Pergoveris lyophilisate for preparation of solution for subcutaneous injection vials
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Active ingredients
Follitropin alfa
Release form
Lyophilisate
Composition
1 bottle contains: Active substance: follitropin alfa 150 IU (11 mcg), lutropin alfa 75 IU (3 mcg). 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, concentrated phosphoric acid - to pH 6.5-7.5, sodium hydroxide - to pH 6.5-7.5. Solvent: water d / and - 1 ml.
Pharmacological effect
A combination product containing recombinant human follicle-stimulating hormone (FSH) (follitropin alfa, r-FSHg) and recombinant human luteinizing hormone (LH) (lutropin alfa, r-LGH). The drug is obtained by the genetic engineering method on the Chinese hamster ovary cell culture. The main role of FSH is to initiate folliculogenesis by affecting the cells of the developing follicle on the granulosa cells, while LH plays an important role in enhancing the production of estradiol by a mature follicle, induces maturation of the follicle, and ovule. . LH supports the functioning of the corpus luteum 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 granulose cell membrane. The impact of LH on theca cells provides androgen production for granulosa cells, where androgen is transformed into estrogens through the aromatase system. Thus, in the absence of LH, FSH can induce follicle growth, but the synthesis of estradiol is reduced. Without a sufficient amount of estradiol, conditions for the onset of pregnancy are violated, as well as secretion of cervical mucus, endometrial growth and maturation of a full-fledged yellow body in response to the introduction of human chorionic gonadotropin (hCG). In clinical studies, the effectiveness of the combination of follitropin alpha and lutropin alpha was shown in hypogonadotropic hypogonadropic hypogonadotropin. women. When stimulating follicle development in women with anovulation with LH and FSH deficiency, the main effect of lutropin alfa is an increase in secretion estradiol follicles, the growth of which, in turn, is stimulated by FSH. It is shownthat in women with hypogonadotropic hypogonadism and LH serum concentrations below 1.2 IU / l daily use of a combination of lutropin alfa at a dose of 75 ME and follitropin alfa at a dose of 150 ME leads to adequate follicle development and an increase in the synthesis of estradiol, while the combination of lutropine alpha 25 ME and follitropina alfa 150 ME does not provide this effect. Thus, when prescribing less than one vial of Pergoveris day, LH activity may not be sufficient for the full development of follicles. Although the efficacy of r-FSH monotherapy using assisted reproductive technologies (ART) has been proven, the published results of clinical studies show the benefits of the additional prescription of r-LGH in patients with insufficient (suboptimal) efficacy of r-FSHH monotherapy. The addition of r-LGCH is intended to increase the sensitivity of the ovaries to r-FSH, to stimulate the secretion of estradiol by the preovulatory follicle, which causes the growth of the endometrium, as well as to ensure later luteinization of the follicles, leading to a normal progesterone level in the luteal phase.
Pharmacokinetics
Follitropin alpha and lutropin alpha, administered in combination, retain the same pharmacokinetic characteristics as separately. Follitropin alphaAfter in / in the administration, follitropin alpha is distributed in extracellular fluids, and its initial T1 / 2 is about 2 hours, whereas the final T1 / 2 2 - about 24 hours. The equilibrium Vd value is 10 liters, the total clearance is 0.6 l / h. One eighth of the dose of follitropin alpha is excreted by the kidneys. When subcutaneously administered, 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 was also shown that in women with suppressed secretion of endogenous gonadotropins, follitropin alfa effectively stimulates follicular development and steroidogenesis, despite an inaccessible low level of LH for in quantitative measurements. , and excreted from the body with a final T1 / 2 of about 10-12 hours. In the equilibrium state, Vd is from 10 to 14 liters.Lutropin alfa exhibits a linear pharmacokinetic profile, as evidenced by the direct, over-all-out dependence of the AUC on the dose administered. 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 s / a administration of lutropin alpha is quickly distributed in organs and tissues, the absolute bioavailability is about 60%; the final T1 / 2 is somewhat lengthened. The pharmacokinetics of lutropin alpha with a single injection is comparable to that with multiple, the degree of cumulation is minimal. With the simultaneous administration of lutropin alpha with follitropin alpha, 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 a small number of preovulatory follicles / oocytes obtained (less than 7), or using high doses of FSH (3000 IU or more / per 1 cycle), or by the age of the patient (35 years and older), both individually and in combination, when conducting the Assisted Reproductive Technologies (ART) program: in vitro fertilization (IVF) , intracytoplasmic sperm injection (ICSI), gamete / zygote transplantation into the fallopian tubes (GIFT / ZIFT).
Contraindications
- Hypothalamus and / or pituitary tumors; - Volumetric neoplasms or ovarian cysts that are not caused by polycystic ovary syndrome; - Uterine and / or other gynecological bleeding of unknown etiology; - Ovarian cancer, uterine cancer, breast cancer; - Primary ovarian insufficiency; - Anomalies development of female genital organs, incompatible with pregnancy; - Uterus fibroid tumors, incompatible with pregnancy; - Pregnancy; - Lactation; - Hypersensitivity to any of the active or auxiliary substances or their combination.
Use during pregnancy and lactation
The drug Pergoveris contraindicated for use during pregnancy and breastfeeding.
Dosage and administration
The drug PergoVeris is intended for subcutaneous administration. The treatment with PergoVeris should be started and carried out only under the supervision of a physician who has the appropriate specialization and experience in the treatment of infertility. The lyophilisate is dissolved with the accompanying solvent just before the administration, the resulting solution for sc administration is used once.The rest of the unused solution, as well as used syringes and empty bottles should be disposed of immediately after the injection. Stimulation of the growth and maturation of the follicles in women with severe LH and FSGR deficiency The recommended initial dose of PergoVeris is 1 vial (150 ME p-FSHC + 75 ME p-LH ) 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 on any day. The duration of the course is chosen individually, in accordance with the growth / size of the follicle, and based on the values of estrogen concentration in the serum. If the decision is made to increase the dose of p-FSH, it is recommended to increase it in 7-14 days, preferably by 37.5-75 IU of follitropin alpha. The solution Pergoveris can be mixed with follitropin alpha and enter these drugs in a single injection. It is possible to increase the duration of stimulation in one of the cycles up to 5 weeks. When the optimal response is reached, from 5,000 to 10,000 IU of HCG or 250 mcg of r-HGCH is injected in a single interval of 24-48 hours after the last injection of PergoVeris. Sexual contact is recommended on the same day and the next day after the administration of hCG. Alternatively, the method of intrauterine insemination (IUI) can be used. It may be necessary to maintain the luteal phase, since the lack of luteotropic activity (LH / HGH) after ovulation can lead to premature failure corpus luteum. In case of excessive response of the ovaries to stimulation, therapy should be suspended, and the introduction of hCG should be postponed. The course of therapy can be resumed in the next cycle using a lower dose of p-FSHg than in the previous cycle. Suboptimal response in patients with an earlier CBS in VRT programs The recommended treatment regimen starts with 300 IpHGH 1 time per day for 5 -7 days. Starting from 6-8 days of controlled ovarian stimulation (CBS), p-FSGch is replaced with 2 bottles of Pergoveris (300 IU p-FSGch and 150 IU p-LGH). An alternative treatment regimen may be the appointment of 2 vials of Pergoveris (300 ME pGHH and 150 MEH LHH) / day, starting from the first day of CBS following desensitization of the pituitary gland. The treatment continues to an adequate level of follicle development, determined by concentration estrogen in the serum and the results of ultrasound, with the selection of the dose of p-FSGch depending on the severity of the effect.When increasing the dose of p-FSHC, it should be borne in mind that the daily dose of p-FSHC should not exceed 450 ME. 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 ovarian hyperstimulation syndrome (OHSS). If an excessive response is received, treatment should be stopped and the administration of hCG should be discontinued. Treatment can be resumed starting from the next cycle with the use of a lower dose than in the previous cycle. Dosage of self-administration of the drug Self-administration of Pergoveris is permissible only for highly motivated and trained patients under constant supervision of the attending physician with appropriate training and experience of treatment infertility The first injection of Pergoveris should be carried out under direct medical supervision. The patient must wash their hands. It is very important that the hands and all the items she uses are as clean as possible.2. It is necessary to prepare a clean surface and spread it on it: a bottle with the drug, a bottle with a solvent, 2 tampons impregnated with an antiseptic, a syringe, a needle for preparing a solution and a needle for subcutaneous injection, a container for recycling3. Connect the needle to prepare the solution with a syringe. Remove the cap from the needle and draw air into the syringe to the 1 ml mark. Insert the needle into the solvent vial, piercing the rubber cap, push the syringe plunger so that all the air comes out of the syringe, turn the vial upside down and slowly draw the entire volume of the solvent into the syringe. Without touching the needle, gently place the solvent-filled syringe on a clean work surface. Preparation of the solution for injection: remove the snap-on lid from the vial with Pergoveris lyophilized. Insert the needle of the syringe with the solvent into the vial by piercing the rubber cap of the vial. Slowly inject the entire contents of the syringe into the vial. It is necessary to rotate the vial for better dissolution, but do not shake it. After the lyophilisate is dissolved (which usually occurs immediately), the purity and transparency of the resulting solution should be checked.You need to make sure that the solution does not contain any particles. Next, turn the vial upside down and slowly draw the solution back into the syringe. Remove the needle from the bottle. Change the needle to prepare the solution for the needle for sc injection, and remove all air bubbles: if air bubbles remain in the syringe, you need to turn it with the needle up and knock gently on the syringe so that all the bubbles gather at the top of the syringe. Press the piston gently until all bubbles disappear. Immediately after that, you need to enter the solution. The physician should instruct the patient in which part of the body it is better to inject (abdomen or front of the thigh). It is necessary to collect the skin in a small fold, and with a single movement of the brush, insert the needle into the fold formed at an angle of 45-90 °. With the injection, slowly press on the plunger until all the contents of the syringe have been inserted. After that, immediately remove the needle and wipe the injection site with an antiseptic swab in a circular motion. All used items and unused solution residue should be disposed of immediately after the injection.8. If a patient accidentally injects more Pergoveris than it should, she should consult a doctor. Cases of overdose are unknown, however the development of OHSS is possible. It should be noted that OHSS often develops only with the use of hcg.9. If the patient missed the injection of Pergoveris, do not need to enter a double dose, you should consult with your doctor.
Side effects
From the nervous system: very often - a headache; often - drowsiness. From the genitals: very often - ovarian cysts; often - HUR of mild severity (accompanied by abdominal pain, nausea, vomiting, weight gain, ovarian enlargement, including due to the formation of cysts), HUR of moderate severity (except for lower abdominal pain, nausea, vomiting, weight gain body and ovarian, dyspnea, oliguria, ascites, pleural effusion, fluid accumulation in the pericardial cavity, pain in the breast, pelvic pain; infrequently, a severe form of OHSS (may be accompanied by severe forms of ascites, pleural effusion, fluid accumulation in the pericardial cavity, oligouria, acute respiratory distress syndrome, and pulmonary embolism (very rarely)); rarely - torsion of ovarian cysts (as a complication of OHSS). On the part of the digestive system: often - abdominal pain, nausea, vomiting, diarrhea, abdominal colic,meteorism. From the side of the cardiovascular system: very rarely - thromboembolism, as a rule, associated with severe OH. 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 (reddening of the skin, urticaria, rash, swelling of the face, difficulty breathing, generalized edema, anaphylaxis, fever, arthralgia). Local reactions: very often - reactions of varying degrees of severity and at the injection site (pain, redness, bruising, swelling). When follitropina alpha (p-FSHg) is used, the following undesirable effects are possible: rarely - ovarian apoplexy, ectopic pregnancy (in women with a history of fallopian tubes), multiple pregnancy. The patient should be warned that all adverse events occurring during the use of the drug Pergoveris, should be immediately reported to your doctor.
Overdose
Cases of overdose of the drug are unknown. Possible development of OHSS and other adverse reactions described in the sections of Side Effects and Special Instructions.
Interaction with other drugs
No incompatibility of Pergoveris with other drugs has been reported. It is not allowed to mix Pergoveris with any other drug in one syringe, with the exception of follitropin alfa.
special instructions
The drug PergoVeris contains active substances of gonadotropins, which can cause adverse reactions of varying severity, therefore the drug should be administered only by a physician who has the appropriate specialization and experience in treating infertility. The examination of the infertile couple should precede the beginning of therapy, in particular, studies should be conducted to rule out hypothyroidism, adrenal insufficiency, hyperprolactinemia, hypothalamic-pituitary neoplasms. For treating gonadotrophins, treating the doctor must have the necessary equipment and sufficient time to monitor the patient. Safe and effective therapy with PergoVeris requires regular monitoring of follicular development using ultrasound and, if possible, monitoring the concentration of estradiol in the blood serum. In patients with porphyria with relatives, during therapy with Pergoveris, careful monitoring is required.When the condition worsens or the first signs of this disease appear, it may be necessary to discontinue therapy. The drug Pergoveris contains less than 1 mmol (23 mg) of sodium in 1 dose, that is, it is not a significant source of sodium. The drug Pergoveris contains 30 mg of sucrose in one 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. use the minimum effective dose. It is known that there is an individual variability of response in the treatment of r-FSH / r-LGH, incl. lack of response in some patients. In clinical studies, the use of a combination of lutropin alpha and follitropin alpha resulted in an increase in the sensitivity of the ovaries to gonadotropins. If it is necessary to increase the dose of p-FSH, it is recommended to increase by 37.5-75 ME of follitropin alpha every 7-14 days. The ovarian hyperstimulation syndrome of EHD should be differentiated from uncomplicated ovarian enlargement. Clinical symptoms of EHH may manifest with increasing severity. Characterized by 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, less often, pericardial cavities. weight gain, shortness of breath, oliguria, gastrointestinal symptoms (nausea, vomiting, diarrhea); hypovolemia, hemoconcentration, electrolyte imbalance, ascites, hemoperitoneum, pleural effusion, acute respiratory distress syndrome, thromboembolic disorders take place. ovulation was not prescribed hCG, then an excessive ovarian response causes the development of substantial overstimulation in rare cases. Therefore, if the ovaries respond excessively 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. EHG can progress rapidly (from a day to a few days) to a serious condition, therefore, after the administration of hCG, it is necessary to observe for at least two weeks. To minimize the risk of OHS and multiple pregnancies, regularly use ultrasound and an assessment of the concentration of estradiol in the blood serum. In anovulation, the risk of developing OHSS increases with an estradiol concentration of> 900 pg / ml (3300 pmol / ml) and there are more than 3 follicles with a diameter of at least 14 mm. Strictly following the recommended dosage of PergoVeris and follitropin alpha, as well as careful monitoring of therapy, minimizes the risk of development OHS and multiple pregnancy. With the onset of pregnancy, the severity of OHS can be exacerbated, and its duration - to increase. Most often, OHSS occurs after the termination of hormone therapy and reaches its maximum in 7-10 days after that. As a rule, OHS spontaneously disappears with the onset of menstruation. With the development of severe OHSS, therapy with gonadotropins, if it continues, should be discontinued. The patient should be hospitalized and a specific for OHSS therapy should be prescribed. In patients with polycystic ovary syndrome, the risk of developing OHSS is higher. Multiple pregnancies Frequency of multiple pregnancies and births with ovulation induction is higher than the risk of multiple births, the most frequent option for multiple births is twofold. pregnancy, careful monitoring of the ovarian response is necessary. In ART, the risk of multiple pregnancies is associated mainly with the number of em Rion, their vitality and age patsientki.Nevynashivanie beremennostiChastota miscarriage VRT higher after ovulation induction and programs than in populyatsii.Ektopicheskaya pregnant patients with diseases of the fallopian tubes in the history of an increased risk of ectopic pregnancy. The probability of ectopic pregnancy after the application of assisted reproductive technologies is from 2 to 5%, compared with 1-1.5% in the general population. New formations of the reproductive system organs There are reports of benign and malignant neoplasms of the ovary and other reproductive organs in women after numerous and varied treatment courses infertilityAt present, no connection has been established between gonadotropin therapy and an increased risk of neoplasms during infertility. Congenital developmental anomalies The frequency of congenital anomalies after the use of assisted reproductive technology programs may be slightly higher than during natural pregnancy and childbirth. However, it is not known whether this is related to the factors causing the infertility of the couple or directly to the procedures of ART. Based on data from clinical studies and post-registration monitoring, there is no evidence that the use of goiadotropins in the treatment of infertility increases the risk of congenital abnormalities in the offspring of patients. 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 EHH or multiple pregnancy, the decision to discontinue therapy should be considered. It is necessary to inform the doctor about all types of allergic reactions that the patient has, as well as all the drugs used before starting treatment with PergoVier. Effect on ability to drive motor vehicles and control mechanisms. Research effects of the drug on the ability to drive and other mechanisms was not carried out.