Pergoveris® (Pergoveris®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Dosage form: & nbsplyophilizate for the preparation of a solution for subcutaneous administration
Composition:

One vial with lyophilizate contains:

active ingredientsa: follitropin alfa-150 ME (11 μg), lutropin alfa-75 ME (3 μg);

Excipients: sucrose 30.00 mg, sodium hydrogen phosphate dihydrate 1.11 mg, sodium dihydrogen phosphate monohydrate 0.45 mg, methionine 0.10 mg, polysorbate 20 0.05 mg, phosphoric acid concentrated to pH 6.5, 7.5, sodium hydroxide to pH 6.5-7.5.

One bottle of solvent contains:

water for injection - 1.0 ml.

The reconstituted solution contains:

150 ME follitropin alfa and 75 ME lutropin alfa in 1 ml.

Description:

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

Reconstituted solution: transparent or slightly opalescent colorless or pale yellow solution.

Solvent: clear, colorless liquid.

Pharmacotherapeutic group:follicle stimulating agent
ATX: & nbsp
  • Foliotropin alfa
  • Lutropin alfa
    • Pharmacodynamics:

    Pergoversion® is a combination drug containing a recombinant human follicle-stimulating hormone (FSH) (follitropin alfa, p-FSHh) and recombinant human luteinizing hormone (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 maturation of the follicle 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 along with estradiol induces LH receptors on the membrane of granulosa cells. The effect of LH on the cells of the leukemia provides the production of androgens 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 sufficient 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 administration of human chorionic gonadotropin (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 deficiency of LH and FSH, the main effect of lutropin alfa is an increase in the secretion of estradiol by follicles, the growth of which, in turn, is stimulated by FSH.

    It was shown that in women with hypogonadotropic hypogonadism and a serum LH concentration below 1.2 IU / L, the daily use of a combination of lutropin alfa in a dose of 75 IU and foliotropin alpha at a dose of 150 IU leads to adequate development of follicles and an increase in the synthesis of estradiol, while as a combination of lutropin alpha 25 ME and follitropin alpha 150 ME does not provide such an effect. Thus, with the appointment of less than one vial of Pergoveris® per day, the activity of LH may not be sufficient for the full development of follicles.

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

    The addition of p-LGH is intended to increase the sensitivity of the ovaries to p-FSHh,to stimulate the secretion of estradiol by the preovulatory follicle that causes the growth of the endometrium, and also to ensure later luteinization of the follicles, which leads to a normalization of the level of progesterone in the luteal phase.
    Pharmacokinetics:

    Foliotropin alfa and lutropin alfa, administered in combination, retain the same pharmacokinetic characteristics as separately.

    Foliotropin alfa

    After intravenous administration follitropin alfa is distributed in extracellular fluids, with the initial half-life of the organism being about 2 hours, while the final half-life is about 24 hours. The equilibrium volume of distribution is 10 liters, the total clearance is 0.6 liters / hour. One eighth of the administered dose of follitropin alfa is excreted by the kidneys.

    With subcutaneous administration, absolute bioavailability is about 70%. After repeated injections, there is a triple cumulation of the drug in the blood compared to a single injection. The steady-state equilibrium concentration in the blood is reached within 3-4 days. It has also been shown that in women with depressed secretion of endogenous gonadotropins follitropin alfa 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 lutropin alfa quickly distributed with an initial half-life of about 1 hour, and is excreted from the body with a finite half-life of about 10-12 hours. In the equilibrium state, the volume of distribution is 10 to 14 liters. Lutropin alfa demonstrates 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 subcutaneous administration lutropin alfa quickly distributed in organs and tissues, absolute bioavailability is about 60%; the final half-life is somewhat prolonged.

    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 severe LH and FSH deficiency.

    - 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 using high doses of FSH (3000 ME and more (per cycle), or the age of the patient (35 years and older), either individually or in combination, during an assisted reproductive technology (ART) program: in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), gammet / zygotic transplantation 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 in the 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.

    Dosing and Administration:

    The preparation Pergoveris ® is intended for subcutaneous injection!

    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 immediately before administration, the resulting solution for subcutaneous 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 growth and maturation of follicles the women with severe LH and FSH deficiency

    The recommended initial dose of Pergoveris® is 1 bottle (150 ME p-FSHh + 75 ME 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 a single 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 hCG or 250 μg p-hChch is administered once in the 24-48 hour period after the last injection of Pergouveris®. Sexual contact is recommended on the same day and the day after the introduction of HCG; as an alternative, the intrauterine insemination method (IUI) can be used.

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

    If the ovarian response to ovarian stimulation is excessive, the 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 p-FSHh lower than in the previous cycle.

    Suboptimal response in patients with previous CBS in ART programs

    The recommended treatment regimen begins with the appointment of 300 IU p-FSHCH once a day for 5-7 days. Starting with the 6-8th day of controlled ovarian stimulation (CBS), p-FSHCH is replaced with 2 vials of the Pergoveris® preparation (300 IU p-FSHh and 150 IU p-LHh).

    An alternative treatment regimen can be the administration of 2 vials of the preparation 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 gland.

    Treatment continues to an adequate level of development of the follicle, determined by the concentration of estrogens in the blood serum and ultrasound results, 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.

    Should refrain fromadministration 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 ovarian hyperstimulation syndrome (OSS). If an excessive response is received, the 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 Pergoversion® 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 Pergoveris® should be performed under direct medical supervision.

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

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

    - the vial of the drug

    - bottle with solvent

    - 2 antiseptic soaked tampons

    - syringe

    - a needle for solution preparation and a hypodermic needle

    - container for recycling

    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 a solvent having pierced the rubber cap, push the plunger of the syringe to the vial has gone out all air from the syringe, vial flip up and down slowly enter the entire volume of the solvent in 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 snap-on lid from the vial of Perhoveris® lyophilizate. Insert the needle of the syringe with the solvent into the vial, piercing the rubber cap of the vial.

    Slowly enter 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 clarity 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 for solution to the needle for subcutaneous injection, and remove any air bubbles: If you see air bubbles in the syringe, turn the needle upwards and tap gently on the syringe,so that all the bubbles come together at the top of the syringe. Push the plunger until all the bubbles disappear.

    6. Immediately after that, inject the solution. Your doctor should instruct you in which part of the body it is best to inject (abdomen or anterior thigh). Collect the skin in a small crease, as shown on the left, and in one movement of the brush, insert the needle into the formed fold at an angle of 45-90 °. When injecting, slowly push the plunger until you inject the entire dose. After this, immediately remove the needle and in a circular motion, wipe the injection site with a tampon with an antiseptic.

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

    8. If you accidentally injected more Pergoveris® than you should, consult your doctor. Cases of overdose are unknown, but the development of an acute hypoxia, detailed in the sections "Side effect" and "Special instructions", is possible. It should be noted that HSH often develops only with the use of hCG.

    9. If you missed the Pergoversion® injection, do not take a double dose, consult a doctor.

    Side effects:

    When using Pergoveris®, side effects may developWhich, depending on the frequency of occurrence divided into very rare (<1/10000 applications), rare (≥1 / 10,000 to <1/1000), infrequent (≥1 / 1000 and <1/100), frequent (≥1 / 100 and <1/10) and very frequent (≥1 / 10).

    Disturbances from the nervous system:

    very often - headache;

    often - drowsiness.

    Violations of the genitals and mammary gland:

    very often - ovarian cysts;

    often - OHSS mild (accompanied by pain in the abdomen, nausea, vomiting, weight gain, an increase in ovarian, including due to the formation of cysts);

    often - extreme weather events of moderate severity (except for lower abdominal pain, nausea, vomiting, weight gain, and ovaries, may experience shortness of breath, oliguria, ascites, pleural effusion, an accumulation of fluid in the pericardial cavity). For detailed information, see "Special instructions";

    often - pain in the area of ​​the mammary glands;

    often - pelvic pain;

    infrequently - severe ovarian hyperstimulation syndrome (may be accompanied by severe forms of ascites, pleural effusions, fluid accumulation in the pericardial cavity, oliguria, acute respiratory distress syndrome and pulmonary embolism (very rare)). For detailed information, see "Special instructions";

    rarely - torsion of ovarian cysts (as a complication of HHV).

    Disorders from the gastrointestinal tract:

    often - abdominal pain, nausea, vomiting, diarrhea, abdominal colic, flatulence.

    Violations from the heart and blood vessels:

    very rarely - thromboembolism, usually associated with a severe form of SWN.

    Disturbances from the respiratory system:

    very rarely - worsening of the course or exacerbation of asthma in patients with bronchial asthma.

    Immune system disorders:

    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 adverse events that occur with the use of Pergoveris® should be reported immediately to your doctor.

    Overdose:

    Cases of drug overdose are unknown.

    It is possible to develop OHSS and other adverse reactions described in the sections "Side effect" and "Special instructions".

    Interaction:

    The incompatibility of Pergoversion® with other medications has not been reported.

    Do not mix Perergovery® with any other drug in a single syringe, except for foliotropin alfa.
    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 treating infertility.

    The initiation of therapy should be preceded by examination of the infertile couple, in particular, studies should be conducted to exclude hypothyroidism, adrenal cortex insufficiency, hyperprolactinaemia, hypothalamic-pituitary neoplasms.

    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 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 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.

    Pergouveris ® 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 estrogen response and multiple development of follicles. The minimum effective dose should be used.

    It is known about the existence of individual variability of the response in the treatment of p-FSHh / p-LGH, including an inadequate response in some patients.

    In clinical studies, the use of combination lutropin alpha and follitropin alfa resulted in an increase in the sensitivity of the ovaries to gonadotropins. If it is necessary to increase the dose of p-FSHhch it is recommended to increase it by 37.5-75 ME follicotropin alfa every 7-14 days.

    Ovarian hyperstimulation syndrome

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

    The following symptoms are most typical for severe CHD: 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, hemoperitoneum occur; pleural effusion, acute respiratory distress syndrome, thromboembolic disorders.

    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.

    HSH can rapidly progress (from days to several days) to a severe 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> 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 - 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 CHD, gonadotropin therapy, if it continues, should be discontinued. The patient should be hospitalized and prescribed a specific treatment 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 in comparison with natural conception; The most common option for multiple pregnancies 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 incidence 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 2 to 5%, compared to 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 of development

    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 is no evidence that the use of gonadotropins in the treatment of infertility 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 risks listed above before starting therapy. With the immediate occurrence of CHD or multiple pregnancies, a decision to discontinue therapy should be considered.

    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 the start of treatment with Pergoversion®.

    Effect on the ability to drive transp. cf. and fur:Studies of the effect of the drug on the ability to drive and other mechanisms have not been carried out.
    Form release / dosage:Lyophilizate for the preparation of a solution for subcutaneous administration, 150 IU + 75 IU.
    Packaging:

    To 150 ME follitropin alfa and 75 ME lutropin alfa into the bottles of colorless transparent glass type I (Hebrew F.) with a capacity of 3 ml, sealed with a bromobutyl rubber stopper, sealed on top by an aluminum cap with a detachable plastic lid of the "Flip off".

    1 ml of solvent (water for injection) into flasks of colorless transparent glass type I (Hebrew 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 lid of the "Flip off".

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

    For 1, 3 or 10 (2 x 5) sets together with instructions for use in a pack of cardboard with the control of the first opening.

    Storage conditions:

    Store in a dark place at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    Lyophilizate - 3 years.

    Solvent - 3 years.

    Do not use after expiry date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-001160
    Date of registration:11.11.2011
    Date of cancellation:2016-11-11
    The owner of the registration certificate:Merck Serono S.A.Merck Serono S.A. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspMERK CERONO division of Merck KGaA MERK CERONO division of Merck KGaA Germany
    Information update date: & nbsp14.03.2016
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