Rekovelle (Ferring, 12 mcg, 36 mcg, 72 mcg) Product Monograph

RECENT MAJOR LABEL CHANGES

DOSAGE AND ADMINISTRATION APR 18, 2019

DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING APR 18, 2019

PATIENT MEDICATION INFORMATION APR 18, 2019

DOSAGE AND ADMINISTRATION JUL 6, 2023

DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING JUL 6, 2023

TABLE OF CONTENTS

RECENT MAJOR LABEL CHANGES ......................................................................................2

TABLE OF CONTENTS ..............................................................................................................2

PART I: HEALTH PROFESSIONAL INFORMATION ............................................................4

1 INDICATIONS....................................................................................................................4

1.1 Pediatrics ....................................................................................................................4

1.2 Geriatrics ....................................................................................................................4

2 CONTRAINDICATIONS ..................................................................................................4

4 DOSAGE AND ADMINISTRATION ...............................................................................5

4.1 Dosing Considerations ...............................................................................................5

4.2 Recommended Dose and Dosage Adjustment ...........................................................5

4.4 Administration ...........................................................................................................6

4.5 Missed Dose ...............................................................................................................7

5 OVERDOSAGE .................................................................................................................7

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................7

7 WARNINGS AND PRECAUTIONS ...............................................................................8

7.1 Special Populations ..................................................................................................11

7.1.1 Pregnant Women ................................................................................................. 11

7.1.2 Breast-feeding ..................................................................................................... 11

7.1.3 Pediatrics ............................................................................................................. 11

7.1.4 Geriatrics ............................................................................................................. 11

8 ADVERSE REACTIONS................................................................................................11

8.1 Adverse Reaction Overview ....................................................................................11

8.2 Clinical Trial Adverse Reactions .............................................................................11

8.3 Less Common Clinical Trial Adverse Reactions .....................................................13

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ...............................................................................................................13

8.5 Post-Market Adverse Reactions ...............................................................................13

9 DRUG INTERACTIONS .................................................................................................14

9.2 Drug Interactions Overview .....................................................................................14

9.3 Drug-Behavioural Interactions.................................................................................14

9.4 Drug-Drug Interactions ............................................................................................14

9.5 Drug-Food Interactions ............................................................................................14

9.6 Drug-Herb Interactions ............................................................................................14

9.7 Drug-laboratory test Interactions .............................................................................14

10 CLINICAL PHARMACOLOGY .....................................................................................14

10.1 Mechanism of Action ...........................................................................................14

10.2 Pharmacodynamics...............................................................................................15

10.3 Pharmacokinetics .................................................................................................15

11 STORAGE, STABILITY AND DISPOSAL..................................................................16

12 SPECIAL HANDLING INSTRUCTIONS .....................................................................16

PART II: SCIENTIFIC INFORMATION ...................................................................................17

13 PHARMACEUTICAL INFORMATION ........................................................................17

14 CLINICAL TRIALS .........................................................................................................18

14.1 Clinical Trials by Indication .................................................................................18

15 MICROBIOLOGY ............................................................................................................19

16 NON-CLINICAL TOXICOLOGY ...................................................................................19

PATIENT MEDICATION INFORMATION ...............................................................................20

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

REKOVELLE (follitropin delta injection) is indicated for controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART) such as an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle.

Selection of patients

Before treatment with Rekovelle is initiated, a thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy.

Primary ovarian failure should be excluded by the determination of gonadotropin levels.

Appropriate evaluation should be performed to exclude pregnancy.

Patients in late reproductive life have a greater predisposition to endometrial carcinoma.

A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting Rekovelle therapy.

Evaluation of the partner’s fertility potential should be included in the initial evaluation.

The product should be used under the supervision of a qualified health professional who is experienced in the use of fertility treatments and in the management of ovarian hyperstimulation syndrome (OHSS), which is the most critical safety concern associated with the use of gonadotropin preparations. Appropriate management of therapy and complications is only possible when adequate diagnostic and treatment facilities are readily available.

1.1 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (>65 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

2 CONTRAINDICATIONS

Rekovelle is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

• Tumours of the hypothalamus or pituitary gland
• Ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome
• Gynecological hemorrhages of unknown etiology
• Ovarian, uterine or mammary carcinoma
• Pregnancy and lactation

Rekovelle must not be used when an effective response cannot be obtained, such as:

• Primary ovarian failure
• Malformations of sexual organs incompatible with pregnancy
• Fibroid tumours of the uterus incompatible with pregnancy

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

The dosing of Rekovelle (follitropin delta injection) is individualized for each patient to obtain an ovarian response with favorable safety/efficacy profile. Rekovelle is dosed in micrograms (mcg) and not in international units (IU) of biological activity. The dosing regimen is specific for Rekovelle and the microgram dose cannot be applied to other gonadotropins.

Treatment with Rekovelle should be initiated under the supervision of a physician experienced in the treatment of fertility problems.

Rekovelle in prefilled cartridges is intended for subcutaneous administration and is designed to be used in conjunction with the Rekovelle injection pen.

Rekovelle in prefilled pens is intended for subcutaneous administration.

4.2 Recommended Dose and Dosage Adjustment

For the first treatment cycle, the individual daily dose will be determined on the basis of the woman’s serum anti-Müllerian hormone (AMH) concentration and body weight. The dose should be based on a recent determination of AMH (i.e. within the last 12 months) measured by the following diagnostic test ELECSYS AMH Plus immunoassay from Roche (see 7 WARNING AND PRECAUTIONS: Monitoring and Laboratory Tests).

For calculation of the Rekovelle dose, the body weight is to be measured without shoes and coat, just prior to start of stimulation.

The individual daily dose is to be maintained throughout the stimulation period.

For the first treatment cycle, the daily dose is 12 mcg for women with AMH <15 pmol/L, irrespective of body weight.

For women with AMH ≥15 pmol/L the daily dose decreases from 0.19 to 0.10 micrograms/kg by increasing AMH concentration (see Table 1). The dose is to be rounded off to the nearest 0.33 mcg to match the dosing scale on the injection pen.

The maximum daily dose for the first treatment cycle is 12 micrograms.

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

Table 1. Calculation of daily dose based on AMH concentration

Treatment with Rekovelle should be initiated day 2 or 3 after start of menstrual bleeding, and continue until adequate follicular development has been achieved as assessed by monitoring with ultrasound alone or in combination with measurement of serum estradiol levels. Adequate follicular development is achieved on average by the ninth day of treatment (range 5 to 20 days). As soon as ≥3 follicles ≥17 mm are observed, a single injection of 250 mcg recombinant human chorionic gonadotropin (hCG) or 5,000 IU hCG is administered to induce final follicular maturation. In patients with excessive ovarian response of >25 follicles with a diameter ≥12 mm, triggering of final follicular maturation should not be performed and the cycle cancelled.

For subsequent treatment cycles, the daily dose of Rekovelle should be maintained or modified according to the patient’s ovarian response in the previous cycle. If the patient had adequate ovarian response in the previous cycle without developing OHSS, the same daily dose of Rekovelle should be used. In case of ovarian hypo-response in the previous cycle, the daily dose of Rekovelle in the subsequent cycle may be increased by 25%, according to the extent of response observed. There is limited data regarding subsequent use of Rekovelle in patients who demonstrated ovarian hyper-response or developed OHSS. The management of these patients should be based on physician discretion. The maximum daily dose is 24 micrograms.

4.4 Administration

Rekovelle in a prefilled pen is intended for subcutaneous administration, preferably in the abdominal wall.

Treatment with Rekovelle should be initiated under the supervision of a physician experienced in the treatment of fertility problems. Patients must be educated on how to use the Rekovelle prefilled pen and to perform injections.

For instructions on administration with the Rekovelle prefilled pen, see “Instructions for Use”.

4.5 Missed Dose

For patients who miss a dose, it is not recommended to double the next dose. The patients should be reminded to contact the physician monitoring their treatment.

5 OVERDOSAGE

The effect of an overdose is unknown, nevertheless, there is a risk that ovarian hyperstimulation syndrome (OHSS) may occur.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Rekovelle (follitropin delta injection) is a sterile solution for subcutaneous injection with a integrated non-replaceable 3 mL cartridge (Type I glass) with a plunger (bromobutyl rubber) and an aluminium crimp cap with a rubber inlay.

Table 2– Dosage Forms, Strengths, Composition and Packaging

Rekovelle contains 33.3 mcg/mL follitropin delta. The other ingredients are disodium hydrogen, L-methionine, phosphate dodecahydrate, phenol, phosphoric acid, polysorbate 20, sodium sulfate decahydrate, sodium hydroxide and water for injections.

Prefilled pens are available in three strengths:

12.0 mcg of follitropin delta in 0.36mL including 1 pen with 3 needles

36.0 mcg of follitropin delta in 1.08mL including 1 pen with 9 needles

72.0 mcg of follitropin delta in 2.16mL including 1 pen with 15 needles

7 WARNINGS AND PRECAUTIONS

General

Careful attention should be given to diagnosis in candidates for Rekovelle (follitropin delta injection) therapy (see 1 INDICATIONS: Selection of Patients).

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

Carcinogenesis and Mutagenesis

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.

No genotoxicity studies and carcinogenicity studies have been conducted, since FSH is an endogenous protein hormone.

Cardiovascular

Thromboembolic events

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

Hepatic/Biliary/Pancreatic

Safety, efficacy and pharmacokinetics of Rekovelle in patients with hepatic impairment have not been established.

Monitoring and Laboratory Tests

Serum anti-Müllerian hormone (AMH) concentration, which is a biomarker of ovarian response to gonadotropins, should be measured prior to treatment, to determine the initial dose. The dose should be based on a recent determination of AMH (i.e. within the last 12 months) measured by the following diagnostic test from Roche: Elecsys^® AMH immunoassay.

Follicular development during treatment with Rekovelle should be assessed by monitoring with ultrasound alone or in combination with measurement of serum estradiol levels. Adequate follicular development is achieved on average by the ninth day of treatment (range 5 to 20 days).

Renal

Safety, efficacy and pharmacokinetics of Rekovelle in patients with renal impairment have not been established.

Respiratory

Serious pulmonary conditions (e.g. atelectasis, acute respiratory distress syndrome and exacerbation of asthma) have been reported following gonadotropin therapy. No severe respiratory adverse reactions were observed in clinical studies with Rekovelle.

Reproductive health

Gonadotropin therapy requires time commitment by physicians and supportive healthcare professionals, as well as the availability of appropriate monitoring facilities (see 7 WARNING AND PRECAUTIONS: Monitoring and Laboratory Tests). Safe and effective use of Rekovelle requires monitoring of ovarian response with ultrasound alone, or in combination with measurement of serum estradiol levels, on a regular basis.

The dose of Rekovelle is individualized for each patient to obtain an ovarian response with favorable safety/efficacy profile. There may be a degree of interpatient variability in response to FSH administration, with poor response to FSH in some patients and exaggerated response in others.

Use of results obtained with assays other than the Elecsys® AMH immunoassay from Roche for Rekovelle dose determination is not recommended, as there currently is no standardization of available AMH assays.

Prior to therapy with Rekovelle, patients should be informed of the duration of treatment and monitoring of their condition that will be required. Possible adverse reactions (see 8 ADVERSE REACTIONS) should also be discussed.

Patients undergoing stimulation of follicular growth may experience ovarian enlargement and may be at risk of developing ovarian hyperstimulation syndrome (OHSS). Adherence to the Rekovelle dose and regimen of administration and careful monitoring of therapy will minimize the incidence of such events.

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

Ovarian Hyperstimulation Syndrome (OHSS)

A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in patients with polycystic ovarian syndrome and usually regresses without treatment. In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities.

It is important to stress the value of careful and frequent monitoring of follicular development in order to reduce the risk of OHSS (see 7 WARNINGS AND PRECAUTIONS: Monitoring and Laboratory Tests). The following symptoms may be observed in severe cases of OHSS: abdominal pain, discomfort and distension, severe ovarian enlargement, weight gain, dyspnea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhea. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion (see 7 WARNINGS AND PRECAUTIONS: Reproductive Health) or thromboembolic events such as pulmonary embolism, ischemic stroke or myocardial infarction (see 7 WARNINGS AND PRECAUTIONS: Cardiovascular).

Excessive ovarian response to gonadotropin treatment seldom gives rise to OHSS unless hCG is administered to trigger final follicular maturation. Furthermore, the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, in cases of ovarian hyperstimulation (see 7 WARNINGS AND PRECAUTIONS: Monitoring and Laboratory Tests) it is prudent to withhold hCG and advise the patient to refrain from coitus or to use barrier contraceptive methods for at least 4 days.

OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event. It most often occurs after hormonal treatment has been discontinued. Also, as a consequence of the hormonal changes during pregnancy, late development of OHSS can occur. Because of the risk of developing OHSS patients should be followed for at least two weeks after triggering of final follicular maturation.

Ovarian torsion

Occurrence of ovarian torsion has been reported for ART cycles. It may be associated with other risk factors 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 blood supply can be limited by early diagnosis and immediate detorsion.

Multiple pregnancy

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

Pregnancy loss

The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing controlled ovarian 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 is obtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after ART has been reported to be higher than in the general population.

Congenital malformation

The prevalence 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 multiple pregnancy.

Other medical conditions

Medical conditions that contraindicate pregnancy should also be evaluated before starting treatment with Rekovelle.

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. It is not established whether or not treatment with gonadotropins increases the risk of these tumors in infertile women.

Polycystic ovarian syndrome patients

Polycystic ovarian syndrome patients with anovulatory disorders have not been studied.

7.1 Special Populations

7.1.1 Pregnant Women

Rekovelle is contraindicated during pregnancy.

7.1.2 Breast-feeding

Rekovelle is contraindicated during lactation.

7.1.3 Pediatrics

Not indicated for use in the pediatric population.

7.1.4 Geriatrics

Not indicated for treatment in geriatric population.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The most frequently reported adverse drug reactions (≥1%) with Rekovelle in clinical phase III studies were headache, pelvic discomfort, ovarian hyperstimulation syndrome (OHSS), pelvic pain, nausea, adnexa uteri pain and fatigue.

8.2 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The pivotal clinical phase III trial with Rekovelle was ESTHER-1, conducted in women aged 18-40 years undergoing controlled ovarian stimulation for IVF/ICSI (see 14 CLINICAL TRIALS). The ESTHER-2 trial was conducted in women who did not achieve pregnancy in the ESTHER-1 trial, and the main objective was to assess the immunogenicity of Rekovelle after up to two additional treatment cycles.

In ESTHER-1, women treated with Rekovelle had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. In ESTHER-2, the

Rekovelle dose was established based on the ovarian response in the previous stimulation cycle. Within each cycle, the daily Rekovelle dose was fixed throughout the stimulation period.

Table displays the adverse drug reactions in patients treated with Rekovelle or GONAL-F in the phase III study ESTHER-1 according to system organ class and frequency.

Table 3. Adverse Drug Reactions (≥1%) in ESTHER-1 study

Table displays the adverse drug reactions in patients treated with Rekovelle or GONAL-F in the phase III study ESTHER-2 according to system organ class and frequency.

Table 4. Adverse Drug Reactions (≥1%) in ESTHER-2 study

8.3 Less Common Clinical Trial Adverse Reactions

Gastrointestinal disorders: Diarrhoea (0.6%), Vomiting (0.2%), Constipation (0.3%), Abdominal discomfort (0.2%)

Nervous system disorders: Somnolence (0.2%), Dizziness (0.4%)

Psychiatric disorders: Mood swings (0.4%)

Reproductive system and breast disorders: Vaginal hemorrhage (0.2%), Breast pain (0.2%), Breast tenderness (0.2%)

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Immunogenicity – Anti-FSH Antibodies

Anti-FSH antibodies were measured pre-dosing and post-dosing in patients undergoing up to three repeated treatment cycles with Rekovelle. Before exposure to Rekovelle, the incidence of anti-FSH antibodies was 1.4%, and after treatment with Rekovelle it was 1.1% in cycle 1, 0.8% in cycle 2 and 1.1% in cycle 3. In all patients with anti-FSH antibodies, titres were undetectable or very low and without neutralizing capacity.

8.5 Post-Market Adverse Reactions

Ovarian torsion has been reported in connection with OHSS.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

No dedicated drug-drug interaction studies have been performed.

Since Rekovelle is a protein, it is highly unlikely that Rekovelle would bind to plasma proteins or interact with the CYP450 system, and therefore no interactions with other medicinal products are anticipated. Moreover, potential clinically relevant interactions of exogenous FSH with other drugs have not been observed in the clinical studies investigating Rekovelle, nor described in the literature.

9.3 Drug-Behavioural Interactions

Rekovelle is expected to have no or negligible influence on the ability to drive and use machines.

9.4 Drug-Drug Interactions

Interactions with other drugs have not been established

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-laboratory test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Rekovelle (follitropin delta injection) stimulates ovarian follicular growth in women who do not have primary ovarian failure. Follicle stimulating hormone (FSH, follitropin), the active component of Rekovelle, is one of the key hormones regulating reproductive functions both in females and in males. In females, the ovary is the target organ, where binding of FSH to the FSH receptor triggers intracellular mechanisms that drive the hormonal and cellular events regulating the maturation of Graafian follicles and granulosa cell estrogen production.

Rekovelle has the amino acid sequence identical to the endogenous human FSH for both α and β subunits but is distinct from other recombinant FSH products (such as follitropin alfa and follitropin beta) by sialic acid pattern, isoforms, and glycosylation profiles of the FSH protein.

10.2 Pharmacodynamics

In a Phase II dose-response study in patients undergoing controlled ovarian stimulation for IVF/ICSI, 265 women randomly received one of five dose levels of Rekovelle (5.2 mcg, 6.9 mcg, 8.6 mcg, 10.3 mcg, or 12.1 mcg) or GONAL-F (150 IU) with baseline serum Anti-Müllerian hormone (AMH) levels within 5.0 - 44.9 pmol/L. Following daily subcutaneous administration of Rekovelle, at the end of stimulation, dose-related increase of follicles and the serum levels of estradiol, inhibin B and inhibin A was observed. The number of oocytes retrieved increases with the dose of Rekovelle and serum AMH concentration. The average number of oocytes retrieved was 5.2, 7.9, 9.2, 10.5, 12.2, and 10.4 for 5.2 mcg, 6.9 mcg, 8.6 mcg, 10.3 mcg and 12.1 mcg Rekovelle and 150 IU GONAL-F groups, respectively.

10.3 Pharmacokinetics

The pharmacokinetic profile of Rekovelle was investigated in healthy gonadotropin down-regulated female volunteers and in IVF/ICSI patients undergoing controlled ovarian stimulation.

Absorption:

After single subcutaneous administration of Rekovelle, the median time to maximum serum concentration (t_max) was 20 hours. After a single daily subcutaneous administration of Rekovelle for 7 days, the median t_max was 10 hours. The absolute bioavailability of Rekovelle by the SC route was approximately 64%.

Distribution:

The volume of distribution (V_ss) in healthy women following intravenous administration was about 9 L. Following daily subcutaneous administrations of Rekovelle at dose range of

5.2 – 12.1 mcg, steady-state serum levels of FSH were reached within 6 to 7 days with accumulation to a three-fold higher concentration compared with the concentration after the first dose.

Metabolism:

The metabolism and excretion of Rekovelle has not been studied.

Elimination:

In healthy women, following intravenous administration, the clearance of Rekovelle was

0.3 L/h and the elimination half-life was 24 hours. Following single subcutaneous administration, the apparent clearance of Rekovelle was 0.4 L/h and the elimination half-life was 40 hours. Following daily subcutaneous administration, the apparent clearance of Rekovelle was 0.6 L/h and the elimination half-life was 28 hours.

In IVF/ICSI patients, following daily subcutaneous administration of Rekovelle (dose range 5.2 mcg -12.1 mcg), the apparent clearance of FSH was 0.6 L/h, based on population PK analysis.

Special Populations and Conditions

No studies in special populations have been performed. The pharmacokinetics of Rekovelle in patients with renal or hepatic insufficiency has not been established.

11 STORAGE, STABILITY AND DISPOSAL

Store refrigerated at 2°C to 8°C, until expiry. Protect from exposure to light. Do not freeze.

Within the shelf life, Rekovelle may be removed from the refrigerator, and stored at or below 25°C for up to 3 months including the 28 day in-use period. After this period, do not refrigerate again and discard the product.

After first injection, store Rekovelle at or below 25°C for up to 28 days. After this period, discard any unused material.

Keep in a safe place and out of the reach and sight of children.

12 SPECIAL HANDLING INSTRUCTIONS

Rekovelle (follitropin delta injection) should not be administered if it contains particles or is not clear.

Any unused solution must be discarded not later than 28 days after first injection.

Discard used needles immediately after injection in appropriate safety containers.

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

The instructions for using the Rekovelle 12 mcg, 36 mcg and 72 mcg prefilled pens must be followed.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: follitropin delta

Chemical name: recombinant human follicle-stimulating hormone (FSH)

Molecular formula and molecular mass:

The molecular formula for the α and β subunits are:

α subunit: C437H682N122O134S13

β subunit: C538H833N145O171S13

Molecular mass:

The average molecular weights of the glycosylated α and β subunits determined by

MALDI-ToF-MS are approximately 15,200 and 18,500 Daltons, respectively. Thus, approximately 40 % of the total molecular weight of the molecule is due to glycosylation.

Structural formula:

Follicle stimulating hormone is a heterodimer composed of one α and one β subunit. The amino acid sequence (black) and glycosylation sites (bold underline italic) of the mature α and β subunits are shown below:

FSH subunit α

1 APDVQDCPEC TLQENPFFSQ PGAPILQCMG CCFSRAYPTP LRSKKTMLVQ KNVTSESTCC

61 VAKSYNRVTV MGGFKVENHT ACHCSTCYYH KS

FSH subunit β

1 NSCELTNITI AIEKEECRFC ISINTTWCAG YCYTRDLVYK DPARPKIQKT CTFKELVYET

61 VRVPGCAHHA DSLYTYPVAT QCHCGKCDSD STDCTVRGLG PSYCSFGEMK E

Product Characteristics:

Rekovelle (follitropin delta injection) is a recombinant human FSH produced in a human cell line by recombinant DNA technology. The amino acid sequences of the two FSH subunits in Rekovelle are identical to the endogenous human FSH sequences. The expressing cell line can influence the characteristics of the recombinant FSH, and differences in glycosylation profile, sialic acid pattern and isoform profile have been documented between Rekovelle and recombinant FSH products such as follitropin alfa and follitropin beta produced in Chinese hamster ovary (CHO) cell lines. Comparisons of Rekovelle versus follitropin alfa indicate that the differences in glycosylation influence both the pharmacokinetic and pharmacodynamic profile.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

The efficacy and safety of Rekovelle was assessed in a randomised, controlled, assessor-blind, parallel groups, multicentre, multinational trial (ESTHER-1: Evidence-based Stimulation Trial with Human rFSH in Europe and Rest of World) in first cycle patients aged 18-40 years undergoing controlled ovarian stimulation for IVF/ICSI following a GnRH antagonist protocol. On day 2-3 of the menstrual cycle, 1329 women were randomised in a 1:1 ratio to treatment with either Rekovelle or GONAL-F, and stimulation was initiated in 1326 women (665 with Rekovelle and 661 with GONAL-F). Randomisation was stratified by centre and according to age (<35, 35-37 and 38-40 years). Women who were randomised to Rekovelle had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily Rekovelle dose was fixed throughout the stimulation period. For women with low AMH (<15 pmol/L) the daily Rekovelle dose was 12 mcg, irrespective of body weight. For women with high AMH (≥15 pmol/L) the daily Rekovelle dose was dependent on AMH level and body weight and the maximum allowed daily dose of Rekovelle was 12 mcg. Women could be treated with Rekovelle for a maximum of 20 days, and coasting was not allowed. For women randomised to GONAL-F the starting dose was 150 IU and fixed for the first five stimulation days after which it could be adjusted by 75 IU based on the individual response. The maximum daily GONAL-F dose allowed was 450 IU. Women could be treated with GONAL-F for a maximum of 20 days, and coasting was not allowed.

The summary of the ESTHER-1 clinical study in IVF/ICSI patients is shown in Table below.

Table 5. Summary of the ESTHER-1 clinical study in IVF/ICSI patients

AMH: anti-Müllerian hormone; ESTHER: Evidence-based Stimulation Trial with Human rFSH in Europe and Rest of World;

ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; IU: international units, SC: subcutaneous

The study enrolled women who had been diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or had partners diagnosed with male factor infertility, and were considered eligible for IVF or ICSI.

One of the primary endpoints was ongoing pregnancy rate, defined as at least one intrauterine viable fetus 10-11 weeks after transfer.

There is no clinical trial experience with Rekovelle in the long GnRH agonist protocol.

Study results

Efficacy

ESTHER-1 study

The study demonstrated that Rekovelle was non-inferior to GONAL-F in terms of ongoing pregnancy rate, as shown in Table .

Table 6. Ongoing pregnancy rate in ESTHER-1 study in patients undergoing controlled ovarian stimulation for IVF/ICSI (mITT population)

The overall average number of oocytes retrieved among the women who underwent triggering of final follicular maturation was 9.6 for patients treated with Rekovelle and 10.1 for patients treated with GONAL-F. The proportion of patients with 8-14 oocytes retrieved was 41.4% with Rekovelle and 37.4% with GONAL-F.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and local tolerance. The overdose of follitropin delta resulted in exaggerated pharmacological actions. When administered in doses ≥0.8 micrograms/kg/day which is above the recommended maximal dose in humans, Follitropin delta had a negative effect on fertility and early embryonic development in rats.