More than one injection of Elnova within one treatment cycle or too high a dose of Elnova and/or (rec)FSH may increase the risk of OHSS.
-
- 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.
- A history of Ovarian Hyperstimulation Syndrome (OHSS).
- A previous COS cycle that resulted in more than 30 follicles > 11 mm measured by ultrasound examination.
- A basal antral follicle count > 20.
- Fibroid tumours of the uterus incompatible with pregnancy.
- Malformations of the reproductive organs incompatible with pregnancy.
- Polycystic ovarian syndrome (PCOS).
In the absence of compatibility studies, the medicinal product must not be mixed with other medicinal products.
Summary of the safety profile
), 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 Elnova 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.
| 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 connective tissue disorders | Uncommon | Back pain |
| Pregnancy, puerperium and perinatal conditions | Uncommon | Abortion spontaneous |
| Reproductive system and breast disorders | Common | OHSS, pelvic pain, pelvic discomfort, breast tenderness |
| Uncommon | Ovarian torsion, adnexa uteri pain, premature ovulation, breast pain | |
| General disorders and administration site conditions | Common | Fatigue |
| Uncommon | Injection site haematoma, injection site pain, irritability | |
| Investigations | Uncommon | Alanine aminotransferase increased, aspartate aminotransferase increased |
| Injury, poisoning and procedural complications | Uncommon | Procedural pain |
*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 Elnova therapy as with other gonadotropins.
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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Preclinical data revealed no special hazard for humans based on conventional studies of single and repeated dose toxicity and safety pharmacology.
Reproduction toxicology studies in rats and rabbits indicated that corifollitropin alfa does not adversely affect fertility. Administration of corifollitropin alfa to rats and rabbits, prior to and directly after mating, and during early pregnancy, resulted in embryotoxicity. In rabbits, when administered prior to mating, teratogenicity has been observed. Both embryotoxicity and teratogenicity are considered a consequence of the superovulatory state of the animal not able to support a number of embryos above a physiological ceiling. The relevance of these findings for the clinical use of Elnova is limited.
Elnova is indicated for Controlled Ovarian Stimulation (COS) in combination with a Gonadotropin Releasing Hormone (GnRH) antagonist for the development of multiple follicles in women participating in an Assisted Reproductive Technology (ART) program.
Pharmacotherapeutic group: sex hormones and modulators of the genital system, gonadotropins,
ATC code: G03GA09
Mechanism of action
Corifollitropin alfa is designed as a sustained follicle stimulant with the same pharmacodynamic profile as (rec)FSH, but with a markedly prolonged duration of FSH activity. Due to its ability to initiate and sustain multiple follicular growth for an entire week, a single subcutaneous injection of the recommended dose of Elnova may replace the first seven injections of any daily (rec)FSH preparation in a COS treatment cycle. The long duration of FSH activity was achieved by adding the carboxy-terminal peptide of the β-subunit of human chorionic gonadotropin (hCG) to the β-chain of human FSH. Corifollitropin alfa does not display any intrinsic LH/hCG activity.
Clinical efficacy and safety
In three randomized, double-blind, clinical trials, treatment with a single subcutaneous injection of Elnova, 100 micrograms (ENSURE study) or 150 micrograms (ENGAGE and PURSUE study), for the first seven days of COS was compared to treatment with a daily dose of 150, 200, or 300 IU of recFSH, respectively. Pituitary suppression with a GnRH antagonist (ganirelix acetate injection at a daily 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 weight less than or equal to 60 kg, were treated for one cycle with 100 micrograms of Elnova and pituitary suppression with a GnRH antagonist as part of an ART program. The primary efficacy endpoint was number 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 stimulation day 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 body weight greater than 60 kg and less than or equal to 90 kg, were treated for one cycle with 150 micrograms of Elnova and pituitary suppression with a GnRH antagonist as part of an ART program. The co-primary efficacy endpoints were ongoing pregnancy rate and number 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 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 body weight greater than or equal to 50 kg, were treated for one cycle with 150 micrograms of Elnova and pituitary suppression with a GnRH antagonist as part of an ART program. The primary efficacy endpoint was vital pregnancy rate. The number of oocytes retrieved was a key secondary efficacy endpoint. The median total duration of stimulation was 9 days for both groups, indicating that one day of recFSH was required to complete ovarian stimulation from stimulation day 8 onwards (no recFSH was given on the day of hCG for this study).
Number of oocytes retrieved
In all three studies, treatment with a single injection of Elnova, 100 or 150 micrograms, for the first seven days of COS, resulted in a higher number of oocytes retrieved compared with a daily dose of recFSH. 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)
| Parameter | ENSURE (18-36 years of age) (body weight less than or equal to 60 kg) | ENGAGE (18-36 years of age) (body weight greater than 60 kg and less than or equal to 90 kg) | PURSUE (35-42 years of age) (body weight greater than or equal to 50 kg) | |||
| Elnova 100 µg | recFSH 150 IU | Elnova 150 µg | recFSH 200 IU | Elnova 150 µg | recFSH 300 IU | |
| N=268 | N=128 | N=756 | N=750 | N=694 | N=696 | |
| Mean number of oocytes | 13.3 | 10.6 | 13.8 | 12.6 | 10.7 | 10.3 |
| 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 Elnova and recFSH, with ongoing pregnancy rate defined as presence of at least one foetus with heart activity assessed at least 10 weeks after embryo transfer.
In the PURSUE study, non-inferiority was demonstrated in vital pregnancy rate between Elnova and recFSH, with vital pregnancy rate defined as the percentage of subjects with at least one foetus with heart activity assessed 5 to 6 weeks after embryo transfer.
The pregnancy results from the fresh cycles of ENGAGE and PURSUE are summarized in Table 2 below.
Table 2: Pregnancy Results from the Fresh Cycles of ENGAGE and PURSUE
Intent-to-Treat Population (ITT)
| Parameter | Fresh Cycles of ENGAGE†(18-36 years of age) (body weight greater than 60 kg and less than or equal to 90 kg) | Fresh Cycles of PURSUE‡ (35-42 years of age) (body weight greater than or equal to 50 kg) | ||||
| Elnova 150 µg | recFSH 200 IU | Difference [95% CI] | Elnova 150 µg | recFSH 300 IU | Difference [95% CI] | |
| N=756 | N=750 |
| N=694 | N=696 | ||
| Vital pregnancy rate | 39.9% | 39.1% | 1.1 [-3.8, 5.9] | 23.9% | 26.9% | -3.0 [-7.3, 1.4] |
| Ongoing pregnancy rate | 39.0% | 38.1% | 1.1 [-3.8, 5.9] | 22.2% | 24.0% | -1.9 [-6.1, 2.3] |
| Live birth rate* | 35.6% | 34.4% | 1.3 [-3.5, 6.1] | 21.3% | 23.4%
| -2.3 [-6.5, 1.9] |
†The primary efficacy endpoint in the ENGAGE study was ongoing pregnancy (assessed at least 10 weeks after embryo transfer).
‡The primary efficacy endpoint in the PURSUE study was vital pregnancy rate defined as the percentage of subjects 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 Elnova was comparable to daily injections 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 use up to at least one year after cryopreservation. The mean number of embryos transferred in the FTET cycles 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 use within two years of the date of the last cryopreservation for this trial. The mean number of embryos transferred in the FTET cycles of PURSUE was 2.4 in both treatment groups. This trial also provided safety 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 summarized 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 (18-36 years of age) (body weight greater than 60 kg and less than or equal to 90 kg) | FTET Cycles of PURSUE (35-42 years of age) (body weight greater than or equal to 50 kg) | ||||||||||
|
| Elnova 150 µg | recFSH 200 IU | Elnova 150 µg | recFSH 300 IU | ||||||||
|
| n | N | % | n | N | % | n | N | % | n | N | % |
| FTET Cycle 1a |
|
|
|
|
|
|
|
|
|
|
|
|
| Ongoing pregnancy | 55 | 148 | 37.2 | 45 | 147 | 30.6 | 43 | 152 | 28.3 | 42 | 145 | 29.0 |
| Live birth | - | - | - | - | - | - | 43 | 152 | 28.3 | 41 | 145 | 28.3 |
| FTET Cycle 2a |
|
|
|
|
|
|
|
|
|
|
|
|
| Ongoing pregnancy | 9 | 38 | 23.7 | 9 | 31 | 29.0 | 8 | 23 | 34.8 | 6 | 14 | 42.9 |
| Live birth | - | - | - | - | - | - | 8 | 23 | 34.8 | 6 | 14 | 42.9 |
| n = number of subjects with the event; N = total number of subjects a Per embryo transfer. | ||||||||||||
Congenital malformations reported in infants born after a frozen-thawed embryo transfer (FTET) cycle
Following use of Elnova, 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 studies combined. The rates for congenital malformations (major and minor combined) reported for infants born after an FTET cycle in the PURSUE study follow-up (16.4%) were similar to those reported for infants born after fresh ART cycles in the ENSURE, ENGAGE and PURSUE studies combined (16.8%).
Immunogenicity
Of the 2,511 women treated with Elnova who were evaluated for the formation of post-treatment antibodies, four (0.16%) had evidence of antibody formation, including three who had been exposed once to Elnova and one who had been exposed twice to Elnova. In each case, these antibodies were non-neutralizing and did not interfere with the response to stimulation or the normal physiologic responses of the Hypothalamic-Pituitary-Ovarian (HPO) axis. Two of these four women became pregnant during the same treatment cycle in which antibodies were detected, suggesting that the presence of non-neutralizing antibodies after stimulation with Elnova is not clinically relevant.
Paediatric population
Pharmacokinetic parameters of corifollitropin alfa were evaluated after subcutaneous administration in women undergoing a COS treatment cycle.
Due to the long elimination half-life, after administration of the recommended dose, serum concentrations of corifollitropin alfa are sufficient to sustain multiple follicular growth for an entire week. This justifies replacement of the first seven injections of daily (rec)FSH with a single subcutaneous injection of Elnova in COS for the development of multiple follicles and pregnancy in an ART program.
Body weight is a determinant of exposure to corifollitropin alfa. Corifollitropin alfa exposure after a single subcutaneous injection is 665 hours*ng/mL (AUC, 426-1,037 hours*ng/mL1) and is similar after administration of 100 micrograms corifollitropin alfa to women with a body weight less than or equal to 60 kilograms and of 150 micrograms corifollitropin alfa to women with a body weight greater than 60 kilograms.
Absorption
After a single subcutaneous injection of Elnova, the maximum serum concentration of corifollitropin alfa is 4.24 ng/mL (2.49-7.21 ng/mL1) and is reached 44 hours (35-57 hours1) postdose. The absolute bioavailability is 58% (48-70%1).
Distribution
Distribution, metabolism and elimination of corifollitropin alfa are very similar to other gonadotropins, such as FSH, hCG and LH. After absorption into the blood, corifollitropin alfa is distributed mainly to the ovaries and the kidneys. The steady state volume of distribution is 9.2 L (6.5-13.1 L1). Exposure to corifollitropin alfa increases proportionally with dose within the range of 60 micrograms to 240 micrograms.
Elimination
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 rate of elimination may be reduced in patients with renal insufficiency. Hepatic metabolism contributes to a minor extent to the elimination of corifollitropin alfa.
Other special populations
Hepatic impairment
Although data in hepatically impaired patients are not available, hepatic impairment is unlikely to affect the pharmacokinetic profile of corifollitropin alfa.
1 Predicted range for 90% of subjects.
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 Elnova.
Dosing during the stimulation cycle
Elnova is intended for single subcutaneous injection only.)
Renal insufficiency
In patients with mild, moderate or severe renal insufficiency the rate of elimination of corifollitropin alfa may be reduced. Therefore, the use of Elnova in these women is not recommended.
Not recommended with a GnRH agonist protocol
There are limited data on the use of Elnova in combination with a GnRH agonist.).
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 Elnova. 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.
To reduce 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. When there are 30 or more follicles in total it is advised to withhold hCG administration.
Depending on the ovarian response, the following measures can be considered to reduce the risk of OHSS:
- withhold further stimulation with a gonadotropin for a maximum of 3 days (coasting);
- withhold hCG and cancel the treatment cycle;
- administer a dose lower than 10,000 IU of hCG for triggering final oocyte maturation, e.g. 5,000 IU hCG or 250 micrograms rec-hCG (which is equivalent to approximately 6,500 IU);
- cancel the fresh embryo transfer and cryopreserve embryos;
- avoid administration of hCG for luteal phase support.
Adherence to the recommended Elnova dose and treatment cycle and careful monitoring of ovarian response is important to reduce the risk of OHSS. 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 Elnova. 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 Elnova. 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 Elnova. 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.
No studies on the ability to drive and use machines have been performed.
Elnova may cause dizziness. Women should be advised that if they feel dizzy, they should not drive or use machines.
Treatment with Elnova should be initiated under the supervision of a physician experienced in the treatment of fertility problems.
Posology
In the treatment of women of reproductive age, the dose of Elnova is based on weight and age.
- A single 100-microgram dose is recommended in women who weigh less than or equal to 60 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 kg | ||
| Age | 36 years or younger | 100 micrograms | 100 micrograms | 150 micrograms |
| Older than 36 years | Not studied. | 150 micrograms | 150 micrograms | |
Stimulation day 1:
Elnova 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 the ovarian response, i.e. the number and size of growing follicles. The concurrent determination of serum oestradiol 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 Elnova on stimulation day 1, COS treatment may be continued with daily injections of (recombinant) Follicle Stimulating Hormone [(rec)FSH] until the criterion for triggering final oocyte maturation (3 follicles > 17 mm) has been reached. The daily dose of (rec)FSH may 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 can be omitted, depending on the ovarian response. In general, adequate follicular development is achieved 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 is administered the same day or the day thereafter to induce final oocyte maturation.(OHSS).
Special populations
Renal impairment
No clinical studies have been performed in patients with renal insufficiency. Since the rate of elimination of corifollitropin alfa may be reduced in patients with renal insufficiency, the use of Elnova in these women is not recommended.
Hepatic impairment
Although data in hepatically impaired patients are not available, hepatic impairment is unlikely to affect the elimination of corifollitropin alfa.
Paediatric population
There is no relevant use of Elnova within the approved indication in the paediatric population.
Method of administration
Subcutaneous injection of Elnova may be carried out by the woman herself or her partner, provided that proper instructions are given by the physician. Self administration of Elnova should only be performed by women who are well-motivated, adequately trained and with access to expert advice.
Do not use Elnova if the solution is not clear.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
