ELONVA Solution for injection Ref.[7198] Active ingredients: Corifollitropin alfa

Traceability

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

Infertility evaluation before starting treatment

Before starting treatment, the couple’s infertility should be assessed as appropriate. In particular, women should be evaluated for hypothyroidism, adrenocortical insufficiency, hyperprolactinemia and pituitary or hypothalamic tumours, and appropriate specific treatment given. Medical conditions that contraindicate pregnancy should also be evaluated before starting treatment with Elonva.

Dosing during the stimulation cycle

Elonva is intended for single subcutaneous injection only. Additional injections of Elonva should not be given within the same treatment cycle. (See also section 4.2.)

After administration of Elonva, no additional FSH-containing product should be administered prior to stimulation day 8 (see also section 4.2).

Renal insufficiency

In patients with mild, moderate or severe renal insufficiency the rate of elimination of corifollitropin alfa may be reduced (see sections 4.2 and 5.2). Therefore, the use of Elonva in these women is not recommended.

Not recommended with a GnRH agonist protocol in women undergoing ART

There are limited data on the use of Elonva in combination with a GnRH agonist. Results of a small uncontrolled study suggest a higher ovarian response than in combination with a GnRH antagonist. Therefore, the use of Elonva is not recommended in combination with a GnRH agonist (see also section 4.2).

Not recommended in adolescent males previously treated with GnRH, gonadotropins, or testosterone treatment

There are no data available in patients previously treated with GnRH, gonadotropins (e.g., hCG, FSH) and androgens (e.g., testosterone, etc.) except for diagnostic testing purposes.

Ovarian hyperstimulation syndrome (OHSS)

OHSS is a medical event distinct from uncomplicated ovarian enlargement. Clinical signs and symptoms of mild and moderate OHSS are abdominal pain, nausea, diarrhoea, mild to moderate enlargement of ovaries and ovarian cysts. Severe OHSS may be life-threatening. Clinical signs and symptoms of severe OHSS are large ovarian cysts, acute abdominal pain, ascites, pleural effusion, hydrothorax, dyspnoea, oliguria, haematological abnormalities and weight gain. In rare instances, venous or arterial thromboembolism may occur in association with OHSS. Transient liver function test abnormalities suggestive of hepatic dysfunction with or without morphologic changes on liver biopsy have also been reported in association with OHSS.

OHSS may be caused by administration of hCG and by pregnancy (endogenous hCG). Early OHSS usually occurs within 10 days after hCG administration and may be associated with an excessive ovarian response to gonadotropin stimulation. Late OHSS occurs more than 10 days after hCG administration, as a consequence of the hormonal changes with pregnancy. Because of the risk of developing OHSS, patients should be monitored for at least two weeks after hCG administration.

Women with known risk factors for a high ovarian response may be especially prone to the development of OHSS following treatment with Elonva. For women having their first cycle of ovarian stimulation, for whom risk factors are only partially known, close observation for early signs and symptoms of OHSS is recommended.

Follow current clinical practice for reducing the risk of OHSS during Assisted Reproductive Technology (ART). Adherence to the recommended Elonva dose and treatment regimen and careful monitoring of ovarian response is important to reduce the risk of OHSS. To monitor the risk of OHSS, ultrasonographic assessments of follicular development should be performed prior to treatment and at regular intervals during treatment; the concurrent determination of serum oestradiol levels may also be useful. In ART there is an increased risk of OHSS with 18 or more follicles of 11 mm or more in diameter. If OHSS develops, standard and appropriate management of OHSS should be implemented and followed.

Ovarian torsion

Ovarian torsion has been reported after treatment with gonadotropins, including Elonva. Ovarian torsion may be related to other conditions, such as OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, and previous or current ovarian cysts. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.

Multiple pregnancy

Multiple pregnancies and births have been reported for all gonadotropin treatments, including Elonva. The woman and her partner should be advised of the potential risks for the mother (pregnancy and delivery complications) and the neonate (low birth weight) before starting treatment. In women undergoing ART procedures the risk of multiple pregnancy is mainly related to the number of embryos transferred.

Ectopic pregnancy

Infertile women undergoing ART have an increased incidence of ectopic pregnancies. It is important to have early ultrasound confirmation that a pregnancy is intrauterine, and to exclude the possibility of extrauterine pregnancy.

Congenital malformations

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

Ovarian and other reproductive system neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women.

Vascular complications

Thromboembolic events, both in association with and separate from OHSS, have been reported following treatment with gonadotropins, including Elonva. Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. In women with generally recognized risk factors for thromboembolic events, such as a personal or family history, severe obesity or thrombophilia, treatment with gonadotropins may further increase this risk. In these women the benefits of gonadotropin administration need to be weighed against the risks. It should be noted, however, that pregnancy itself also carries an increased risk of thrombosis.

Paediatric population

Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to Elonva/hCG therapy.

After completion of pubertal transition with combined Elonva and hCG treatment, long-term treatment with testosterone is required in HH patients to maintain secondary sexual characteristics. However, follow-up treatment protocols for hormonal support have not been evaluated.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, that is to say essentially ‘sodium-free’.

No interaction studies with Elonva and other medicines have been performed. Since corifollitropin alfa is not a substrate of cytochrome P450 enzymes, no metabolic interactions with other medicinal products are anticipated.

Elonva may cause a false positive hCG pregnancy test if the test is administered during the ovarian stimulation portion of the ART cycle. This may be due to cross-reactivity of hCG pregnancy tests with the carboxy-terminal peptide of the beta subunit of Elonva.

Pregnancy

In case of inadvertent exposure to Elonva during pregnancy, clinical data are not sufficient to exclude an adverse outcome of pregnancy. In animal studies reproductive toxicity has been observed (see preclinical safety data in section 5.3). The use of Elonva during pregnancy is not indicated.

Breast-feeding

The use of Elonva during breast-feeding is not indicated.

Fertility

Elonva is indicated for use in infertility in women

In women Elonva is used in the treatment of Controlled Ovarian Stimulation in combination with GnRH in ART programs (see section 4.1).

Elonva is indicated for treatment of HH in adolescent males

In adolescent males (14 years and older), Elonva is used in treatment of hypogonadotropic hypogonadism in combination with hCG (see section 4.1). However, whether this treatment has effect on fertility is unknown.

No studies on the ability to drive and use machines have been performed. Elonva may cause dizziness. Patients should be advised that if they feel dizzy, they should not drive or use machines.

Summary of the safety profile

The most frequently reported adverse reactions during treatment with Elonva in clinical trials (N=2,397) are pelvic discomfort (6.0%), OHSS (4.3%, see also section 4.4), headache (4.0%), pelvic pain (2.9%), nausea (2.3%), fatigue (1.5%), and breast tenderness (1.3%).

Tabulated list of adverse reactions

The table below displays the main adverse reactions in women treated with Elonva in clinical trials and post-marketing surveillance according to system organ class and frequency; 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), and not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

^* Adverse reactions were identified through post-marketing surveillance.

Description of selected adverse reactions

In addition, ectopic pregnancy and multiple gestations have been reported. These are considered to be related to ART or subsequent pregnancy.

In rare instances, thromboembolism has been associated with Elonva therapy as with other gonadotropins.

Paediatric population (14 years and older)

The table below lists the adverse reactions with Elonva reported in a clinical trial in adolescent males (17 patients dosed) according to system organ class and frequency: common (≥1/100 to <1/10).

¹ Adverse reactions that are reported only once are listed as common because a single report raises the frequency above 1%.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, the medicinal product must not be mixed with other medicinal products.