Pergoveris®

Brand Merck Serono

In stock 1853 Items

Available since: 2019-09-19

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Clinical Pharmacology

Drug Pergoveris^® - This is a combined drug containing recombinant human FSH (follitropin alpha, p-FSHch) and recombinant human LH (lutropin alpha, r-LGH). The drug is obtained by the genetic engineering method on the culture of Chinese hamster ovary cells.

The main role of FSH is to initiate folliculogenesis by exposing the developing follicle to granulosa cells, while LH plays an important role in enhancing the production of estradiol by the mature follicle, and induces follicle maturation and ovulation at the peak of its activity. 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 membrane of granulosa cells.

The impact of LH on theca cells provides androgen production for granulosa cells, where androgens are 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, 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 the full-fledged yellow body in response to the administration of human HGH (hCG).

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

When stimulating the development of follicles in women with anovulation with LH and FSH deficiency, 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 has been shown that in women with hypogonadotropic hypogonadism and LH concentration in serum below 1.2 IU / l, 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 follicle development and an increase in estradiol synthesis, while as a combination of lutropin alfa 25 IU and follitropin alfa 150 IU does not provide this effect.

Thus, with the appointment of less than one vial of the drug Pergoveris^® per day, LH activity may not be sufficient for the full development of follicles.

Although the efficacy of p-FSH monotherapy using assisted reproductive technologies (ART) has been proven, published results of clinical studies suggest the benefits of supplemental p-LGH administration in patients with insufficient (suboptimal) efficacy of p-FSH 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 provide for the later luteinization of the follicles, leading to the normalization of the progesterone level in the luteal phase.

Pharmacokinetics

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

Follitropin alfa

After iv administration, follitropin alpha is distributed in extracellular fluids, with the initial T_1/2 its excretion is about 2 h, whereas the final T_1/2 - about 24 hours. V value_ss makes 10 l, the general clearance - 0,6 l / h. One-eighth of the dose of follitropin alpha is excreted by the kidneys.

When s / c administration, the absolute bioavailability is about 70%. After repeated injections, there is a threefold cumulation of the drug in the blood compared to a single injection. Stationary C_ss in 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 the level of PH that is inaccessibly low for quantitative measurement.

Lutropin alfa

After iv administration, lutropin alpha is rapidly distributed with initial T_1/2 about 1 h, and excreted with a final T_1/2 about 10–12 hours. V_ss ranges from 10 to 14 liters. Lutropin alfa shows a linear pharmacokinetic profile, as evidenced by the direct proportionality of the AUC to the dose administered. 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 / c administration, lutropin alpha is rapidly distributed in organs and tissues, the absolute bioavailability is about 60%; end T_1/2 somewhat lengthened. The pharmacokinetics of lutropin alpha with a single injection is comparable to that with multiple, the degree of cumulation is minimal. With simultaneous administration of lutropin alpha with follitropin alpha, no pharmacokinetic interaction was observed.

Indications

Stimulation of the growth and maturation of follicles in women - with a pronounced 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 (less than 7), or using high doses of FSH (3000 IU or more / per 1 cycle), or the patient's age (35 years and older), both individually and in combination, during the assisted reproductive technology (ART) program: in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), gamete transplantation / zygotes in fallopian tubes (GIFT / ZIFT).

Composition

1 bottle contains:

Active substances: follitropin alfa 150 IU (11 mcg), lutropin alfa 75 IU (3 mcg);

Excipients: sucrose - 30 mg, sodium hydrophosphate dihydrate - 1.11 mg, sodium dihydrogen phosphate monohydrate - 0.45 mg, methionine - 0.1 mg, polysorbate 20 - 0.05 mg, phosphoric acid concentrated to a pH of 6.5–7, 5, sodium hydroxide - to pH 6.5–7.5.

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Dosage and Administration

Drug Pergoveris^® designed for s / c introduction!

Drug Treatment Pergoveris^® should begin and be 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 attached solvent immediately before administration, the resulting solution for sc injection is used once.

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

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

Recommended initial dose of Pergoveris^® is 1 bottle (150 IU p-FSHC + 75 IU p-LGG) per day. Since this group of patients is characterized by amenorrhea and a low endogenous level of estrogen secretion, therapy can be started on any given 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 estrogen concentration in the blood serum.

If the decision is made to increase the dose of p-FSHch, it is recommended to increase it in 7–14 days, preferably by 37.5–75 IU of follitropin alfa.

PergoVeris preparation solution^® You can mix with follitropin alpha and enter these drugs in a single injection. Perhaps an increase in the duration of stimulation in one of the cycles up to 5 weeks. Upon reaching the optimal response, from 5,000 to 10,000 IU of hCG or 250 mcg p-hCG are injected in a single dose in the range of 24–48 hours after the last injection of Pergovéris^®. Sexual contact 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.

It may be necessary to support the luteal phase, since a deficiency of luteotropic activity (LH / HGCH) after ovulation can lead to premature failure of the corpus luteum.

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 lower dose of p-FSHg than in the previous cycle.

Suboptimal response in patients with CBS previously performed in ART programs

The recommended treatment regimen begins with ME p-FSHch 1 time per day for 5–7 days. Starting from the 6th-8th day of controlled ovarian stimulation (CBS), p-FSHch is replaced with 2 fl. Pergoveris^® (300 IU r-FSHch and 150 IU r-LGG). An alternative treatment regimen may be the appointment of 2 bottles of the drug Pergoveris^® (300 IU of p-FSHch and 150 IU of p-LGG) per 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 the concentration of estrogen in the serum and the results of ultrasound, with the selection of the dose of p-FSHh depending on the severity of the effect. When increasing the dose of p-FSH, it should be borne in mind that the daily dose of p-FSH should not exceed 450 IU.

When an adequate follicle development level is reached, HGCH should be injected to induce the final maturation of the follicles and preparation for puncture to extract the oocyte. 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 you receive an excessive response, treatment should be suspended, and the introduction of HCG should be canceled. Treatment can be resumed from the next cycle with the use of a lower dose than in the previous cycle.

Recommendations for patients with self-administered drug

Self-administration of the drug Pergoveris^® It is permissible only for highly motivated and trained patients who are under constant supervision of the attending physician who has the appropriate training and experience in treating infertility. The first injection of the drug Pergoveris^® must be carried out under direct medical supervision.

Adverse reactions

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

From the genital and breast organs: very often - ovarian cysts; often - ovarian hyperstimulation syndrome (OHSS) of mild severity (accompanied by lower abdominal pain, nausea, vomiting, weight gain, ovarian enlargement, including due to the formation of cysts); often - HUR of moderate severity (except for lower abdominal pain, nausea, vomiting, weight gain and ovarian weight, shortness of breath, oliguria, ascites, pleural effusion, fluid accumulation in the pericardial cavity can occur). Detailed information - in the section "Special Instructions"; often - pain in the mammary glands; pelvic pain; infrequently, severe form of 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). For more information, see the Special Instructions section; rarely - torsion ovarian cysts (as a complication of OHSS).

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

From the heart and blood vessels: very rarely - thromboembolism, usually associated with severe OHSS.

On the part of 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 (skin redness, hives, rash, swelling of the face, difficulty breathing, generalized edema, anaphylaxis, fever, arthralgia).

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

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

About all adverse events that occur during the use of the drug Pergoveris^®, the patient should immediately inform the attending physician.

Contraindications

hypersensitivity to any of the active or auxiliary substances or their combination;
hypothalamic and / or pituitary tumors;
bulky 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;
pregnancy and lactation;
primary ovarian failure;
abnormalities of the development of female genital organs, incompatible with pregnancy;
fibroid tumors of the uterus, incompatible with pregnancy.

Drug interactions

On the incompatibility of the drug Pergoveris^® no other medications were reported. Mixing Pergoveris is not allowed.^® with any other drug in the same syringe, with the exception of follitropin alfa.

Pregnancy and Lactation

Drug Pergoveris^® contraindicated for use during pregnancy and breastfeeding.

Special instructions

Drug Pergoveris^® contains active substances of gonadotropins, which can cause adverse reactions of varying severity, so the drug should be administered only by a doctor who has the appropriate specialization and experience in treating infertility. The examination of the infertile couple should precede the treatment, in particular, studies should be conducted to rule out hypothyroidism and cortical insufficiency adrenal glands, hyperprolactinemia, hypothalamic-pituitary tumors.

In order to conduct therapy with gonadotropins, the attending physician should 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, control of serum estradiol concentration.

In patients with porphyria, as well as in the presence of porphyria in 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.

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

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.

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

Minimum effective doses should be used.

It is known that there is an individual response variability 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 led to 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 it by 37.5–75 IU of follitropin alfa every 7–14 days.

OHSS must be differentiated from uncomplicated enlargement of the ovaries. Clinical symptoms of OHSS can 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, rarely, pericardial cavities.

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

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

If HCG was not prescribed to induce ovulation, 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.

EHH can rapidly progress (from a day to several days) to a serious condition, therefore, after the introduction of hCG, observation is necessary for at least two weeks.

To minimize the risk of OHS and multiple pregnancies, ultrasound and an estimate of serum estradiol concentration are regularly used. In anovulation, the risk of developing OHSS increases with an estradiol concentration of> 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 the drug Pergoveris^® and follitropina alfa, as well as careful monitoring of therapy, minimizes the risk of developing OSS and multiple pregnancies.

With the onset of pregnancy, the severity of OHH can worsen, and its duration - to increase. Most often, OHSS occurs after discontinuation of hormone therapy and reaches its maximum 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 prescribed specific therapy for OHSS.

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

Multiple pregnancy

The frequency of multiple pregnancies and deliveries during the induction of ovulation is higher compared to natural conception, the most frequent option for multiple babies is twins. To minimize the risk of multiple pregnancies, careful monitoring of the ovarian response is necessary.

In case of ART, the risk of multiple pregnancy is mainly related to the number of transferred embryos, their viability and the patient's age.

Miscarriage of pregnancy

The frequency of miscarriage after induction of ovulation and ART programs is higher than in the population.

Ectopic pregnancy

In patients with diseases of the fallopian tubes in 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 reproductive organs

There are reports of benign and malignant neoplasms of the ovary and other reproductive organs in women after conducting numerous and varied courses of infertility treatment. At present, no link has been established between gonadotropin therapy and the increased risk of neoplasm in infertility.

Congenital malformations

The frequency of congenital anomalies after the application of assisted reproductive technology programs may be slightly higher than during natural pregnancy and childbirth. However, it is not known whether this is due to the factors contributing to the infertility of the couple or directly to the procedures of ART.

Based on data from clinical studies and post-registration monitoring, no evidence has been found that the use of gonadotropins in infertility treatment increases the risk of congenital abnormalities in the offspring of patients.

Thromboembolic complications

In patients with recent or ongoing thromboembolic diseases, as well as at the likely 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 EHH or multiple pregnancy, the decision to discontinue therapy should be considered.

The patient must inform the doctor about all types of allergic reactions that are present, as well as about all the preparations used before starting treatment with PergoVeris^®.

Influence on ability to drive a car and work with mechanisms. Studies on the effect of the drug on the ability to drive and other mechanisms have been conducted.