REKOVELLE 12mcg / 0.36ml injectible solution medication leaflet

REKOVELLE 12 micrograms/0.36 mL solution for injection in a pre-filled pen

REKOVELLE 36 micrograms/1.08 mL solution for injection in a pre-filled pen

REKOVELLE 72 micrograms/2.16 mL solution for injection in a pre-filled pen

REKOVELLE 12 micrograms/0.36 mL solution for injection

One pre-filled multidose pen delivers 12 micrograms follitropin delta* in 0.36 mL solution.

REKOVELLE 36 micrograms/1.08 mL solution for injection

One pre-filled multidose pen delivers 36 micrograms follitropin delta* in 1.08 mL solution.

REKOVELLE 72 micrograms/2.16 mL solution for injection

One pre-filled multidose pen delivers 72 micrograms follitropin delta* in 2.16 mL solution.

One mL of solution contains 33.3 micrograms of follitropin delta*

*recombinant human follicle-stimulating hormone (FSH) produced in a human cell line (PER.C6) byrecombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection in a pre-filled pen (injection).

Clear and colourless solution with a pH of 6.0-7.0.

Controlled ovarian stimulation for the development of multiple follicles in women undergoing assistedreproductive technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperminjection (ICSI) cycle.

Treatment should be initiated under the supervision of a physician experienced in the treatment offertility problems.

The posology of REKOVELLE is individualised for each patient and aims to obtain an ovarianresponse which is associated with a favourable safety/efficacy profile, i.e. aims to achieve an adequatenumber of oocytes retrieved and reduce the interventions to prevent ovarian hyperstimulationsyndrome (OHSS). REKOVELLE is dosed in micrograms (see section 5.1). The dosing regimen isspecific for REKOVELLE and the microgram dose cannot be applied to other gonadotropins.

For the first treatment cycle, the individual daily dose will be determined on the basis of the woman’sserum anti-Müllerian hormone (AMH) concentration and her body weight. The dose should be basedon a recent determination of AMH (i.e. within the last 12 months) measured by the followingdiagnostic tests: ELECSYS AMH Plus immunoassay from Roche (i.e. assay used in clinicaldevelopment trials), or alternatively the ACCESS AMH Advanced from Beckman Coulter or

LUMIPULSE G AMH from Fujirebio (see section 4.4). The individual daily dose is to be maintainedthroughout the stimulation period. For women with AMH <15 pmol/L the daily dose is12 micrograms, irrespective of body weight. For women with AMH ≥15 pmol/L the daily dosedecreases from 0.19 to 0.10 micrograms/kg by increasing AMH concentration (Table 1). The dose isto be rounded off to the nearest 0.33 micrograms to match the dosing scale on the injection pen. Themaximum daily dose for the first treatment cycle is 12 micrograms.

For calculation of the REKOVELLE dose, the body weight is to be measured without shoes andovercoat just prior to start of stimulation.

Table 1 Dosing regimen

AMH (pmol/L) <15 15-16 17 18 19-20 21-22 23-24 25-27 28-32 33-39 ≥40

Fixed daily dose 12 0.19 0.18 0.17 0.16 0.15 0.14 0.13 0.12 0.11 0.10of REKOVELLE mcg mcg/kg

The AMH concentration is to be expressed in pmol/L and is to be rounded off to the nearest integer. Ifthe AMH concentration is in ng/mL, the concentration should be converted to pmol/L by multiplyingwith 7.14 (ng/mL x 7.14 = pmol/L) before use.mcg: micrograms

Potential high responders (patients with AMH >35 pmol/L) have not been studied in a protocol usingdown-regulation with GnRH agonist.

Time of initiating treatment with REKOVELLE depends on the type of protocol.

- in a protocol using a gonadotropin-releasing hormone (GnRH) antagonist, the treatment with

REKOVELLE should be initiated on day 2 or 3 after start of menstrual bleeding;

- in a protocol using down-regulation with a GnRH agonist, the treatment with REKOVELLEshould be initiated approximately 2 weeks after the start of agonist treatment.

Treatment should continue until adequate follicular development (≥3 follicles ≥17 mm) has beenachieved, which on average is by the ninth or tenth day of treatment (range 5 to 20 days). Withpituitary desensitisation caused by a GnRH agonist, a longer duration of stimulation and therefore ahigher total dose of REKOVELLE may be necessary to achieve adequate follicular response. A singleinjection of 250 micrograms recombinant human chorionic gonadotropin (hCG) or 5,000 IU hCG isadministered to induce final follicular maturation. In patients with excessive follicular development(of ≥25 follicles ≥12 mm), treatment with REKOVELLE should be stopped and triggering of finalfollicular maturation with hCG should not be performed.

For subsequent treatment cycles, the daily dose of REKOVELLE should be maintained or modifiedaccording to the patient’s ovarian response in the previous cycle. If the patient had adequate ovarianresponse in the previous cycle without developing OHSS, the same daily dose should be used. In caseof ovarian hypo-response in the previous cycle, the daily dose in the subsequent cycle should beincreased by 25% or 50%, according to the extent of response observed. In case of ovarian hyper-response in the previous cycle, the daily dose in the subsequent cycle should be decreased by 20% or33%, according to the extent of response observed. In patients who developed OHSS or were at risk of

OHSS in a previous cycle, the daily dose for the subsequent cycle is 33% lower than the dose used inthe cycle where OHSS or risk of OHSS occurred. The maximum daily dose is 24 micrograms.

There is no relevant use of REKOVELLE in the elderly population.

Safety, efficacy and pharmacokinetics of REKOVELLE in patients with renal or hepatic impairmenthave not been specifically studied in clinical trials. Although limited, data did not indicate a need for adifferent dosing regimen of REKOVELLE in this patient population (see section 4.4).

Polycystic ovarian syndrome patients with anovulatory disorders

Anovulatory patients with polycystic ovarian syndrome have not been studied. Ovulatory patients withpolycystic ovaries have been included in clinical trials (see section 5.1).

There is no relevant use of REKOVELLE in the paediatric population.

REKOVELLE is intended for subcutaneous use, preferably in the abdominal wall. The first injectionshould be performed under direct medical supervision. Patients must be educated on how to use the

REKOVELLE injection pen and to perform injections. Self-administration should only be performedby patients who are well motivated, adequately trained and have access to expert advice.

For instructions on the administration with the pre-filled pen, see the ”Instructions for Use”.

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

* tumours of the hypothalamus or pituitary gland

* ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome

* gynaecological haemorrhages of unknown aetiology (see section 4.4)

* ovarian, uterine or mammary carcinoma (see section 4.4)

In the following situations, treatment outcome is unlikely to be favourable, and therefore

REKOVELLE should not be administered:

* primary ovarian failure

* malformations of sexual organs incompatible with pregnancy

* fibroid tumours of the uterus incompatible with pregnancy

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

REKOVELLE contains a potent gonadotropic substance capable of causing mild to severe adversereactions, and should only be used by physicians who are thoroughly familiar with infertility problemsand their management.

Gonadotropin therapy requires time commitment by physicians and supportive healthcareprofessionals, as well as the availability of appropriate monitoring facilities. Safe and effective use of

REKOVELLE calls for monitoring of ovarian response with ultrasound alone, or in combination withmeasurement of serum estradiol levels, on a regular basis. The dose of REKOVELLE is individualisedfor each patient to obtain an ovarian response with favourable safety/efficacy profile. There may be adegree of interpatient variability in response to FSH administration, with poor response to FSH insome patients and exaggerated response in others.

Before starting treatment, the couple’s infertility should be assessed as appropriate and putativecontraindications for pregnancy evaluated. In particular, patients should be evaluated forhypothyroidism and hyperprolactinemia, and the appropriate specific treatment should be given.

Use of results obtained with other assays than the ELECSYS AMH Plus immunoassay from Roche,the ACCESS AMH Advanced from Beckman Coulter and LUMIPULSE G AMH from Fujirebio for

REKOVELLE dose determination is not recommended, as there currently is no standardisation ofavailable AMH assays.

Patients undergoing stimulation of follicular growth may experience ovarian enlargement and may beat risk of developing OHSS. Adherence to the REKOVELLE dose and regimen of administration andcareful monitoring of therapy will minimise the incidence of such events.

Ovarian Hyperstimulation Syndrome (OHSS)

A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It ismore commonly seen in patients with polycystic ovarian syndrome and usually regresses withouttreatment. In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifestitself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sexsteroids, and an increase in vascular permeability which can result in an accumulation of fluid in theperitoneal, pleural and, rarely, in the pericardial cavities.

It is important to stress the value of careful and frequent monitoring of follicular development in orderto reduce the risk of OHSS. The following symptoms may be observed in severe cases of OHSS:abdominal pain, discomfort and distension, severe ovarian enlargement, weight gain, dyspnoea,oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluationmay reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum,pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may becomplicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemicstroke or myocardial infarction.

Excessive ovarian response to gonadotropin treatment seldom gives rise to OHSS unless hCG isadministered to trigger final follicular maturation. Furthermore, the syndrome may be more severe andmore protracted if pregnancy occurs. Therefore, in cases of ovarian hyperstimulation it is prudent towithhold hCG and advise the patient to refrain from coitus or to use barrier contraceptive methods forat least 4 days. OHSS may progress rapidly (within 24 hours) to several days to become a seriousmedical event. Early OHSS can occur within 9 days after triggering of final follicular maturation. Late

OHSS can develop as a consequence of the hormonal changes during pregnancy 10 or more days aftertriggering of final follicular maturation. Because of the risk of developing OHSS patients should befollowed for at least two weeks after hCG administration.

Women with recent or ongoing thromboembolic disease or women with generally recognised riskfactors for thromboembolic events, such as personal or family history, severe obesity (body massindex >30 kg/m2) or thrombophilia may have an increased risk of venous or arterial thromboembolicevents, during or following treatment with gonadotropins. Treatment with gonadotropins may furtherincrease the risk for aggravation or occurrence of such events. In these women, the benefits ofgonadotropin administration need to be weighed against the risks. It should be noted however thatpregnancy itself as well as OHSS also carry an increased risk of thromboembolic events.

Ovarian torsion

Occurrence of ovarian torsion has been reported for ART cycles. It may be associated with other riskfactors such as OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion,previous or current ovarian cyst and polycystic ovaries. Damage to the ovary due to reduced bloodsupply can be limited by early diagnosis and immediate detorsion.

Multiple pregnancy

Multiple pregnancy carries an increased risk of adverse maternal and perinatal outcomes. In patientsundergoing ART procedures the risk of multiple pregnancy is related mainly to the number ofembryos replaced, their quality and the patient age, although twin pregnancy can in rare occasionsdevelop from single embryo transfers. The patients should be advised of the potential risk of multiplebirths before starting treatment.

Pregnancy loss

The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing controlledovarian stimulation for ART than following natural conception.

Ectopic pregnancy

Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy isobtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancyafter ART has been reported to be higher than in the general population.

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.

Congenital malformation

The prevalence 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 multiple pregnancy.

Other medical conditions

Medical conditions that contraindicate pregnancy should also be evaluated before starting treatmentwith REKOVELLE.

REKOVELLE has not been studied in patients with moderate/severe renal or hepatic impairment.

REKOVELLE contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially“sodium-free”.

No interaction studies have been performed with REKOVELLE. Clinically significant interactionswith other medicinal products have neither been reported during REKOVELLE therapy, nor areexpected.

REKOVELLE is not indicated during pregnancy. No teratogenic risk has been reported, followingcontrolled ovarian stimulation, in clinical use with gonadotropins. There are no data from theinadvertent exposure to REKOVELLE in pregnant women. Studies in animals have shownreproductive toxicity with REKOVELLE doses above the recommended maximal dose in humans(section 5.3).

REKOVELLE is not indicated during breastfeeding.

REKOVELLE is indicated for use in infertility (see section 4.1).

REKOVELLE has no or negligible influence on the ability to drive and use machines.

The most frequently reported adverse reactions during treatment with REKOVELLE are OHSS,headache, pelvic pain, nausea and fatigue. The frequency of these adverse reactions might decreasewith repeated treatment cycles, as this has been observed in clinical trials.

The table below (Table 2) displays the adverse reactions experienced in clinical trials by patientstreated with REKOVELLE using the algorithm-based dosing regimen. Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 Adverse reactions in pivotal clinical trials

System Organ Class Common Uncommon(≥1/100 to <1/10) (≥1/1,000 to <1/100)

Psychiatric disorders Mood swings

Nervous system disorders Headache Somnolence

Dizziness

Gastrointestinal disorders Nausea Diarrhoea

Abdominal discomforta

Reproductive system and breast OHSS Vaginal haemorrhagedisorders Pelvic painb Breast discomfortc

General disorders and Fatigueadministration site conditionsa Abdominal discomfort includes abdominal pain/distention.b Pelvic pain includes pelvic discomfort and adnexa uteri pain.c Breast discomfort includes breast pain, breast swelling, breast tenderness and/or nipple pain.

OHSS is an intrinsic risk of the ovarian stimulation. Known gastrointestinal symptoms associated with

OHSS include abdominal pain, discomfort, and distension, nausea, vomiting and diarrhoea. Ovariantorsion and thromboembolic events are known to be rare complications of ovarian stimulationtreatment (see section 4.4).

Immunogenicity in terms of development of anti-FSH antibodies is a potential risk of gonadotropintherapy (see section 5.1).

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.

The effect of an overdose is unknown, nevertheless, there is a risk that OHSS may occur (seesection 4.4).

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

ATC code: G03GA10

The most important effect resulting from parenteral administration of FSH is the development ofmultiple mature follicles.

Follitropin delta is a recombinant human FSH. The amino acid sequences of the two FSH subunits infollitropin delta are identical to the endogenous human FSH sequences. Because follitropin delta isproduced in the human cell line PER.C6, the glycosylation profile is different from follitropin alfa andfollitropin beta.

Following daily administration of equal IU doses of REKOVELLE and follitropin alfa as determinedin the rat in vivo bioassay (Steelman-Pohley assay), higher ovarian response (i.e. estradiol, inhibin Band follicular volume) was observed in patients after administration of REKOVELLE compared tofollitropin alfa. As the rat bioassay might not fully reflect the potency of the FSH in REKOVELLE inhumans, REKOVELLE is dosed in micrograms and not in IU. The clinical trial data suggest that adaily dose of 10.0 [95% CI 9.2; 10.8] micrograms REKOVELLE provides, for the majority ofpatients, an ovarian response close to that obtained with 150 IU/day follitropin alfa.

The number of oocytes retrieved increases with the dose of REKOVELLE and serum AMHconcentration. Conversely, increasing body weight leads to a decrease in the number of oocytesretrieved (only clinically relevant for REKOVELLE doses below 12 micrograms). The resulting

REKOVELLE dosing regimen is in section 4.2.

The ESTHER-1 trial was a randomised, assessor-blinded, controlled trial in 1,326 IVF/ICSI patients.

The trial compared the individualised dosing regimen of REKOVELLE where the daily dose isestablished for each patient and fixed throughout stimulation with no adjustments (see section 4.2) tofollitropin alfa filled-by-mass at a starting dose of 11 micrograms (150 IU) for the first five daysfollowed by dose adjustments from day 6 of stimulation based on follicular development in a GnRHantagonist protocol. The patients were up to 40 years of age and had regular menstrual cyclespresumed to be ovulatory. Single blastocyst transfer on day 5 was compulsory with the exception ofpatients 38-40 years in whom double blastocyst transfer was performed if no good-quality blastocystswere available. The two co-primary endpoints were ongoing pregnancy rate and ongoing implantationrate in the fresh cycle, defined as at least one intrauterine viable fetus 10-11 weeks after transfer andnumber of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocyststransferred, respectively.

The trial demonstrated that REKOVELLE was at least as effective as follitropin alfa in terms ofongoing pregnancy rate and ongoing implantation rate, as shown in Table 3.

Table 3 Ongoing pregnancy rate and ongoing implantation rate in ESTHER-1 trial

REKOVELLE in an Follitropin alfa Difference [95% CI]individualised dosingregimen(N=665) (N=661)

Ongoing pregnancy rate 30.7% 31.6% -0.9% [-5.9%; 4.1%]

Ongoing implantation rate 35.2% 35.8% -0.6% [-6.1%; 4.8%]

Population: all randomised and exposed

The impact of the AMH-based dosing regimen of REKOVELLE was also assessed in secondaryendpoints, such as ovarian response and OHSS risk management.

In the overall trial population, the mean number of oocytes retrieved was 10.0 ± 5.6 with

REKOVELLE (N=636) in the individualised dosing regimen and 10.4 ± 6.5 with follitropin alfa(N=643) at a starting dose of 150 IU followed by dose adjustments.

Among patients with AMH ≥15 pmol/L, the ovarian response with REKOVELLE (N=355) andfollitropin alfa (N=353), respectively, was as follows: mean number of oocytes retrieved 11.6 ± 5.9and 13.3 ± 6.9, and proportion of patients with ≥20 oocytes 10.1% (36/355) and 15.6% (55/353).

In ovulatory patients with polycystic ovaries undergoing a GnRH antagonist cycle, the incidence ofearly moderate/severe OHSS and/or preventive interventions for early OHSS was 7.7% with

REKOVELLE and 26.7% with follitropin alfa.

In a controlled trial evaluating the ovarian response with individualised REKOVELLE dosing inpatients with AMH ≤35 pmol/L, the mean number of oocytes was 11.1 ± 5.9 in a GnRH agonist cycle(N=202) compared to 9.6 ± 5.5 in a GnRH antagonist cycle (N=204), and the mean duration ofstimulation with REKOVELLE was 10.4 ± 1.9 days in a GnRH agonist cycle compared to 8.8 ±1.8 days in a GnRH antagonist cycle.

Safety - immunogenicity

Anti-FSH antibodies were measured pre-dosing and post-dosing in patients undergoing up to threerepeated treatment cycles with REKOVELLE (665 patients in cycle 1 in the ESTHER-1 trial as wellas 252 patients in cycle 2 and 95 patients in cycle 3 in the ESTHER-2 trial). The incidence of anti-FSHantibodies after treatment with REKOVELLE was 1.1% in cycle 1, 0.8% in cycle 2 and 1.1% incycle 3. These rates were similar to the incidence of pre-existing anti-FSH antibodies before exposureto REKOVELLE in cycle 1 which was 1.4%, and comparable to the incidences of anti-FSH antibodiesafter treatment with follitropin alfa. In all patients with anti-FSH antibodies, titres were undetectableor very low and without neutralising capacity. Repeated treatment with REKOVELLE of patients withpre-existing or treatment-induced anti-FSH antibodies did not increase the antibody titre, was notassociated with decreased ovarian response, and did not induce immune-related adverse events.

Clinical trial experience with REKOVELLE in the long GnRH agonist protocol is limited.

The pharmacokinetic profile of follitropin delta has been investigated in healthy female subjects and in

IVF/ICSI patients undergoing COS. Following repeated daily subcutaneous administrations,

REKOVELLE reaches steady-state within 6 to 7 days with a threefold higher concentration comparedwith the concentration after the first dose. Circulating levels of follitropin delta are inversely related tothe body weight, which supports individualised dosing based on body weight. Follitropin delta leads togreater exposure than follitropin alfa.

After daily subcutaneous administration of REKOVELLE, the time to maximum serum concentrationis 10 hours. The absolute bioavailability is about 64%.

The apparent volume of distribution is about 25 L after subcutaneous administration and the volume ofdistribution at steady state is 9 L after intravenous administration. Within the therapeutic dose range,exposure to follitropin delta increases proportionally with the dose.

Following subcutaneous administration, the apparent clearance of follitropin delta is 0.6 L/h and theclearance after intravenous is 0.3 L/h. The terminal elimination half-life after single subcutaneousadministration is 40 hours and after multiple subcutaneous administration is 28 hours. The apparentclearance for follitropin delta is low, i.e. 0.6 L/h after multiple subcutaneous administration, leading tohigh exposure. Follitropin delta is expected to be eliminated similarly to other follitropins, i.e. mainlyby the kidneys. The fraction of follitropin delta excreted unchanged in the urine was estimated to 9%.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity and local tolerance. The overdose of follitropin delta resulted inpharmacological or exaggerated pharmacological actions. Follitropin delta had a negative effect onfertility and early embryonic development in rats when administered in doses ≥0.8 micrograms/kg/daywhich is above the recommended maximal dose in humans. The relevance of these findings for theclinical use of REKOVELLE is limited.

Phenol

Polysorbate 20

L-methionine

Sodium sulphate decahydrate

Disodium phosphate dodecahydrate

Phosphoric acid, concentrated (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

Water for injections

Not applicable.

3 years

In use: 28 days when stored at or below 25 °C.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

REKOVELLE may be removed from the refrigerator, without being refrigerated again, and stored ator below 25 °C for up to 3 months including the period after first use. It must be discarded afterwards.

For storage conditions after first use of the medicinal product, see section 6.3.

REKOVELLE 12 micrograms/0.36 mL solution for injection3 mL multidose cartridge (Type I glass) with a plunger (halobutyl rubber) and a crimp cap(aluminium) with an inlay (rubber). Each cartridge contains 0.36 mL of solution.

Pack size of 1 pre-filled pen and 3 injection needles (stainless steel).

REKOVELLE 36 micrograms/1.08 mL solution for injection3 mL multidose cartridge (Type I glass) with a plunger (halobutyl rubber) and a crimp cap(aluminium) with an inlay (rubber). Each cartridge contains 1.08 mL of solution.

Pack size of 1 pre-filled pen and 9 injection needles (stainless steel).

REKOVELLE 72 micrograms/2.16 mL solution for injection3 mL multidose cartridge (Type I glass) with a plunger (halobutyl rubber) and a crimp cap(aluminium) with an inlay (rubber). Each cartridge contains 2.16 mL of solution.

Pack size of 1 pre-filled pen and 15 injection needles (stainless steel).

The solution should not be administered if it contains particles or is not clear.

The instructions for use of the pen must be followed. Discard used needles immediately after injection.

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

Ferring Pharmaceuticals A/S

Amager Strandvej 4052770 Kastrup

Denmark

EU/1/16/1150/004

EU/1/16/1150/005

EU/1/16/1150/006

Date of first authorisation: 12 December 2016

Date of latest renewal: 16 July 2021

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

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