Luveris - instructions for use, dose, side effects, contraindications

Active substanceLutropin alfaLutropin alfa

Similar drugsTo uncover

Luveris®

lyophilizate PC

Merck Serono SpA Italy

Dosage form: & nbsplyophilizate for the preparation of a solution for subcutaneous administration

Composition:

One bottle with lyophilizate contains:

Active substance: lutropin alfa 75 ME (3.4 μg);

Excipients: polysorbate 20 0.05 mg, methionine 0.1 mg, sodium hydrogen phosphate dihydrate 0.825 mg, sodium dihydrogen phosphate monohydrate 0.052 mg, sucrose 47.75 mg, phosphoric acid q.s., sodium hydroxide q.s.

One bottle with a solvent contains: water for injection - 1.0 ml.

Description:

Lyophilizate: lyophilized powder or a porous mass of white.

Solvent: clear, colorless liquid.

Pharmacotherapeutic group:Follicle stimulating agent

ATX: & nbsp

G.03.G.A Gonadotropins

G.03.G.A.07 Lutropin alfa

Pharmacodynamics:

Luveris® (lutropin alfa), recombinant human luteinizing hormone (r-hLH), identical to human natural hormone, was created using biotechnological methods. He belongs to a family of hormones called gonadotropins, which participate in the physiological regulation of reproductive function.

Luveris® compensates for the lack of luteinizing hormone in the body. Under the influence of Luveris ®, stimulation of the formation of estradiol follicles occurs.The introduction of Luveris® in the middle of the menstrual cycle triggers the formation of the yellow body and ovulation.

The administration of Luveris® in the post-vivorational period supports the functioning of the yellow body.

In a clinical study involving women with hypogonadotropic hypogonadism who had a concentration of endogenous LH in blood plasma of less than 1.2 IU / L, the use of p-hLH at appropriate doses was evaluated. It was shown that the use of r-hLH at a dose of 75 IU / day (in combination with recombinant human follicle stimulating hormone (p-hFSH) at a dose of 150 IU) provides the most adequate development of the follicle in 80% of patients.

Pharmacokinetics:

The pharmacokinetic profile of lutropin alfa is analogous to the human luteinizing hormone released from urine.

Suction

After subcutaneous administration of lutropin alfa, the maximum concentration in the blood plasma (C_max) is reached in about 4 to 16 hours. The average absolute bioavailability of lutropin alfa, determined by the immunological method, after a single subcutaneous injection (at a dose significantly higher than that allowing an adequate quantitative determination, i.e., 10,000 IU), is 56% ± 23% in healthy female volunteers.

There was no significant difference C_max, t_max (time to reach the maximum concentration) or bioavailability for intramuscular and subcutaneous administration of the drug.

Distribution

After intravenous administration of lutropin alfa in a dose of 300 ME the rapid distribution phase lasts approximately 1 hour; terminal half-life (t_1/2) p-hLH is approximately 11 hours. The volume of distribution (Vss) in the equilibrium state is approximately 10-14 liters. The average retention time (MRT) is approximately 6 hours.

Lutropin alfa has a linear pharmacokinetics - value AUC (area under the pharmacokinetic concentration-time curve) directly in proportion to the administered dose. The pharmacokinetics of lutropin alfa after single and multiple administration of Luveris® is comparable, and cumulation of lutropin alfa is minimal. There was no pharmacokinetic interaction of the drug with follitropin alpha when administered concomitantly.

Excretion

After subcutaneous administration of Luveris®, lutropin alfa is excreted from the body with an average terminal half-life period of approximately 18 hours.The total ground clearance is approximately 2-3 l / h; less than 5% of the administered dose of the drug is excreted by the kidneys unchanged.

Pharmacokinetics in special populations

The pharmacokinetics of lutropin alfa in the elderly, children, as well as in patients with renal or hepatic insufficiency has not been investigated.

Indications:

Treatment of infertility, caused by hypothalamic-pituitary disorders, leading to a decrease in the level of luteinizing and follicle-stimulating hormones in the body.

Contraindications:

- Increased sensitivity to lutropin alpha or any of the excipients;

- ovarian cancer, uterine cancer, breast cancer;

- tumors of the hypothalamus or pituitary gland;

- ovarian enlargement, polycystic ovary, ovarian cysts of unclear etiology not caused by polycystic ovaries;

- bleeding or bleeding from the vagina of an unclear etiology;

- pregnancy, lactation.

The drug Luveris® is contraindicated in cases when the normal course of pregnancy is impossible:

- primary failure of the ovaries;

- abnormalities of genital organs incompatible with pregnancy;

- fibroids of the uterus, incompatible with pregnancy.

Pregnancy and lactation:

The drug Luveris® is contraindicated during pregnancy or during breastfeeding.

Dosing and Administration:

Treatment with Luveris® should be started under the supervision of a doctor with experience in treating infertility. Louveris® is administered subcutaneously. The solution is prepared immediately before injection using the supplied solvent. Each bottle is intended for single use.

In women with a deficiency of luteinizing (LH) and follicle-stimulating (FSH) hormones, Luveris® is administered as daily injections in combination with follitropin alfa (r-hFSH). Since these patients suffer from amenorrhea and are characterized by low secretion of endogenous estrogens, therapy with them can be initiated at any time. The recommended dose for the initial regimen is 75 ME lutropin alfa (that is, one vial of Luveris®) per day in combination with r-hFSH in a dose of 75 ME -150 ME. In clinical trials, Luveris® demonstrated the ability to increase the sensitivity of the ovaries to follitropin alfa. If an increase in the dose of p-hFSH is nevertheless required, it should be performed at intervals of 7-14 days at 37.5 to 75 ME. It is acceptable to carry out treatment within a single cycle of therapy up to 5 weeks.

When the desired result is achieved 24-48 hours after the last injection of Luveris® and r-hFSH a single injection of recombinant human chorioradotropin (p-hXE) at a dose of 250 μg or human chorionic gonadotropin (hXE) at a dose of 5000-10,000 ME. It is recommended to have sexual intercourse on the day of the introduction of human chorionic gonadotropin and the next day.

Alternatively, assisted reproductive technologies may be used.

If an excessive / excessive response is necessary, discontinue treatment and reverse the introduction of hXE (see "Side effect"). Treatment can be resumed during the next cycle using a lower FSH dose than during the previous cycle.

Recommendations for self-administration of the drug.

Self-administration of Luveris® can be performed only by highly motivated patients who have received appropriate training, provided there is a constant possibility of obtaining specialist advice. Louveris® is administered subcutaneously. The injection site should be changed daily.

If the patient enters Luveris® alone, she should carefully read and strictly follow the instructions given below for the administration of the drug:

- Wash your hands.Injection should be carried out in accordance with the rules of asepsis and antiseptics.

- Prepare a clean surface and put everything on it:

· a thin needle for subcutaneous injection;

· one bottle of Luveris®;

· one bottle with a solvent,

· two tampons moistened with alcohol;

· one syringe;

· One needle for dissolving the powder in a solvent;

· A container for sharp objects for the safe disposal of glass parts and needles.

- Remove the protective cap from the solvent bottle. Connect the mixing needle to the syringe and draw some air into it by pulling the piston to about 1 ml. Then insert the needle into the vial, drown the piston to release air, and gently fill all the solvent.

Carefully place the syringe on the work surface, trying not to touch the needle.

- Prepare the injection solution: remove the protective cap of the vial with the drug, take the syringe, pierce the rubber stopper with a needle and slowly insert the solvent into the vial with the drug. Smoothly shake the bottle without taking out the needles. Do not shake the bottle.

After the powder has dissolved (usually occurs immediately), make sure that the resulting solution is clear and does not contain solid particles.Turn the bottle over and gently pour the solution back into the syringe.

It is also possible to mix Luveris® and follitropin alfa as an alternative to the separate administration of each drug. After dissolving the Luveris®, draw the solution back into the syringe and re-enter it into the container with the follitropin alfa preparation. Once the drug has dissolved, put the solution back into the syringe. Inspect for solids. Do not use the solution if it is not clear.

In 1 ml of solvent can dissolve up to 3 vials with the drug.

- Replace the needle with a thin one and release air bubbles: if air bubbles are visible in the syringe, point the needle with the needle up and gently tap on it until all the air accumulates at the top. Gently push the plunger to remove air.

- Enter the solution immediately: your doctor or nurse will advise you where to inject (for example, the forearm, the front surface of the thigh).

Wipe the selected area with a swab moistened with alcohol. Collect the skin in a crease and move the needle at an angle of 45-90 ° with a quick movement. Enter the drug under your skin as you were trained.

Do not enter the contents directly into the vein.Enter the solution by gently pressing the piston. Use as long as you need to enter the entire solution. Immediately after this, remove the needle and in a circular motion, wipe the skin with a swab dampened with alcohol.

- Dispose of all used items: once you have completed the injection, immediately place all needles and empty glass containers in a sharps container. Unused solution must be discarded.

In the event that the patient forgot to enter the next dose of Luveris ®, you can not enter a double dose, but you should see a doctor.

Do not use the vial if there are signs of damage to the drug, such as a discoloration of the powder or damage to the vial.

Side effects:

The drug Luveris® is used together with foliotropin alfa, so it is difficult to differentiate any side effect to the action of one of these two drugs.

In clinical trials, light and moderate reactions at the injection site (pain, redness, itching, swelling, bruising) were 7.4% or 0.9%, respectively.

Ovarian hyperstimulation syndrome (OCG) was observed in less than 6% of patients. No cases of severe form of SWN have been noted.

There have been no cases of torsion of the ovarian cyst and bleeding in the abdominal cavity with Luveris®, however, rarely with the use of human menopausal gonadotropin (hMG) isolated from urine and containing luteinizing hormone, these cases are described, so they can not be ruled out.

Ectopic pregnancy may develop, especially in women with a history of tubal larynx, a multiple pregnancy.

If a patient finds any side effects not mentioned above, she should consult a doctor. The following categories of the frequency of adverse events are used below:

Very often (≥1 / 10);

Often (≥1 / 100, but <1/10);

Not infrequently (≥1 / 1000, but <1/100);

Rarely (≥1 / 10000, but <1/1000);

Very rarely (<1/10000);

The frequency is unknown (can not be determined from the available data).

Following the administration of Luveris®, the following undesirable reactions can occur:

Immune system disorders

Very rarely: reactions hypersensitivity (from mild to severe severity), including anaphylactic reactions and shock.

Disturbances from the nervous system

Often: headache.

Vascular disorders

Very rarely: thromboembolism, usually associated with severe form of SWN (see section "Special instructions");

Disorders from the gastrointestinal tract

Often: abdominal pain, abdominal discomfort, nausea, vomiting, diarrhea.

Violations of the genitals and mammary gland

Often: HSH of mild or moderate severity with concomitant symptoms (see section "Special instructions"), ovarian cysts, pain in the mammary gland, pain in the pelvic region.

General disorders and disorders at the site of administration

Often: reactions at the site of administration (eg, pain, erythema, hematoma, edema and / or tissue irritation at the site of administration).

Overdose:

Symptoms of an overdose of Luveris® are unknown. Single injection up to 40,000 ME lutropin alfa was well tolerated and not accompanied by severe side effects. However, with an overdose, there is a possibility of a syndrome of ovarian hyperstimulation.

Treatment of CHD is symptomatic.

Interaction:

Do not mix Luveris® with other medicinal substances in the same syringe, except foliotropin alfa.Studies have shown that these two drugs can be mixed and administered simultaneously, this does not affect their therapeutic activity.

Clinically significant drug interaction between Luveris® and other medications has not been described.

Special instructions:

Before starting therapy, an appropriate examination of the patient and her partner for the cause of infertility is necessary. The use of Luveris® is not recommended when its effect is not expected, in particular, with primary ovarian failure, malformations of the genitals or uterine fibroids that are incompatible with pregnancy. Before starting treatment, it is necessary to check for hypothyroidism, adrenocortical insufficiency and hyperprolactinaemia and, if necessary, administer appropriate therapy.

In patients with porphyria or its presence in a family history, Luveris® may increase the risk of exacerbation of the disease. If the condition worsens or the first signs of porphyria appear, therapy may need to be stopped.

Ovarian hyperstimulation syndrome (OSS)

Ovarian enlargement is an expected effect of controlled ovarian stimulation.It is more often observed in women with polycystic ovary syndrome and usually regresses with treatment.

In contrast to an uncomplicated enlargement of the ovaries, the HNS is a heavier condition corresponding to a significant increased ovaries, accompanied by the creation of high concentrations of sex steroid hormones in blood plasma and increased vascular permeability, which can lead to the accumulation of fluid in the cavity of the peritoneum, pleural cavity and, in rare cases, in the pericardial cavity. Manifestations of HSH mild may include pain or discomfort in the abdomen, an increase in its size, or an increase in the size of the ovaries. With CHS of moderate severity, nausea, vomiting, and a significant increase in the size of the ovaries can also be noted according to ultrasound data.

In severe HSH, in addition, there is a pronounced increase in the ovaries, an increase in body weight, dyspnea or oliguria. There may be hypovolemia, hemoconcentration, electrolyte disorders, ascites, pleural effusion, or acute respiratory distress syndrome.Very rarely, the severe form of SWN can be complicated by torsion of ovarian cysts or thromboembolic events such as pulmonary embolism, ischemic stroke, or myocardial infarction.

Independent risk factors for the development of CHD are young age, low body weight, polycystic ovary syndrome, high doses of exogenous gonadotropins, high absolute or rapidly increasing estradiol plasma concentration, presence of previous history of HSH, a large number of maturing follicles and a large number of oocytes collected in the cycle of reproductive technology. Observance of recommended doses and regimens therapy of Luveris® and FSH can minimize the risk of ovarian hyperstimulation. To identify risk factors, it is recommended to monitor the stimulation of follicle growth through ultrasound, it is also recommended to determine the concentration of estradiol.

There is evidence that hCG plays a role in the induction of CHD, and this syndrome can acquire a more severe course in the event of pregnancy.Therefore, with the development of ovarian hyperstimulation, it is recommended to postpone hCG administration and recommend the patient to abstain from sexual intercourse or use barrier contraceptives for at least 4 days. Since HSH can progress rapidly (within 24 hours) or can acquire severe course for several days, it is necessary to observe patients for at least 2 weeks after hCG administration.

HSH of mild to moderate severity is usually resolved spontaneously. In the case of the development of severe hypoglycemia, it is recommended to stop gonadotropin and hospitalize patient with the appointment of appropriate treatment.

Multiple pregnancy

After induction of ovulation increases frequency of multiple pregnancy by compared with that of natural conception. Most of these fruits are twins. In multiple pregnancy, especially with a large number of fetuses, the risk of adverse outcomes for the mother, fetus and newborn increases.

In order to minimize the risk of developing a multiple pregnancy with a large number of fruits, careful monitoring of the ovarian response to stimulation is recommended.

Patients receiving assisted reproductive technology (ART), the risk of multiple pregnancy is predominantly is due to the number of displaced embryos, their quality and age of the patient.

Unintention of pregnancy

The frequency of miscarriage and spontaneous abortions is higher in patients who underwent stimulation of follicle growth with the aim of inducing ovulation than with natural conception.

Ectopic pregnancy

Women who have a history of ectopic pregnancy, characterized by an increased risk of this condition in the future, regardless of the fact of receiving ancillary reproductive technologies. However, the prevalence of ectopic pregnancy has been shown to be higher with ART than in the general population.

Congenital anomalies

The prevalence of congenital anomalies after ART is slightly higher than after natural conception, although it is not clear whether this is due to factors contributing to infertility in a couple or ART procedures. According to the results of clinical and marketing no evidence has been obtained that the use of gonadotropins increases the risk of congenital anomalies in children receiving infertility treatment.

Thromboembolism

Women who have had recent or current thromboembolism, and women who have known risk factors for thromboembolism in a personal or family history, gonadotropins can further increase the risk of aggravation or development of these disorders. In such cases, the benefits and risks of using gonadotropins should be correlated. It should be noted, however, that pregnancy in itself, as well as OHSS, increases the risk of developing thromboembolism.

Neoplasms of genital organs

Cases of development of neoplasms (both benign and malignant) of ovaries and other genital organs in women who received combined therapy for infertility are described. At present, it is not clear whether gonadotropin therapy promotes an increased risk of these neoplasms in women suffering from infertility.

Special Populations

Use in children

Indications for the use of Luveris ® in children are absent.

Application in elderly patients

Indications for the use of Luveris ® in elderly people are absent.

Patients with impaired renal or hepatic function

Safety, efficacy and pharmacokinetics of Luveris ® in patients with renal or hepatic Insufficiency is not known.

Effect on the ability to drive transp. cf. and fur:

Study of the effect of the drug the ability to manage vehicles and other mechanisms was not carried out.

Form release / dosage:

Lyophilizate for the preparation of a solution for subcutaneous administration 75 ME.

Packaging:

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

1 ml of solvent (water for injection) into bottles of colorless transparent glass type I (Hebrew F) with a capacity of 2 ml, sealed with a rubber stopper, sealed on top by an aluminum cap with a detachable plastic lid type "Flip off". 1, 3 or 10 vials of lyophilizate, complete with a solvent (1, 3 or 10 vials) in a plastic container together with instructions for use in a cardboard pack.

Storage conditions:

In the original packaging 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 the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015642 / 01

Date of registration:15.05.2009 / 22.09.2011

Expiration Date:Unlimited

The owner of the registration certificate:Merck Serono SpAMerck Serono SpA Italy

Manufacturer: & nbsp