Recovell^® (Solution) Instructions for Use

Marketing Authorization Holder

Ferring Pharmaceuticals A/C (Denmark)

Manufactured By

Vetter Pharma-Fertigung, GmbH & Co. KG (Germany)

Labeled By

FERRING CONTROLLED THERAPEUTICS, Limited (United Kingdom)

Quality Control Release

FERRING, GmbH (Germany)

ATC Code

G03GA10 (Follitropin delta)

Active Substance

Follitropin delta (Rec.INN registered by WHO)

Dosage Forms

	Recovell®	Solution for subcutaneous injection 33.3 mcg/1 ml: 0.36 ml cartridge with a pen injector, incl. with needles (3 pcs.)
		Solution for subcutaneous injection 33.3 mcg/1 ml: 1.08 ml cartridge with a pen injector, incl. with needles (9 pcs.)
		Solution for subcutaneous injection 33.3 mcg/1 ml: 2.16 ml cartridge with a pen injector, incl. with needles (15 pcs.)

Dosage Form, Packaging, and Composition

Solution for s.c. injection transparent, colorless.

Excipients: phenol, polysorbate 20, L-methionine, sodium sulfate decahydrate, sodium hydrogen phosphate dodecahydrate, concentrated phosphoric acid, sodium hydroxide, water for injections.

0.36 ml – cartridge (1), built into a pen injector, in a set with needles for injections (3 pcs.) – blister packs (1) – cardboard packs.

Solution for s.c. injection transparent, colorless.

Excipients: phenol, polysorbate 20, L-methionine, sodium sulfate decahydrate, sodium hydrogen phosphate dodecahydrate, concentrated phosphoric acid, sodium hydroxide, water for injections.

1.08 ml – cartridge (1), built into a pen injector, in a set with needles for injections (9 pcs.) – blister packs (1) – cardboard packs.

Solution for s.c. injection transparent, colorless.

Excipients: phenol, polysorbate 20, L-methionine, sodium sulfate decahydrate, sodium hydrogen phosphate dodecahydrate, concentrated phosphoric acid, sodium hydroxide, water for injections.

2.16 ml – cartridge (1), built into a pen injector, in a set with needles for injections (15 pcs.) – blister packs (1) – cardboard packs.

Clinical-Pharmacological Group

Recombinant human follicle-stimulating hormone

Pharmacotherapeutic Group

Follicle-stimulating agent

Pharmacological Action

Follitropin delta is a recombinant human follicle-stimulating hormone (r-hFSH) that stimulates the growth and development of follicles.

After s.c. administration of r-hFSH, the formation of multiple mature follicles is observed.

The amino acid sequence of the two subunits of follitropin delta is identical to the amino acid sequence in endogenous human r-hFSH.

The synthesis of follitropin delta is carried out using human PER.C6 cell line, therefore the glycosylation profile is different from follitropin alpha and follitropin beta.

Pharmacokinetics

With daily s.c. administration, the C_ss of follitropin delta is reached in 6-7 days, while its plasma concentration is 3 times higher than the concentration of the drug after the first administration.

The plasma concentration of follitropin delta is inversely proportional to body weight.

The systemic effect of follitropin delta is more pronounced than that of follitropin alpha.

With daily s.c. administration, the C_max of follitropin delta is reached in approximately 10 hours.

The absolute bioavailability is about 64%.

After s.c. administration, the apparent V_d is about 25 L, and after i.v. administration, the V_d is 9 L (at C_ss).

In the therapeutic range, the severity of the systemic effect of follitropin delta is directly proportional to the administered dose.

It is mainly excreted by the kidneys, like other follitropins.

About 9% of the active substance is excreted unchanged by the kidneys.

After a single s.c. administration of follitropin delta, the T_1/2 is about 40 hours, and after subsequent s.c. administrations, it is about 28 hours.

After s.c. administration, the apparent clearance of the drug is 0.6 L/h, and after i.v. administration, it is 0.3 L/h.

Due to the pronounced systemic effect with subsequent administrations of follitropin delta, a low apparent clearance of about 0.6 L/h is observed, leading to high efficacy.

Indications

Controlled ovarian hyperstimulation for the induction of growth of multiple follicles during the following assisted reproductive technologies (ART): in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).

ICD codes

Dosage Regimen

Administer as a subcutaneous injection only.

Determine the individual dose using the dosing algorithm incorporated into the RECHECK^® calculator, based on the patient’s serum Anti-Müllerian Hormone (AMH) level and body weight.

Initiate treatment on day 2 or 3 of the menstrual cycle.

The recommended starting dose typically ranges from 8 to 14 micrograms per day.

Adjust the dose after at least 5 days of treatment based on the individual ovarian response, as assessed by ultrasound and serum estradiol levels.

The maximum daily dose should not exceed 24 micrograms.

Continue treatment until adequate follicular development is achieved.

Administer human Chorionic Gonadotropin (hCG) for final follicular maturation 24-48 hours after the last follitropin delta injection, provided the risk of Ovarian Hyperstimulation Syndrome (OHSS) is acceptable.

Withhold hCG administration if there is an excessive ovarian response or an elevated risk of OHSS.

Use the pre-filled pen injector for administration; ensure the selected dose is within the available cartridge volume.

Rotate injection sites between the abdomen and thigh.

Adverse Reactions

From the central nervous system common – headache; uncommon – emotional lability, drowsiness, dizziness.

From the digestive system common – nausea; uncommon – diarrhea, vomiting, constipation, abdominal discomfort.

From the reproductive system common – OHSS, pelvic pain, uterine adnexa pain, pelvic discomfort; uncommon – vaginal bleeding, breast pain, breast tenderness.

General increased fatigue.

Contraindications

Hypersensitivity to follitropin delta; tumors of the pituitary gland or hypothalamus; age under 18 years; ovarian, uterine, or breast cancer; pregnancy and breastfeeding; genital bleeding of unknown etiology; presence of cysts or enlargement of the ovaries not associated with polycystic ovary syndrome (PCOS); primary ovarian insufficiency; developmental abnormalities of the genital organs incompatible with pregnancy; uterine fibroids incompatible with pregnancy.

With caution

In the presence of risk factors for thromboembolic complications in a woman (individual or family predisposition, obesity with BMI >30 kg/m²), thrombophilia); history of fallopian tube diseases.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

The drug is contraindicated for use in hepatic impairment.

Use in Renal Impairment

The drug is contraindicated for use in renal impairment.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is contraindicated for use in elderly patients.

Special Precautions

The medicinal product has pronounced gonadotropic activity, therefore adverse reactions from mild to severe may develop when using the drug.

The use of gonadotropins requires the presence of qualified medical personnel, as well as appropriate equipment.

Before starting and during therapy with follitropin delta, the condition of the ovaries should be monitored (ultrasound, including determination of plasma estradiol concentration).

In patients undergoing controlled follicular growth stimulation, ovarian enlargement may be observed and there is a risk of developing OHSS.

By adhering to the dosage regimen in combination with therapy monitoring, it is possible to minimize the risk of the above reactions.

To some extent, ovarian enlargement is an expected response to controlled ovarian hyperstimulation and develops more often in patients with PCOS, usually regressing on its own, without additional therapy.

Unlike uncomplicated ovarian enlargement, the clinical symptoms of OHSS may manifest with increasing severity.

They include: significant ovarian enlargement, high plasma estrogen concentration, as well as increased vascular permeability, which can lead to the accumulation of fluid in the abdominal, pleural and, less commonly, pericardial cavities.

To reduce the risk of developing OHSS, careful and frequent monitoring of follicular maturation is necessary.

In severe cases of OHSS, the following symptoms are possible: abdominal pain, abdominal bloating, significant ovarian enlargement, weight gain, shortness of breath, oliguria, and gastrointestinal disorders, including nausea, vomiting, and diarrhea.

Clinical examination may reveal hypovolemia, hemoconcentration, electrolyte disturbances, ascites, hemoperitoneum, exudative pleurisy, hydrothorax, acute respiratory distress syndrome.

Very rarely, severe OHSS can be complicated by ovarian torsion or thromboembolic complications, such as pulmonary embolism, ischemic stroke, or myocardial infarction.

An excessive ovarian response to the administration of gonadotropins rarely leads to the development of OHSS if hCG is not administered for final follicular maturation.

OHSS can be more severe and prolonged if pregnancy occurs.

Therefore, in case of OHSS, hCG should not be administered, and the patient should be warned about the need to refrain from sexual intercourse or use barrier methods of contraception for at least 4 days.

OHSS can progress rapidly (within 24 hours to several days), becoming a serious medical complication.

OHSS most often develops after the completion of hormonal therapy; late development of OHSS is possible due to hormonal changes during pregnancy.

Therefore, careful monitoring of patients is necessary for at least 2 weeks after final follicular maturation.

Women with known risk factors for thromboembolic complications, such as individual or family predisposition, obesity (BMI >30 kg/m²) or thrombophilia, may have an increased risk of venous or arterial thromboembolic complications during or after treatment with gonadotropins.

In such cases, the benefit of their use should be weighed against the possible risk.

It should be taken into account that pregnancy itself also increases the risk of thromboembolic complications.

Cases of ovarian torsion have been described during ART.

The cause of ovarian torsion can be OHSS, pregnancy, previous abdominal surgeries, history of ovarian torsion, current or history of ovarian cyst, as well as PCOS.

Ovarian damage due to impaired blood flow can be reduced with timely diagnosis and emergency ovarian detorsion.

In multiple pregnancy, there is an increased risk of adverse maternal and perinatal outcomes.

In the case of ART, the likelihood of multiple pregnancy depends on the number of embryos transferred, their quality, and the patient’s age.

In rare cases, twin pregnancies have been reported even with the transfer of a single embryo.

The patient should be warned about the potential risk of multiple pregnancy before starting treatment.

The frequency of pregnancy termination (miscarriage, spontaneous abortion) in patients undergoing controlled ovarian stimulation within ART programs is higher than in healthy women.

In patients with a history of fallopian tube diseases, both with natural conception and with infertility treatment, there is a high risk of ectopic pregnancy.

The prevalence of ectopic pregnancy after ART is higher compared to the general population.

There is information about neoplasms of the ovaries and other organs of the reproductive system, both benign and malignant, in women after several courses of infertility treatment.

It has not been currently established whether treatment with gonadotropins increases the baseline risk of these tumors in women with infertility.

The prevalence of congenital malformations of the fetus when using ART is somewhat higher than with natural conception.

It is believed that this may be due to the individual characteristics of the parents (maternal age, sperm characteristics) and multiple pregnancy.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°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.