени¤ бесплоди¤. Ќа сегодн¤ св¤зи между терапией гонадотропинами и повышенным риском новообразований при бесплодии установлено не было.

¬рожденные аномалии развити¤

„астота врожденных аномалий после применени¤ программ вспомогательных репродуктивных технологий может быть слегка выше, чем при естественной беременности и родах. “ем не менее, неизвестно, св¤зано ли это с факторами, обуславливающими бесплодие пары или же непосредственно с процедурами ¬–“. ќсновыва¤сь на данных клинических исследований и пострегистрационного мониторинга, не обнаружено признаков того, что применение гоиадотропинов при лечении бесплоди¤ повышает риск развити¤ врожденных аномалий у потомства пациентов.

“ромбоэмболические осложнени¤

” пациенток с недавно перенесенными или текущими тромбоэмболическими заболевани¤ми, а также при веро¤тном риске их возникновени¤, применение гонадотропинов может увеличить этот риск или осложнить течение данных заболеваний. ?л¤ пациенток данной группы польза от терапии должна быть соотнесена с возможным риском. —ледует отметить, что беременность сама по себе несет повышенный риск тромбоэмболических нарушений.

ѕациентки должны быть осведомлены о вышеперечисленных рисках перед началом терапии. ѕри непосредственном возникновении —vя или многоплодной беременности следует рассмотреть решение о прекращении терапии.

Ќеобходимо информировать врача обо всех типах аллергических реакций, которые имеютс¤ у пациентки, а также обо всех препаратах, используемых до начала лечени¤ препаратом ѕерговерисЃ.

Influence on the ability to drive vehicles and mechanisms

Studies of the effect of the drug on the ability to drive a car and other mechanisms have not been conducted.

Overdose

Cases of drug overdose are unknown.

Perhaps the development of OHSS and other adverse reactions described in the sections 'Side effects' and 'Special instructions'.

Drug interactions

The incompatibility of the drug PergoverisЃ with other drugs has not been reported.

It is not allowed to mix the drug PergoverisЃ with any other drug in the same syringe, with the exception of follitropin alfa.