ELONVA 150mcg / 0.5ml solution for injection medication leaflet

Elonva 100 micrograms solution for injection

Elonva 150 micrograms solution for injection

Elonva 100 micrograms solution for injection

Each pre-filled syringe contains 100 micrograms of corifollitropin alfa* in 0.5 mL solution forinjection.

Elonva 150 micrograms solution for injection

Each pre-filled syringe contains 150 micrograms of corifollitropin alfa* in 0.5 mL solution forinjection.

*corifollitropin alfa is a glycoprotein produced in Chinese Hamster Ovary (CHO) cells byrecombinant DNA technology.

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

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear and colourless aqueous solution.

Elonva is indicated for Controlled Ovarian Stimulation (COS) in combination with a Gonadotropin

Releasing Hormone (GnRH) antagonist for the development of multiple follicles in womenparticipating in an Assisted Reproductive Technology (ART) program.

Elonva is indicated for the treatment of adolescent males (14 years and older) with hypogonadotropichypogonadism, in combination with human Chorionic Gonadotropin (hCG).

Treatment with Elonva for COS should be initiated under the supervision of a physician experiencedin the treatment of fertility problems.

Treatment with Elonva for hypogonadotropic hypogonadism should be initiated and supervised by aphysician experienced in the treatment of hypogonadotropic hypogonadism.

In the treatment of women of reproductive age, the dose of Elonva is based on weight and age.

- A single 100-microgram dose is recommended in women who weigh less than or equal to60 kilograms and who are 36 years of age or younger.

- A single 150-microgram dose is recommended in women:

- who weigh more than 60 kilograms, regardless of age.

- who weigh 50 kilograms or more and who are older than 36 years of age.

Women older than 36 years of age who weighed less than 50 kilograms were not studied.

Body Weight

Less than 50 kg 50 - 60 kg More than 60 kg36 years or 100 micrograms 100 micrograms 150 micrograms

Age younger

Older than 36 Not studied 150 micrograms 150 microgramsyears

The recommended doses of Elonva have only been established in a treatment cycle with a GnRHantagonist that was administered from stimulation day 5 or day 6 onwards (see sections 4.1, pct. 4.4, and5.1).

Stimulation day 1:

Elonva should be administered as a single subcutaneous injection, preferably in the abdominal wall,during the early follicular phase of the menstrual cycle.

Stimulation day 5 or 6:

Treatment with a GnRH antagonist should be started on stimulation day 5 or day 6 depending on theovarian response, i.e. the number and size of growing follicles. The concurrent determination of serumoestradiol levels may also be useful. The GnRH antagonist is used to prevent premature Luteinising

Hormone (LH) surges.

Stimulation day 8:

Seven days after the injection with Elonva on stimulation day 1, COS treatment may be continuedwith daily injections of (recombinant) Follicle Stimulating Hormone [(rec)FSH] until the criterion fortriggering final oocyte maturation (3 follicles ≥ 17 mm) has been reached. The daily dose of (rec)FSHmay depend on the ovarian response. In normal responders a daily dose of 150 IU (rec)FSH is advised.

Administration of (rec)FSH on the day of human Chorionic Gonadotropin (hCG) administration canbe omitted, depending on the ovarian response. In general, adequate follicular development isachieved on average by the ninth day of treatment (range 6 to 18 days).

As soon as three follicles ≥ 17 mm are observed, a single injection of 5,000 up to 10,000 IU hCG isadministered the same day or the day thereafter to induce final oocyte maturation. In case of anexcessive ovarian response, see the recommendations given in section 4.4 in order to reduce the riskfor developing ovarian hyperstimulation syndrome (OHSS).

No clinical studies have been performed in patients with renal insufficiency. Since the rate ofelimination of corifollitropin alfa may be reduced in patients with renal insufficiency, the use of

Elonva in these patients is not recommended (see sections 4.4 and 5.2).

Although data in hepatically impaired patients are not available, hepatic impairment is unlikely toaffect the elimination of corifollitropin alfa (see section 5.2).

In the treatment of adolescent males (14 years and older) with hypogonadotropic hypogonadism, thedose of Elonva is based on body weight.

For adolescent males weighing less than or equal to 60 kg100 micrograms of Elonva once every two weeks for 12 weeks, followed by concomitantadministration of Elonva (once every 2 weeks) with hCG. For patients initiating therapy with100 micrograms, consider increasing the dose if their body weight increases to greater than 60 kgduring the course of treatment.

For adolescent males weighing more than 60 kg150 micrograms of Elonva once every two weeks for 12 weeks, followed by concomitantadministration of Elonva (once every 2 weeks) with hCG.

Combination therapy with hCG twice weekly (500 - 5000 IU) may be necessary for 52 weeks orlonger to achieve adult gonadal development.

There are no data to support safety and efficacy when treatment is used for more than 52 weeks and/orafter 17 years of age.

In females

Subcutaneous injection of Elonva may be carried out by the woman herself or her partner, providedthat proper instructions are given by the physician. Self administration of Elonva should only beperformed by women who are well-motivated, adequately trained and with access to expert advice.

In adolescent males (14 years and older)

Subcutaneous injection in the abdominal wall may be carried out by the patient or a caregiver,provided they have been appropriately trained. Elonva should be administered once every two weeks,in the morning on the same day of the week in combination with hCG twice weekly (500 - 5000 IU).

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

 Tumours of the ovary, breast, uterus, pituitary or hypothalamus.

 Abnormal (not menstrual) vaginal bleeding without a known/diagnosed cause.

 Primary ovarian failure.

 Ovarian cysts or enlarged ovaries.

 Fibroid tumours of the uterus incompatible with pregnancy.

 Malformations of the reproductive organs incompatible with pregnancy.

 Risk factors for OHSS:

o A history of Ovarian Hyperstimulation Syndrome (OHSS).

o A previous COS cycle that resulted in more than 30 follicles  11 mm measured byultrasound examination.

o A basal antral follicle count > 20.

o Polycystic ovarian syndrome (PCOS).

In order to improve the traceability of biological medicinal products, the name and the batch numberof 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 andpituitary or hypothalamic tumours, and appropriate specific treatment given. Medical conditions thatcontraindicate 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 notbe given within the same treatment cycle. (See also section 4.2.)

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

In patients with mild, moderate or severe renal insufficiency the rate of elimination of corifollitropinalfa may be reduced (see sections 4.2 and 5.2). Therefore, the use of Elonva in these patients is notrecommended.

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 smalluncontrolled 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 alsosection 4.2).

Not recommended in adolescent males previously treated with GnRH, gonadotropins, or testosteronetreatment.

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 andsymptoms of mild and moderate OHSS are abdominal pain, nausea, diarrhoea, mild to moderateenlargement of ovaries and ovarian cysts. Severe OHSS may be life-threatening. Clinical signs andsymptoms 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 testabnormalities suggestive of hepatic dysfunction with or without morphologic changes on liver biopsyhave also been reported in association with OHSS.

OHSS may be caused by administration of hCG and by pregnancy (endogenous hCG). Early OHSSusually occurs within 10 days after hCG administration and may be associated with an excessiveovarian response to gonadotropin stimulation. Late OHSS occurs more than 10 days after hCGadministration, as a consequence of the hormonal changes with pregnancy. Because of the risk ofdeveloping 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 thedevelopment of OHSS following treatment with Elonva. For women having their first cycle of ovarianstimulation, for whom risk factors are only partially known, close observation for early signs andsymptoms of OHSS is recommended.

Follow current clinical practise for reducing the risk of OHSS during Assisted Reproductive

Technology (ART). Adherence to the recommended Elonva dose and treatment regimen and carefulmonitoring 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 atregular intervals during treatment; the concurrent determination of serum oestradiol levels may also beuseful. In ART there is an increased risk of OHSS with 18 or more follicles of 11 mm or more indiameter. If OHSS develops, standard and appropriate management of OHSS should be implementedand followed.

Ovarian torsion

Ovarian torsion has been reported after treatment with gonadotropins, including Elonva. Ovariantorsion 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 toreduced 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 anddelivery complications) and the neonate (low birth weight) before starting treatment. In womenundergoing ART procedures the risk of multiple pregnancy is mainly related to the number ofembryos transferred.

Ectopic pregnancy

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

Congenital malformations

The incidence of congenital malformations after ART may be slightly higher than after spontaneousconceptions. 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 andmalignant, in women who have undergone multiple treatment regimens for infertility treatment. It isnot established whether or not treatment with gonadotropins increases the risk of these tumours ininfertile women.

Vascular complications

Thromboembolic events, both in association with and separate from OHSS, have been reportedfollowing treatment with gonadotropins, including Elonva. Intravascular thrombosis, which mayoriginate in venous or arterial vessels, can result in reduced blood flow to vital organs or theextremities. In women with generally recognised risk factors for thromboembolic events, such as apersonal or family history, severe obesity or thrombophilia, treatment with gonadotropins may furtherincrease this risk. In these women the benefits of gonadotropin administration need to be weighedagainst the risks. It should be noted, however, that pregnancy itself also carries an increased risk ofthrombosis.

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

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

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

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

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

In case of inadvertent exposure to Elonva during pregnancy, clinical data are not sufficient to excludean adverse outcome of pregnancy. In animal studies reproductive toxicity has been observed (seesection 5.3). The use of Elonva during pregnancy is not indicated.

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

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 hypogonadotropichypogonadism in combination with hCG (see section 4.1). However, whether this treatment has effecton 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 oruse machines.

The most frequently reported adverse reactions during treatment with Elonva in clinical trials inwomen (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%).

The table below displays the main adverse reactions in adults treated with Elonva in clinical trials andpost-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), veryrare (< 1/10,000), and not known (cannot be estimated from available data). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

System organ class Frequency Adverse reaction

Immune system disorders Not known Hypersensitivity reactions,both local and generalised,including rash*

Psychiatric disorders Uncommon Mood swings

Nervous system disorders Common Headache

Uncommon Dizziness

Vascular disorders Uncommon Hot flush

Gastrointestinal disorders Common Nausea

Uncommon Abdominal distension,vomiting, diarrhoea,constipation

Musculoskeletal and Uncommon Back painconnective tissue disorders

Pregnancy, puerperium and Uncommon Abortion spontaneousperinatal conditions

Reproductive system and Common OHSS, pelvic pain, pelvicbreast disorders discomfort, breast tenderness

Uncommon Ovarian torsion, adnexa uteripain, premature ovulation,breast pain

General disorders and Common Fatigueadministration site conditions

Uncommon Injection site haematoma,injection site pain, irritability

Investigations Uncommon Alanine aminotransferaseincreased, aspartateaminotransferase increased

Injury, poisoning and Uncommon Procedural painprocedural complications

*Adverse reactions were identified through post-marketing surveillance.

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

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

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).

SOC Frequency1 Adverse reaction

Gastrointestinal disorders Common Vomiting

Vascular disorders Common Hot flush

General disorders and Common Injection site painadministration site conditions1 Adverse reactions that are reported only once are listed as common because a single report raises thefrequency above 1%.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In females

More than one injection of Elonva within one treatment cycle or too high a dose of Elonva and/or(rec)FSH may increase the risk of OHSS (see OHSS in section 4.4).

The effects of an overdose of Elonva in the adolescent male population are unknown.

Pharmacotherapeutic group: sex hormones and modulators of the genital system, gonadotropins,

ATC code: G03GA09

Corifollitropin alfa is designed as a sustained follicle stimulant with the same pharmacodynamicprofile as (rec)FSH, but with a markedly prolonged duration of FSH activity. The long duration of

FSH activity was achieved by adding the carboxy-terminal peptide of the β-subunit of humanchorionic gonadotropin (hCG) to the β-chain of human FSH. Corifollitropin alfa does not display anyintrinsic LH/hCG activity.

In females

Due to corifollitropin alfa’s ability to initiate and sustain multiple follicular growth for an entire week,a single subcutaneous injection of the recommended dose of Elonva may replace the first seveninjections of any daily (rec)FSH preparation in a COS treatment cycle.

Paediatric adolescent male population (14 years and older)

Corifollitropin alfa’s sustained FSH activity stimulates the immature Sertoli cells in the testis toinitiate gonadal development in support of future spermatogenesis. The combination of FSH with hCGis to initiate puberty with stimulation of Leydig cell function and increase testosterone production untiltesticular volumes attain adult size.

In three randomised, double-blind, clinical trials, treatment with a single subcutaneous injection of

Elonva, 100 micrograms (ENSURE study) or 150 micrograms (ENGAGE and PURSUE study), forthe first seven days of COS was compared to treatment with a daily dose of 150, 200, or 300 IU ofrecFSH, respectively. Pituitary suppression with a GnRH antagonist (ganirelix acetate injection at adaily dose of 0.25 mg) was used in each of the three clinical trials.

In the ENSURE study, 396 healthy normal ovulatory women, aged 18 to 36 years with a body weightless than or equal to 60 kg, were treated for one cycle with 100 micrograms of Elonva and pituitarysuppression with a GnRH antagonist as part of an ART program. The primary efficacy endpoint wasnumber of oocytes retrieved. The median total duration of stimulation was 9 days for both groups,indicating that two days of recFSH were required to complete ovarian stimulation from stimulationday 8 onwards (recFSH was given on the day of hCG for this study).

In the ENGAGE Study, 1,506 healthy normal ovulatory women, aged 18 to 36 years with a bodyweight greater than 60 kg and less than or equal to 90 kg, were treated for one cycle with150 micrograms of Elonva and pituitary suppression with a GnRH antagonist as part of an ARTprogram. The co-primary efficacy endpoints were ongoing pregnancy rate and number of oocytesretrieved. The median total duration of stimulation was 9 days for both groups, indicating that twodays of recFSH were required to complete ovarian stimulation from stimulation day 8 onwards(recFSH was given on the day of hCG for this study).

In the PURSUE study, 1,390 healthy normal ovulatory women, aged 35 to 42 years with a bodyweight greater than or equal to 50 kg, were treated for one cycle with 150 micrograms of Elonva andpituitary suppression with a GnRH antagonist as part of an ART program. The primary efficacyendpoint was vital pregnancy rate. The number of oocytes retrieved was a key secondary efficacyendpoint. The median total duration of stimulation was 9 days for both groups, indicating that one dayof recFSH was required to complete ovarian stimulation from stimulation day 8 onwards (no recFSHwas given on the day of hCG for this study).

Number of oocytes retrieved

In all three studies, treatment with a single injection of Elonva, 100 or 150 micrograms, for the firstseven days of COS, resulted in a higher number of oocytes retrieved compared with a daily dose ofrecFSH. However, the differences were within the predefined equivalence (ENGAGE and ENSURE)or non-inferiority (PURSUE) margins. See Table 1 below.

Table 1: Mean Number of Oocytes Retrieved from ENSURE, ENGAGE, and PURSUE

Intent-to-Treat Population (ITT)

ENGAGE

PURSUE

ENSURE (18-36 years of age)(35-42 years of age)(18-36 years of age) (body weight greater than

Parameter (body weight greater than(body weight less than or 60 kg and less than oror equal to 50 kg)equal to 60 kg) equal to 90 kg)

Elonva recFSH Elonva recFSH Elonva recFSH100 µg 150 IU 150 µg 200 IU 150 µg 300 IU

N=268 N=128 N=756 N=750 N=694 N=696

Meannumber of 13.3 10.6 13.8 12.6 10.7 10.3oocytes

Difference[95% CI] 2.5 [1.2; 3.9] 1.2 [0.5, 1.9] 0.5 [-0.2, 1.2]

Pregnancy from the fresh cycles of ENGAGE and PURSUE

In the ENGAGE study, non-inferiority was demonstrated in ongoing pregnancy rates between Elonvaand recFSH, with ongoing pregnancy rate defined as presence of at least one foetus with heart activityassessed at least 10 weeks after embryo transfer.

In the PURSUE study, non-inferiority was demonstrated in vital pregnancy rate between Elonva andrecFSH, with vital pregnancy rate defined as the percentage of subjects with at least one foetus withheart activity assessed 5 to 6 weeks after embryo transfer.

The pregnancy results from the fresh cycles of ENGAGE and PURSUE are summarised in Table 2below.

Table 2: Pregnancy Results from the Fresh Cycles of ENGAGE and PURSUE

Intent-to-Treat Population (ITT)

Parameter † ‡

Fresh Cycles of ENGAGE Fresh Cycles of PURSUE(18-36 years of age) (35-42 years of age)(body weight greater than 60 kg and (body weight greater than or equal toless than or equal to 90 kg) 50 kg)

Elonva recFSH Difference Elonva recFSH Difference150 µg 200 IU [95% CI] 150 µg 300 IU [95% CI]

N=756 N=750 N=694 N=696

Vital 39.9% 39.1% 1.1 [-3.8, 5.9] 23.9% 26.9% -3.0 [-7.3,pregnancy rate 1.4]

Ongoing 39.0% 38.1% 1.1 [-3.8, 5.9] 22.2% 24.0% -1.9 [-6.1,pregnancy rate 2.3]

Live birth 35.6% 34.4% 1.3 [-3.5, 6.1] 21.3% 23.4% -2.3 [-6.5,rate* 1.9]†

The primary efficacy endpoint in the ENGAGE study was ongoing pregnancy (assessed at least 10 weeks afterembryo transfer).‡The primary efficacy endpoint in the PURSUE study was vital pregnancy rate defined as the percentage ofsubjects with at least one foetus with heart activity assessed 5 to 6 weeks after embryo transfer.

*Live birth rate was a secondary efficacy endpoint in ENGAGE and PURSUE.

In these clinical trials, the safety profile of a single injection with Elonva was comparable to dailyinjections with recFSH.

Pregnancy from the Frozen-Thawed Embryo Transfer (FTET) cycles of ENGAGE and PURSUE

The follow-up FTET trial for ENGAGE included women who had at least one embryo thawed for useup to at least one year after cryopreservation. The mean number of embryos transferred in the FTETcycles of ENGAGE was 1.7 in both treatment groups.

The follow-up FTET trial for PURSUE included women who had at least one embryo thawed for usewithin two years of the date of the last cryopreservation for this trial. The mean number of embryostransferred in the FTET cycles of PURSUE was 2.4 in both treatment groups. This trial also providedsafety data on the infants born from cryopreserved embryos.

The maximum number of FTET cycles was 5 and 4 for the follow-up FTET trial for ENGAGE and

PURSUE, respectively. The pregnancy results from the first two FTET cycles of ENGAGE and

PURSUE are summarised in Table 3 below.

Table 3: Pregnancy Results from the FTET cycles of ENGAGE and PURSUE

Intent-to-Treat Population (ITT)

FTET Cycles of ENGAGE FTET Cycles of PURSUE(18-36 years of age) (35-42 years of age)(body weight greater than 60 kg (body weight greater than or equal toand less than or equal to 90 kg) 50 kg)

Elonva recFSH Elonva recFSH150 µg 200 IU 150 µg 300 IUn N % n N % n N % n N %

FTET Cycle 1a

Ongoing 55 148 37.2 45 147 30.6 43 152 28.3 42 145 29.0pregnancy

Live birth - - - - - - 43 152 28.3 41 145 28.3

FTET Cycle 2a

Ongoing 9 38 23.7 9 31 29.0 8 23 34.8 6 14 42.9pregnancy

Live birth - - - - - - 8 23 34.8 6 14 42.9n = number of subjects with the event; N = total number of subjectsa Per embryo transfer.

Congenital malformations reported in infants born after a frozen-thawed embryo transfer (FTET)cycle

Following use of Elonva, 61 infants were born after an FTET cycle in the PURSUE study follow-up,and 607 infants were born after fresh ART cycles in the ENSURE, ENGAGE and PURSUE studiescombined. The rates for congenital malformations (major and minor combined) reported for infantsborn after an FTET cycle in the PURSUE study follow-up (16.4%) were similar to those reported forinfants born after fresh ART cycles in the ENSURE, ENGAGE and PURSUE studies combined(16.8%).

Of the 2,511 women treated with Elonva who were evaluated for the formation of post-treatmentantibodies, four (0.16%) had evidence of antibody formation, including three who had been exposedonce to Elonva and one who had been exposed twice to Elonva. In each case, these antibodies werenon-neutralizing and did not interfere with the response to stimulation or the normal physiologicresponses of the Hypothalamic-Pituitary-Ovarian (HPO) axis. Two of these four women becamepregnant during the same treatment cycle in which antibodies were detected, suggesting that thepresence of non-neutralizing antibodies after stimulation with Elonva is not clinically relevant.

A single-group, open-label efficacy and safety study was conducted to evaluate the treatment with

Elonva in combination with hCG to induce and/or restore puberty and to induce and/or restorespermatogenesis in 17 adolescent males aged 14 years and older for the treatment of hypogonadotropichypogonadism. A priming period with Elonva instead of hCG in adolescents with HH was included tomimic the gonadotropin pattern of normal puberty, stimulating FSH receptors on Sertoli cells withcorifollitropin alfa prior to stimulation of LH receptors on Leydig cells with hCG. The study excludedmales who had previously received GnRH, gonadotropins or testosterone treatment. Elonva wasadministered once every 2 weeks for 64 weeks, alone for the first 12 weeks (priming period), followedby 52 weeks in combination with twice weekly doses of hCG (500 to 5000 IU) (combined treatmentperiod).

The primary endpoint for efficacy was shown by increase in testicular volume, measured as the sum ofvolumes of left and right testes by ultrasound. During the overall treatment period, the increase notedin testicular volume at Week 64 changed from a geometric mean of 1.4 mL to 12.9 mL, mean foldincrease of 9.43 (95% CI: 7.44, 11.97). The primary endpoint for safety showed that corifollitropinalfa was generally well tolerated with no cases of confirmed anti-corifollitropin alfa antibodies, nounexpected values or changes in clinical laboratory data or vitals sign assessments (see also section4.8).

Additional findings at Week 64 included, increased testosterone levels, growth velocity andprogression of puberty (Tanner III, IV and V) indicated appropriate responses to hCG. Decreasinganti-müllerian hormone levels and increases in Inhibin B levels were suggestive of initiation ofspermatogenesis.

Pharmacokinetic parameters of corifollitropin alfa were evaluated after subcutaneous administration inwomen undergoing a COS treatment cycle.

Due to the long elimination half-life, after administration of the recommended dose, serumconcentrations of corifollitropin alfa are sufficient to sustain multiple follicular growth for an entireweek. This justifies replacement of the first seven injections of daily (rec)FSH with a singlesubcutaneous injection of Elonva in COS for the development of multiple follicles and pregnancy inan ART program (see section 4.2).

Body weight is a determinant of exposure to corifollitropin alfa. Corifollitropin alfa exposure after asingle subcutaneous injection is 665 hours*ng/mL (AUC, 426-1,037 hours*ng/mL1) and is similarafter administration of 100 micrograms corifollitropin alfa to women with a body weight less than orequal to 60 kilograms and of 150 micrograms corifollitropin alfa to women with a body weight greaterthan 60 kilograms.

After a single subcutaneous injection of Elonva, the maximum serum concentration of corifollitropinalfa is 4.24 ng/mL (2.49-7.21 ng/mL1) and is reached 44 hours (35-57 hours1) postdose. The absolutebioavailability is 58% (48-70%1).

Distribution, metabolism and elimination of corifollitropin alfa are very similar to othergonadotropins, such as FSH, hCG and LH. After absorption into the blood, corifollitropin alfa isdistributed mainly to the ovaries and the kidneys. The steady state volume of distribution is 9.2 L1 Predicted range for 90% of subjects.

(6.5-13.1 L1). Exposure to corifollitropin alfa increases proportionally with dose within the range of60 micrograms to 240 micrograms.

Corifollitropin alfa has an elimination half-life of 70 hours (59-82 hours1) and a clearance of 0.13 L/h(0.10-0.18 L/h1). Elimination of corifollitropin alfa predominantly occurs via the kidneys, and the rateof elimination may be reduced in patients with renal insufficiency (see sections 4.2 and 4.4). Hepaticmetabolism contributes to a minor extent to the elimination of corifollitropin alfa.

Although data in hepatically impaired patients are not available, hepatic impairment is unlikely toaffect the pharmacokinetic profile of corifollitropin alfa.

In a study of adolescent males 14 to less than 18 years of age with hypogonadotropic hypogonadism(n=17) who were administered 100 micrograms (body weight less than or equal to 60 kg) or150 micrograms (body weight greater than 60 kg) of Elonva once every two weeks, mean serumtrough Elonva concentrations (two weeks postdose) were 591 ng/mL when Elonva was administeredalone and 600 ng/mL when Elonva was co-administered with hCG (given twice weekly). Elonvaserum concentrations were comparable in participants receiving 100 micrograms and 150 microgramsdoses of Elonva.

Preclinical data revealed no special hazard for humans based on conventional studies of single andrepeated dose toxicity and safety pharmacology.

Reproduction toxicology studies in rats and rabbits indicated that corifollitropin alfa does notadversely affect fertility. Administration of corifollitropin alfa to rats and rabbits, prior to and directlyafter mating, and during early pregnancy, resulted in embryotoxicity. In rabbits, when administeredprior to mating, teratogenicity has been observed. Both embryotoxicity and teratogenicity areconsidered a consequence of the superovulatory state of the animal not able to support a number ofembryos above a physiological ceiling. The relevance of these findings for the clinical use of Elonva islimited.

Sodium citrate

Sucrose

Polysorbate 20

Methionine

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

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

3 years

Store in a refrigerator (2°C-8°C).

Do not freeze.

For convenience, the patient is allowed to store the product at or below 25°C for a period of not morethan 1 month.

Keep the syringe in the outer carton in order to protect from light.

Elonva is supplied in pre-filled luerlock syringes of 1 mL (type I hydrolytic glass), closed with abromobutyl elastomer plunger and a tip cap. The syringe is equipped with an automatic safety systemto prevent needle stick injuries after use and is packed together with a sterile injection needle. Eachpre-filled syringe contains 0.5 mL solution for injection.

Elonva is available in pack sizes of 1 pre-filled syringe.

Do not use Elonva if the solution is not clear.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

N.V. Organon

Kloosterstraat 65349 AB Oss

The Netherlands

EU/1/09/609/001

EU/1/09/609/002

Date of first authorisation: 25 January 2010

Date of latest renewal: 22 August 2014

DD month YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.