Pergoveris, lyophilizate 150 me+75 me

Pergoveris^® is a combined drug containing recombinant human FSH (folletropin alpha, p-FSHh) and recombinant human LH (lutropin alpha, p-LHhh). The drug is produced by genetically engineered method on Chinese hamster ovary cell culture.

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

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

The effect of LH on theca cells ensures the production of androgens for granulosa cells, where the transformation of androgens into estrogens takes place through the aromatase system. Thus, in the absence of LH, FSH can induce follicular growth, but estradiol synthesis is reduced. Without sufficient estradiol, the conditions for pregnancy are impaired, as well as cervical mucus secretion, endometrial growth and maturation of the full corpus luteum in response to human hCG (hCG) administration.

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

In stimulating follicle development in women with anovulation with LH and FSH deficiency, the main effect of lutropin alfa is to increase estradiol secretion by follicles, whose growth is in turn stimulated by FSH.

. In women with hypogonadotropic hypogonadism and a serum LH concentration below 1.2 IU/L, daily use of a combination of lutropin alfa at 75 IU and follitropin alfa at 150 IU has been shown to result in adequate follicle development and increased estradiol synthesis, whereas a combination of lutropin alfa 25 IU and follitropin alfa 150 IU does not provide this effect.

Hence, when less than one vial of Pergoveris^® per day is prescribed, LH activity may not be sufficient for full follicle development.

While the efficacy of p-LHF monotherapy in assisted reproductive technology (ART) has been proven, published results from clinical trials suggest the benefits of p-LHF supplementation in patients with insufficient (suboptimal) efficacy of p-LHF monotherapy.

The addition of p-LHF is intended to increase ovarian sensitivity to p-FSHh, to stimulate oestradiol secretion by the preovulatory follicle to induce endometrial growth, and to allow later luteinization of follicles, resulting in normalization of progesterone levels in the luteal phase.

Pharmacokinetics

Follitropin alfa and lutropin alfa administered in combination retain the same pharmacokinetic characteristics as they do individually.

Follitropin alfa

After IV administration, follitropin alfa is distributed in extracellular fluids, with an initial T_1/2 of about 2 h from the body, whereas the final T_1/2 is about 24 h. The V_ss value 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.

When administered by injection the absolute bioavailability is about 70%. After repeated injections, a threefold cumulation of the drug in blood is observed compared to a single injection. Stationary C_ss in the blood is reached within 3-4 days. It has also been shown that in women with suppressed endogenous gonadotropin secretion, follitropin alfa effectively stimulates follicle development and steroidogenesis despite inaccessibly low LH levels for quantitative measurement.

Lutropin alfa

After IV administration, lutropin alfa is rapidly distributed with an initial T_1/2 of about 1 h, and excreted with a final T_1/2 of about 10-12 h. V_ss is 10 to 14 L. Lutropin alfa exhibits a linear pharmacokinetic profile, as evidenced by a direct proportional relationship of AUC to the administered dose. 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 oral administration lutropin alfa is rapidly distributed in organs and tissues, the absolute bioavailability is about 60%; the final T_1/2 is slightly prolonged. The pharmacokinetics of lutropin alfa with single administration is comparable with that with multiple administration, the degree of cumulation is minimal. No pharmacokinetic interaction was observed when lutropin alfa was administered concomitantly with follitropin alfa.

Indications

Infertility

Stimulation of follicle growth and maturation in women – with severe LH and FSH deficiency; Suboptimal response in patients with previous controlled ovarian stimulation (COS), characterized by either a low number of received preovulatory follicles/oocytes (less than 7), or the use of high doses of FSH (3000 IU or more per cycle), or the patient’s age (35 years or older), either separately or in combination, – in the program of assisted reproductive technology (ART): in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), gamete/zygote transplantation into fallopian tubes (GIFT/ZIFT).

Active ingredient

Follytropin alpha, Lutropin alpha

Composition

Active ingredients:

Follitropin alpha 150 IU (11 µg);

Lutropin alpha 75 IU (3 µg);

Associates:

sucrose – 30 mg,

sodium hydrophosphate dihydrate – 1.11 mg,

sodium dihydrophosphate 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

How to take, the dosage

Pergoveris^® is for oral administration!

The treatment with Pergoveris^® should only be started and carried out under the supervision of a doctor with appropriate expertise and experience in treating infertility.

The lyophilisate is dissolved with the included solvent immediately prior to administration; the resulting solution for single infusion is used.

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

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

The recommended starting dose of Pergoveris ^® is 1 fl (150 IU p-FSHh + 75 IU LHH) daily. Since this group of patients is characterized by amenorrhea and low endogenous estrogen secretion, the therapy can be started on any day.

The duration of the course of treatment is individually determined according to the follicle growth/size determined by ultrasound monitoring and based on the estrogen concentration in the serum.

If the decision is made to increase the p-FSHh dose, it is recommended that it be increased after 7-14 days, preferably by 37.5-75 IU of folletropin alfa.

Pergoveris^® solution can be mixed with follitropin alfa and administered in a single injection. It is possible to increase the duration of stimulation within a cycle up to 5 weeks. When an optimal response is achieved, 5000 to 10,000 IUHg or 250 mcg p-CGH should be injected once within 24 to 48 hours of the last injection of Pergoveris®. Sexual intercourse is recommended on the same day and the day after HCGH injection; intrauterine insemination (IUI) may be used as an alternative.

Luteal phase support may be required because a deficiency of luteotropic activity (LH/ChGH) after ovulation can lead to premature corpus luteum failure.

If the ovaries respond excessively to stimulation, therapy should be suspended and hCG injections delayed. Therapy can be resumed in the next cycle using a lower dose of p-FSHc than in the previous cycle.

Suboptimal response in patients with prior CBT in ART programs

The recommended treatment regimen begins with IU of r-FSHc once daily for 5-7 days. Starting on days 6-8 of controlled ovarian stimulation (COS) p-FSGHh is replaced with 2 fls of Pergoveris® (300 IU p-FSGHh and 150 IU p-LGH). An alternative treatment regimen may be to administer 2 vials of Pergoveris^® (300 IU p-FSHh and 150 IU p-LHh) per day starting on the first day of COS following pituitary desensitization.

The treatment continues until an adequate level of follicular development as determined by serum estrogen concentrations and ultrasound findings, with the p-FSHh dose adjusted according to the severity of the effect. When increasing the dose of r-FSGHc, it should be kept in mind that the daily dose of r-FSGHc should not exceed 450 IU.

If adequate follicle development is achieved, hCG should be administered to induce final follicle maturation and prepare for puncture for oocyte retrieval. HCG should be withheld if the ovaries are significantly enlarged on the last day of treatment to reduce the likelihood of SVF. If there is an excessive response, treatment should be suspended and hCG withdrawn. Treatment may be resumed starting the next cycle with a lower dose of the drug than in the previous cycle.

Pergoveris®

Pergoveris® self-injection is only suitable for highly motivated and trained patients who are under the close supervision of a physician with appropriate training and experience in infertility treatment. The first injection of Pergoveris® should be given under direct medical supervision.

Before starting the manipulation, you should:

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

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

– vial of product;

– vial of solvent;

– 2 antiseptic-soaked swabs; <

– syringe;

– syringe for preparing the solution and needle for injection;

– container for disposal.

3. Connect the solution needle to the syringe. Remove the cap from the needle, and fill the syringe with air to the 1 ml mark. Insert the needle into the bottle with the solvent by piercing the rubber cap, push down on the syringe plunger to release all of the air from the syringe into the bottle, turn the bottle upside down, and slowly draw all of the solvent into the syringe. Without touching the needle, carefully place the solvent-filled syringe on a clean work surface.

4. Preparation of the solution for injection: Remove the snap-on cap from the vial with Pergoveris^® lyophilizate. 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. Rotate the vial for better dissolution, but do not shake it. After dissolving the lyophilizate (which usually happens immediately), check the purity and transparency of the resulting solution. Make sure that the solution does not contain any particles. Turn the vial upside down and slowly draw the solution back into the syringe. Remove the needle from the vial.

5. Change the preparation needle to an IV needle and remove any air bubbles: if air bubbles are visible in the syringe, turn it up with the needle up and tap gently on the syringe so that all of the bubbles collect at the top of the syringe. Press down on the plunger until all the bubbles are gone.

6. Immediately thereafter, inject the solution. The physician should instruct the patient in which part of the body it is best to inject (abdomen or anterior surface of the thighs). To perform the injection you should: gather the skin into a small fold and with one movement of the hand introduce the needle into the formed fold at an angle of 45-90°. When injecting, slowly press the plunger until the entire dose is injected. After that, immediately remove the needle and wipe the injection site with an antiseptic tampon in a circular motion.

Dispose of all used objects and unused residual solution immediately after injection.

8. If a larger dose of Pergoveris® is inadvertently injected than should be, consult a physician. There are no known cases of overdose; however, SGBP is possible, which is described in detail in sections “Adverse effects” and “Precautions”. It should be noted that SGH is more likely to occur only when using hCG.

9. If the patient misses an injection of Pergoveris^®, a double dose should not be administered and a physician should be consulted.

Interaction

The incompatibility of Pergoveris^® with other medicinal products has not been reported.

Pergoveris^® should not be mixed with any other drug in the same syringe except folletropin alfa.

Special Instructions

Pergoveris^® contains active gonadotropin substances which may cause adverse reactions of varying severity, so it should only be prescribed by a physician with appropriate expertise and experience in treating infertility.The start of therapy should be preceded by an examination of the infertile couple, in particular tests to rule out hypothyroidism, adrenal insufficiency, hyperprolactinemia, and hypothalamic-pituitary neoplasms.

The treating physician must have the necessary equipment and enough time to observe the patient in order to administer gonadotropin therapy.

The safe and effective therapy with Pergoveris ^® requires regular monitoring of follicle development by ultrasound and, if possible, monitoring of serum estradiol concentrations.

In patients with porphyria and also in the presence of porphyria in relatives, close monitoring is required during therapy with Pergoveris^®. If the condition worsens or the first signs of this disease appear, therapy may have to be discontinued.

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

Pergoveris^® contains 30 mg of sucrose in 1 dose, which should be considered when prescribing to patients with concomitant diabetes mellitus.

The risk of ovarian hyperstimulation increases with ovarian stimulation because of the possibility of excessive estrogen response and multiple follicle development.

The lowest effective doses should be used.

The individual variability in response to p-FSHh/r-LHh treatment is known to exist, including an inadequate response in some patients. In clinical studies, the use of a combination of lutropin alfa and follitropin alfa led to an increase in the sensitivity of the ovaries to gonadotropins. If the p-FSHh dose needs to be increased, it is recommended that it be increased by 37.5-75 IU of follitropin alfa every 7-14 days.

SHF should be differentiated from uncomplicated ovarian enlargement. The clinical symptoms of SGY can appear with increasing severity. A significant increase in the size of the ovaries, high levels of sex hormones, increased vascular permeability leading to the accumulation of fluid in the abdominal, pleural and, less frequently, pericardial cavities are characteristic.

The following symptoms are most characteristic of severe SUI: pain and feeling of tumescence 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 have occurred.

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

If hCG has not been administered to induce ovulation, the excessive ovarian response causes the development of significant hyperstimulation in rare cases.

Hence, if the ovaries respond excessively to stimulation, HCG is not prescribed, and patients are advised to refrain from coitus or use barrier contraception for at least 4 days.

HCG can progress rapidly (from days to days) to severe, so follow-up for at least two weeks after HCG is administered.

In order to minimize the risk of SUGS and multiple pregnancies, regular ultrasound and assessment of serum estradiol concentrations are used. In cases of anovulation, the risk of SVF is increased when the estradiol concentration is >900 pg/mL (3300 pmol/mL) and there are more than 3 follicles with a diameter of at least 14 mm.

Strict adherence to the recommended dosage of Pergoveris^® and follitropin alfa, and close monitoring of therapy, minimizes the risk of SGN and multiple pregnancies.

When pregnancy occurs, the severity of SHF may worsen and its duration may increase. IUF most often occurs after discontinuation of hormone therapy and peaks 7-10 days thereafter. As a rule, SGI disappears spontaneously with the onset of menstruation.

In the case of severe SGH, gonadotropin therapy, if still ongoing, should be discontinued. The patient should be admitted to the hospital and given a SNF-specific therapy.

Patients with polycystic ovarian syndrome have a higher risk of SGI.

Multiple pregnancies

The frequency of multiple pregnancies and deliveries with ovulation induction is higher compared to natural conception; twins are the most common option for multiple pregnancy. To minimize the risk of multiple pregnancies, careful monitoring of the ovarian response is necessary.

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

Pregnancy failure

The incidence of pregnancy failure after ovulation induction and ART programs is higher than in the population.

Ectopic pregnancy

Patients with a history of fallopian tube disease have an increased risk of ectopic pregnancy. The likelihood of an ectopic pregnancy after the use of assisted reproductive technology is 2 to 5%, compared with 1 to 1.5% in the general population.

Reproductive neoplasms

There have been reports of benign and malignant neoplasms of the ovary and other reproductive organs in women after multiple and varied fertility treatments. To date, no association between gonadotropin therapy and an increased risk of neoplasia in infertility has been established.

Congenital anomalies

The incidence of congenital anomalies after the use of assisted reproductive technology programs may be slightly higher than for natural pregnancies and births. However, it is not known whether this is due to factors contributing to the couple’s infertility or directly to the ART procedures.

Based on data from clinical studies and post-registration monitoring, there is no indication that the use of gonadotropins in infertility treatment increases the risk of congenital anomalies in patients’ offspring.

Thromboembolic complications

In patients with recent or ongoing thromboembolic disease, or with a probable risk of such, the use of gonadotropins may increase this risk or complicate the course of these diseases. For patients in this group, the benefit of therapy must be weighed against the possible risk. It should be noted that pregnancy itself carries an increased risk of thromboembolic events.

Patients should be aware of the above risks before initiating therapy. The decision to discontinue therapy should be considered if there is an immediate onset of SUI or multiple pregnancies.

The patient should inform her physician of all types of allergic reactions she has, as well as any medications used before starting treatment with Pergoveris^®.

Contraindications

• hypersensitivity to any of the active or excipients or their combination;
• hypothalamic and/or pituitary tumors;
• matric and/or other gynecological bleeding of unclear etiology;
• Ovarian cancer, uterine cancer, breast cancer;
• pregnancy and lactation;
• primary ovarian insufficiency;
• Primary ovarian insufficiency;fibroid tumors incompatible with pregnancy
• fibroid tumors of the uterus incompatible with pregnancy.

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Side effects

CNS disorders: very common – headache; common – somnolence.

Gender and mammary glands: very common – ovarian cysts; common – ovarian hyperstimulation syndrome (OHS) of mild severity (accompanied by lower abdominal pain, nausea, vomiting, weight gain, ovarian enlargement, including cysts.(accompanied by lower abdominal pain, nausea, vomiting, weight gain and ovarian enlargement, including due to cyst formation); frequently – SHGF of moderate severity (in addition to lower abdominal pain, nausea, vomiting, weight gain and ovarian enlargement, dyspnea, oliguria, ascites, pleural effusion, fluid accumulation in the pericardial cavity may be observed).

For more information, see section “Special indications”; frequently – pain in the breast area; pelvic pain; infrequently – severe form of SUI (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 section “Special indications”; rarely – torsion of ovarian cysts (as a complication of OAI).

Gastrointestinal disorders: often – abdominal pain, nausea, vomiting, diarrhea, abdominal colic, flatulence.

Heart and vascular disorders: very rare – thromboembolism, usually associated with a severe form of SHG.

Respiratory system: very rare – worsening of the course or exacerbation of asthma in patients with bronchial asthma.

In immune system disorders: very rare – 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).

Pregnancy use

Pergoveris^® is contraindicated during pregnancy and breastfeeding.