Pergoveris^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Merck LLC (Russia)

Manufactured By

Merck Serono S.A., Succursale d'Aubonne (Switzerland)

ATC Code

G03GA30 (Gonadotropins in combination)

Active Substances

Follitropin alfa (Rec.INN registered by WHO)

Lutropin alfa (Rec.INN registered by WHO)

Dosage Form

Pergoveris®

Lyophilisate for preparation of solution for subcutaneous administration 150 IU+75 IU: vial 1, 3 or 10 pcs. in set with solvent

Dosage Form, Packaging, and Composition

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

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 – to adjust pH to 6.5-7.5, sodium hydroxide – to adjust pH to 6.5-7.5.

Solvent water for injections – 1 ml (vials).

Colorless glass vials with a capacity of 3 ml (1) in a set with solvent (vial 1 pc.) – plastic containers (1) – cardboard packs.
Colorless glass vials with a capacity of 3 ml (1) in a set with solvent (vial 1 pc.) – plastic containers (3) – cardboard packs.
Colorless glass vials with a capacity of 3 ml (1) in a set with solvent (vial 1 pc.) – plastic containers (10) – cardboard packs.

Clinical-Pharmacological Group

Combination of recombinant human follicle-stimulating hormone and luteinizing hormone

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; gonadotropins and other ovulation stimulants; gonadotropins

Pharmacological Action

Combined medicinal product. Contains recombinant human FSH (Follitropin alfa, r-hFSH) and recombinant human LH (Lutropin alfa, r-hLH).

In clinical studies, the efficacy of the combination of follitropin alfa and lutropin alfa was demonstrated in hypogonadotropic hypogonadism in women.

When stimulating follicle development in women with anovulation with LH and FSH deficiency, the main effect of lutropin alfa is to increase the secretion of estradiol by the 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, 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 increased estradiol synthesis.

Although the efficacy of r-hFSH monotherapy in the use of assisted reproductive technologies (ART) has been proven, published results of clinical studies indicate the benefits of additional administration of r-hLH in patients with insufficient (suboptimal) efficacy of r-hFSH monotherapy. The addition of r-hLH is intended to increase ovarian sensitivity to r-hFSH, to stimulate estradiol secretion by the preovulatory follicle, causing endometrial growth, and to ensure later luteinization of follicles, leading to normalization of progesterone levels in the luteal phase.

Pharmacokinetics

Follitropin alfa and Lutropin alfa, administered in combination, retain the same pharmacokinetic characteristics as when administered separately.

After IV administration, Follitropin alfa is distributed in extracellular fluids, with its initial T_1/2 being about 2 hours, while the terminal T_1/2 is about 24 hours. The equilibrium V_d is 10 L, total clearance is 0.6 L/h. One-eighth of the administered dose of follitropin alfa is excreted by the kidneys. With SC administration, the absolute bioavailability is about 70%. After repeated injections, a threefold accumulation of the drug in the blood is observed compared to a single injection. C_ss 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 follicle development and steroidogenesis, despite an immeasurably low level of LH.

After IV administration, Lutropin alfa is rapidly distributed with an initial T_1/2 of about 1 hour, and is eliminated from the body with a terminal T_1/2 of about 10-12 hours. At equilibrium, V_d ranges from 10 to 14 L. Lutropin alfa demonstrates a linear pharmacokinetic profile, as evidenced by a directly proportional dependence of AUC on the administered dose. Total clearance is about 2 L/h, less than 5% of the dose is excreted by the kidneys. Mean residence time in the body is 5 hours. After SC administration, Lutropin alfa is rapidly distributed in organs and tissues, absolute bioavailability is about 60%; the terminal T_1/2 is somewhat prolonged. The pharmacokinetics of lutropin alfa after a single administration is comparable to that after multiple administrations, the degree of accumulation is minimal.

No pharmacokinetic interaction was observed when lutropin alfa was administered simultaneously with follitropin alfa.

Indications

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

Suboptimal response in patients during previously performed controlled ovarian stimulation (COS), which was characterized either by a small number of obtained preovulatory follicles/oocytes (less than 7), or by the use of high doses of FSH (3000 IU or more per 1 cycle), or by the patient’s age (35 years and older) either individually or in combination, when conducting an ART program: in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), gamete/zygote intrafallopian transfer (GIFT/ZIFT).

ICD codes

Dosage Regimen

Administer subcutaneously only.

Initiate and conduct treatment exclusively under the supervision of a physician experienced in infertility management.

Determine the dose and regimen individually based on the indication and the patient’s therapeutic response.

For stimulation of follicular growth in women with severe LH and FSH deficiency, the typical daily dose is one reconstituted vial containing 150 IU follitropin alfa and 75 IU lutropin alfa.

For patients with a suboptimal response during previous controlled ovarian stimulation in ART cycles, add 75 IU lutropin alfa daily to the ongoing follitropin alfa regimen.

Continue treatment until adequate follicular development is achieved, as confirmed by ultrasound and serum estradiol levels.

Administer hCG as a single dose to trigger final follicular maturation once optimal follicular development is observed.

Discontinue treatment if there is an excessive ovarian response or signs of severe ovarian hyperstimulation syndrome (OHSS).

Withhold treatment in cases of ovarian cyst formation not related to polycystic ovary syndrome.

Use the minimum effective dose to achieve the desired response and minimize the risk of adverse events.

Reconstitute the lyophilisate immediately before use with the supplied solvent (water for injections).

Gently swirl the vial until the powder is completely dissolved; do not shake.

Inspect the reconstituted solution visually for particulate matter and discoloration prior to administration.

Discard any unused solution.

Adverse Reactions

Nervous system disorders: very common – headache; common – drowsiness.

Reproductive system and breast disorders: very common – ovarian cysts; common – mild OHSS (accompanied by lower abdominal pain, nausea, vomiting, weight gain, enlarged ovaries, including due to cyst formation), moderate OHSS (in addition to lower abdominal pain, nausea, vomiting, weight gain and enlarged ovaries, shortness of breath, oliguria, ascites, pleural effusion, fluid accumulation in the pericardial cavity may be noted), breast pain, pelvic pain; uncommon – 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)); rare – ovarian cyst torsion (as a complication of OHSS).

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

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

Respiratory, thoracic and mediastinal disorders: very rare – worsening or exacerbation of asthma in patients with bronchial asthma.

Immune system disorders: very rare – systemic allergic reactions of varying severity (skin redness, urticaria, rash, facial swelling, difficulty breathing, generalized edema, anaphylaxis, fever, arthralgia).

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

When using follitropin alfa (r-hFSH) the following adverse events are possible: rare – ovarian apoplexy, ectopic pregnancy (in women with a history of fallopian tube diseases), multiple pregnancy.

Contraindications

Tumors of the hypothalamus and/or pituitary gland; space-occupying lesions or ovarian cysts not associated with polycystic ovary syndrome; uterine and/or other gynecological bleeding of unknown etiology; ovarian cancer, uterine cancer, breast cancer; primary ovarian failure; malformations of the female genital organs incompatible with pregnancy; uterine fibroid tumors incompatible with pregnancy; pregnancy; breastfeeding period; hypersensitivity to the components of the combination.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Pediatric Use

Not used.

Geriatric Use

Not used.

Special Precautions

Before starting therapy, the infertile couple should be examined; in particular, studies should be conducted to rule out hypothyroidism, adrenal cortex insufficiency, hyperprolactinemia, hypothalamic-pituitary neoplasms.

To conduct therapy with gonadotropins, the attending physician must have the necessary equipment and sufficient time to monitor the patient.

Safe and effective therapy with a drug containing this combination requires regular monitoring of follicle development using ultrasound, and, if possible, monitoring of serum estradiol concentration.

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

During ovarian stimulation, the risk of ovarian hyperstimulation increases due to the possibility of an excessive estrogen response and multiple follicle development.

The minimum effective doses should be used.

There is known individual variability in response to treatment with r-hFSH/r-hLH, including 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 pregnancy occurs, the severity of OHSS may worsen and its duration may increase. OHSS most often occurs after discontinuation of hormone therapy and reaches its maximum 7-10 days after that. As a rule, OHSS resolves spontaneously with the onset of menstruation.

If a severe form of OHSS develops, gonadotropin therapy, if it is still ongoing, should be discontinued. The patient should be hospitalized and specific therapy for OHSS should be prescribed.

The risk of developing OHSS is higher in patients with polycystic ovary syndrome.

The frequency of multiple pregnancy and childbirth during ovulation induction is higher compared to natural conception, with twins being the most common variant in multiple pregnancies.

To minimize the risk of multiple pregnancy, careful monitoring of the ovarian response is necessary.

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

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

Patients with a history of fallopian tube diseases have an increased risk of ectopic pregnancy. The likelihood of ectopic pregnancy after the use of ART is from 2 to 5%, compared with 1-1.5% in the general population.

In patients with recently experienced or current thromboembolic diseases, as well as with a probable 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 benefit of therapy should be weighed against the possible risk. It should be noted that pregnancy itself carries an increased risk of thromboembolic disorders.

Patients should be informed of the above risks before starting therapy. If OHSS or multiple pregnancy occurs directly, consideration should be given to discontinuing therapy.

It is necessary to inform the doctor about all types of allergic reactions that the patient has, as well as about all drugs used before starting treatment with this combination.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.