INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OVTRELLEâ (OVITRELLEâ)

Composition:

Active substance: choriogonadotropin alfa;

1 pre-filled injection pen (0.5 mL of solution) contains 250 mcg (6500 IU) of choriogonadotropin alfa;

Excipients: mannitol (E 421), methionine, disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate, poloxamer 188, phosphoric acid concentrated, sodium hydroxide, water for injections.

Medicinal form. Solution for injection.

Main physicochemical properties: solution, practically free from visible particles.

Pharmacotherapeutic group. Sex hormones and modulators of the genital system. Gonadotropins. Choriogonadotropin alfa.

ATC code G03G A08.

Pharmacological Properties

Pharmacodynamics

Ovitrelle® is a medicinal product containing recombinant human chorionic gonadotropin alfa produced by recombinant DNA technology. Chorionic gonadotropin alfa has the same amino acid sequence as human chorionic gonadotropin (hCG) isolated from urine. In ovarian theca and granulosa cells, chorionic gonadotropin binds to transmembrane LH/hCG receptors, which also bind luteinizing hormone (LH).

The primary pharmacodynamic effect of the drug in women is the resumption of oocyte meiosis, follicular rupture (ovulation), formation of the corpus luteum, and production of progesterone and estradiol by the corpus luteum. In women, the action of chorionic gonadotropin mimics the sharp rise in LH levels that triggers ovulation.

Ovitrelle® is used to initiate final follicular maturation and early luteinization following treatment with medications that stimulate follicular growth. In comparative clinical studies, administration of Ovitrelle® at a dose of 250 mcg was as effective as administration of 5000 IU or 10,000 IU of urinary hCG for inducing final follicular maturation and early luteinization in assisted reproductive technology (ART) cycles, and as effective as 5000 IU of urinary hCG for inducing ovulation.

To date, no evidence of antibody development against Ovitrelle® has been observed in humans. Repeated administration of Ovitrelle® has been studied only in men. Clinical studies of the drug in women undergoing ART or treatment for anovulation have been limited to a single treatment cycle.

Pharmacokinetics

Following intravenous administration, chorionic gonadotropin alfa distributes into the interstitial fluid with a distribution half-life of approximately 4.5 hours. The steady-state volume of distribution and total clearance are approximately 6 L and 0.2 L/hour, respectively. There is no evidence indicating that chorionic gonadotropin alfa is metabolized or eliminated differently from endogenous hCG.

After subcutaneous administration, the terminal elimination half-life of chorionic gonadotropin alfa is approximately 30 hours, and absolute bioavailability is approximately 40%.

Comparative studies of the lyophilized and liquid formulations of the drug demonstrated bioequivalence between these two forms.

Clinical characteristics.

Indications.

Initiation of final follicular maturation and luteinization following follicular growth stimulation in adult women undergoing a superovulation procedure prior to assisted reproductive technology (ART) procedures such as in vitro fertilization (IVF);
Initiation of ovulation and luteinization in adult women with anovulation or oligoovulation following follicular growth stimulation.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Tumors of the hypothalamus or pituitary gland.
Enlargement of the ovaries or ovarian cysts not caused by polycystic ovary syndrome.
Gynecological bleeding of unknown etiology.
Carcinoma of the ovaries, uterus, or breasts.
Active forms of thromboembolic disorders.

Ovitrel® must not be used in cases where an effective response to treatment cannot be achieved, such as:

Primary ovarian insufficiency.
Congenital malformations of the genital organs incompatible with pregnancy.
Uterine fibroids incompatible with pregnancy.
Postmenopausal state.

Interaction with other medicinal products and other forms of interaction.

No specific studies on drug interactions between Ovitrel® and other medicinal products have been conducted; however, during therapy with recombinant luteinizing hormone (r-hLH), no clinically significant drug interactions have been observed.

Special precautions for use.

Tracking

To improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

General recommendations

Prior to initiating treatment, the infertility of the couple should be evaluated to determine their suitability for treatment and to identify any contraindications to pregnancy. In particular, patients should be examined for hypothyroidism, adrenal insufficiency, hyperprolactinemia, and appropriate specific treatment should be prescribed.

Currently, there is no clinical experience with the use of the drug for other indications (such as luteal phase deficiency or male pathologies); therefore, Ovitrel® is not indicated for the treatment of such conditions.

Ovarian hyperstimulation syndrome (OHSS)

An expected consequence of controlled ovarian stimulation is a certain degree of ovarian enlargement. This phenomenon, which is most common in women with polycystic ovary syndrome, usually resolves spontaneously without specific treatment.

In contrast to uncomplicated ovarian enlargement, OHSS is a syndrome that progresses in severity. It includes marked ovarian enlargement, high serum levels of sex steroids, and increased vascular permeability, which may lead to fluid accumulation in the abdominal, pleural, and rarely, pericardial cavities.

Mild manifestations of OHSS may include abdominal pain, abdominal discomfort, bloating, and ovarian enlargement. Moderate OHSS may additionally present with nausea, vomiting, ultrasound-confirmed ascites, and significant ovarian enlargement.

In severe cases, OHSS may additionally manifest with the following symptoms: severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical examination may reveal hypovolemia, hemoconcentration, electrolyte imbalance, ascites, pleural effusions, or acute respiratory distress syndrome. In very rare cases, severe OHSS may be complicated by ovarian torsion and thromboembolic events such as pulmonary artery embolism, ischemic stroke, and myocardial infarction.

Independent risk factors for the development of OHSS include young age, low body weight, polycystic ovary syndrome, high doses of exogenous gonadotropins, high or rapidly rising serum estradiol levels, previous episodes of OHSS, and a large number of growing ovarian follicles or oocytes obtained in ART cycles.

Adherence to the recommended dosage and administration regimen of Ovitrel® may minimize the risk of ovarian hyperstimulation. To detect risk factors early, monitoring of stimulation cycles by ultrasound and serum estradiol measurement is recommended.

There is evidence to suggest that hCG plays a key role in the initiation of OHSS and that this syndrome may become more severe and prolonged if pregnancy occurs. Therefore, in the presence of signs of ovarian hyperstimulation, administration of hCG should be discontinued and patients should be advised to abstain from sexual intercourse or use barrier contraception for at least 4 days.

OHSS can rapidly progress (within 24 hours) and become a serious medical complication within a few days; therefore, patients should remain under medical supervision for at least 2 weeks after hCG administration.

Mild or moderate forms of OHSS usually resolve spontaneously. If severe OHSS occurs, gonadotropin treatment must be discontinued, the patient should be hospitalized, and appropriate OHSS therapy initiated.

Multiple pregnancy

The rate of multiple pregnancies and multiple births is increased during ovulation induction compared to natural conception. Most multiple pregnancies are twin pregnancies. Multiple pregnancy, especially of higher order, carries an increased risk of adverse obstetric and perinatal outcomes.

To minimize the risk of higher-order multiple pregnancy, careful monitoring of ovarian response is recommended. In ART procedures, the risk of multiple pregnancy is primarily related to the number of embryos transferred, their quality, and the patient's age.

Pregnancy loss

The rate of pregnancy loss is higher both in patients with anovulation and in those undergoing ART, compared to spontaneous conception.

Ectopic pregnancy

Women with a history of tubal disease have an increased risk of ectopic pregnancy, regardless of whether conception occurs spontaneously or following infertility treatment. The incidence of ectopic pregnancy after ART has been reported to be higher than in the general population.

Congenital malformations

The incidence of congenital malformations after ART may be slightly higher than after spontaneous conception. This is believed to be due to differences in parental characteristics (e.g., maternal age, sperm quality) and the higher frequency of multiple pregnancies.

Thromboembolic events

In women with recent thromboembolic disorders or in women with established risk factors for thromboembolic events (such as personal or family history), gonadotropin treatment may further increase the risk of exacerbation or occurrence of such disorders. In such women, the benefits of gonadotropin treatment should be weighed against the risk of such events. However, it should be noted that pregnancy itself and OHSS also increase the risk of thromboembolic complications.

Neoplasms of the reproductive system

There have been reports of both benign and malignant neoplasms of the ovaries and other reproductive organs in women who have used multiple fertility drugs. It has not yet been established whether gonadotropin treatment increases the baseline risk of such tumors in infertile women.

Effect on blood or urine test results

For up to 10 days after administration, Ovitrel® may affect immunological assays for serum or urinary hCG levels, potentially leading to false-positive pregnancy test results. Patients should be informed of this.

Sodium content

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, i.e., it is essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy

There are no indications for the use of Ovitrel® during pregnancy. Data from a small number of cases of drug use during pregnancy indicate no congenital malformations or fetal or neonatal toxicity. Studies on the effects of chorionic gonadotropin alpha on reproductive function in animals have not been conducted; therefore, the potential risk of such use in humans is unknown.

Breastfeeding

Ovitrel® is not indicated for use during breastfeeding. Data on the excretion of chorionic gonadotropin alpha in breast milk are lacking.

Ability to affect reaction speed when driving or operating machinery.

Ovitrel® has no or negligible effect on the ability of patients to drive or operate machinery.

Method of administration and dosage

The medication should be administered under the supervision of a physician experienced in the treatment of infertility.

The maximum dose of the medication is 250 mcg. The following treatment regimens should be followed.

Women undergoing controlled ovarian stimulation prior to assisted reproductive technologies such as in vitro fertilization (IVF)

The contents of one pre-filled pen of Ovitrelleâ (250 mcg) should be administered 24–48 hours after the last injection of follicle-stimulating hormone (FSH) or human menopausal gonadotropin (hMG), i.e., upon achieving optimal follicular stimulation.

Women with anovulation or oligoovulation

The contents of one pre-filled pen of Ovitrelleâ (250 mcg) should be administered 24–48 hours after achieving optimal follicular stimulation. Patients are advised to have sexual intercourse on the day of Ovitrelleâ administration and the following day.

Patients with renal or hepatic impairment

The safety, efficacy, and pharmacokinetic parameters of Ovitrelleâ in patients with renal or hepatic impairment have not been established.

If you are self-administering Ovitrelleâ, please carefully read and follow the instructions below.

Ovitrelleâ is intended for subcutaneous administration. The pre-filled pen of Ovitrelleâ is intended for single use only. The administration pen and/or needles must not be shared with other individuals.

Each package of the pre-filled pen Ovitrelleâ contains one injection needle and one spare needle.

You may use Ovitrelleâ only after your physician has trained you in the correct use of the pre-filled pen.

Always follow all instructions provided by your physician during training and the recommendations in this medical instruction leaflet: they may differ from your previous experience. This will also help prevent incorrect treatment or infection due to needlestick injuries or glass fragments.

The medication should be stored in a refrigerator. Do not freeze.

The pre-filled pen of Ovitrelleâ must not be used if it has been dropped, cracked, or damaged, as this may result in injury.

Familiarization with the pre-filled pen for Ovitrelleâ administration

Pen injector with labels: needle outer and inner caps, plunger, reservoir, pen cap, dose display, control label, dose knob

Preparation stage.
1. Prepare a clean, flat surface, such as a table, with good lighting.
1. You will also need alcohol swabs and a sharps disposal container, which are not included in the package.
1. Wash your hands with soap and dry them thoroughly.
1. Remove the pen from its packaging, without using any tools or devices that could damage the pen.
1. Check the medication name and expiration date on the pen label. If the expiration date has passed, the pre-filled pen of Ovitrelleâ must not be used.
Preparing the pre-filled pen for injection.

1. Remove the cap from the pen (Fig. 1).
2. Check that the solution is clear, colorless or slightly yellow and contains no particles.

Do not use the pre-filled pen if the solution has changed color or become cloudy, as this may lead to infection.

Two hands holding a pen injector, one hand pressing the plunger in the direction of the arrow, the other stabilizing the injection device body

Fig. 1

3. Choose the injection site: Your doctor should show you the injection sites on the abdominal area (Fig. 2).
4. Clean the skin at the injection site with an alcohol swab.

Do not touch or cover the cleaned skin.

Patch with a central opening applied to the abdominal skin, indicating the site for transdermal medication administration

Fig. 2

Attach the needle.
1. Take a new needle. Use only disposable needles provided in the medicine package.
1. Check that the outer needle cap is undamaged.
1. Holding the outer needle cap, check that the tamper-evident label on the outer needle cap is present and intact, and that the needle's expiration date has not passed.
1. Remove the tamper-evident label.

Do not use the needle if it is damaged, if the expiration date has passed, or if the outer needle cap or tamper-evident label is damaged or missing. Using such a needle may lead to the development of infection. Dispose of such a needle by placing it in a sharps container and use another needle from the medicine package.

5. Screw the outer needle cap firmly onto the threaded tip until it stops (Fig. 3).

Do not overtighten the cap, as it may become difficult to unscrew after the injection.

Fig. 3

6. Gently pull to remove the outer needle cap and place it nearby for later use (Fig. 4).

Do not discard the outer needle cap: it will be needed to cover the needle after injection to prevent needlestick injuries and contamination.

Fig. 4

7. Holding the pre-filled Ovitrelleâ pen with the needle pointing upwards, carefully remove and discard the green inner needle cap (Fig. 5).

Do not reuse the green inner needle cap: reattaching it may cause needlestick injury and contamination.

Fig. 5

8. Carefully inspect the needle tip for small drops of liquid (Fig. 6).

If you see small drops of liquid at the needle tip, proceed to step 4. Set the dose to 250.
If you do not see small drops of liquid at the needle tip, follow the instructions below to remove air from the system.

Fig. 6

If you do not see small drops of liquid at the tip of the needle:

Carefully turn the dose knob forward until the mark «∙» appears on the display. If you pass this mark, turn the dose knob back to the mark «∙» (Fig. 7).

Hands holding a pen injector, inserting the needle into a special adapter, close-up showing precise positioning of the needle in the adapter

Fig. 7

Holding the pen with the needle pointing upwards, gently tap the reservoir with your finger (Fig. 8).
Press the dose knob fully . A small drop of liquid should appear at the tip of the needle (Fig. 9).
Check that «0» is displayed on the screen (Fig. 10).

Hand holding a syringe with an arrow indicating plunger depression, another hand holding a syringe with a magnified view of a droplet, third hand injecting needle into muscle tissue

If no drop appears, repeat the procedure only once more, starting from the section "If you do not see small drops of liquid at the tip of the needle." If no drop appears after the second attempt, consult your doctor.

Set the dose to 250.

1. Carefully turn the dose knob forward until the number "250" appears on the display (Fig. 11). Do not press or pull the dose knob while turning.

Fig. 11

2. Check that the number "250" is displayed on the screen (Fig. 12).

Fig. 12

Enter the dose.

Important: The injection should be administered according to the instructions provided by your doctor or nurse.

1. First, slowly and completely insert the needle into the skin (Fig. 13).

Fig. 13

2. Place your thumb on the dosing button. Slowly press the dosing button all the way down and hold it in this position until the injection is complete (Fig. 14).

Fig. 14

3. Hold the dosing button fully pressed for at least 5 seconds (Fig. 15).
- The number displayed will return to "0".
- After at least 5 seconds, remove the needle from the skin, keeping the dosing button pressed (Fig. 16).
- Once the needle is removed from the skin, release the dosing button.

Do not release the dosing button until the needle is removed from the skin.

Fig. 15

Fig. 16

Removal of the needle after injection.

1. Place the outer needle cap on a flat surface.
2. Firmly holding the pen with one hand, insert the needle into the outer cap (Fig. 17).
3. Continue pushing the cap with the needle against a hard surface until the cap clicks into place (Fig. 18).

Hand holding a syringe, inserting the needle into muscle tissue of the arm at a 45-degree angle, with an arrow indicating direction of insertion

Fig. 17

Syringe with dose markings, arrow indicating direction of rotation to set the required medication dose

Fig. 18

4. Hold the outer cap firmly and unscrew the needle by rotating it away from yourself (Fig. 19).
5. Dispose of the used needle carefully by placing it into a sharps container, avoiding injury.

Do not reuse the needle and do not share it with other people.

Hand holding a syringe with needle being inserted into an ampoule to draw solution, on a white background

Fig. 19

After injection.

1. Check that you have injected the full dose:
- Check that the display shows "0" (Fig. 20).

If the display shows "0", you have injected the full dose.

If the display does not show "0", contact your doctor.

Do not attempt to inject a second injection.

Fig. 20

Disposal of the Ovitrelle® pre-filled pen.

Important: The Ovitrelleâ pre-filled pen and needles are intended for single use only.

1. Replace the cap on the pen.
1. Carefully dispose of the needles and the pen.

Children.

There are no indications for the use of Ovitrelleâ in pediatric patients.

Overdose.

The effects of Ovitrelleâ overdose are unknown. However, overdose may lead to the development of OHSS (see section "Special precautions").

Adverse Reactions.

Summary of safety profile

In comparative studies using different doses of Ovidrel®, it has been established that OHSS associated with Ovidrel® is dose-dependent. OHSS was observed in approximately 4% of patients treated with Ovidrel®. Severe OHSS occurred in less than 0.5% of patients (see section "Dosage and Administration").

Listing of adverse reactions

Frequency categories of adverse reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Immune system disorders

Rare: hypersensitivity reactions ranging from mild to severe, including rash, anaphylactic reactions and shock.

Nervous system disorders

Common: headache.

Vascular disorders

Rare: thromboembolism, associated or not associated with OHSS.

Gastrointestinal disorders

Common: abdominal pain, abdominal distension, nausea, vomiting.

Uncommon: abdominal discomfort, diarrhea.

Reproductive system and breast disorders

Common: mild or moderate OHSS.

Uncommon: severe OHSS.

General disorders and administration site conditions

Common: injection site reactions.

Shelf life. 2 years.

For immediate use after first opening.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at 2 − 8 °C (in the refrigerator). Do not freeze.

Keep out of the reach of children.

Packaging.

0.5 ml of solution for injection in a 3 ml cartridge with a stopper-plunger and aluminum crimp cap with a rubber liner, contained in a delivery device. The pre-filled delivery device with 2 injection needles, packed in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Merk Serono S.p.A./Merck Serono S.p.A.

Manufacturer's name and address of the place of business.

Via delle Magnolie 15 (loc. frazione Zona Industriale), 70026 Modugno (Bari), Italy / Via delle Magnolie 15 (loc. frazione Zona Industriale), 70026 Modugno (Bari), Italy.