Follitropin Beta

In adult females:

Puregon is indicated for the treatment of female infertility in the following clinical situations: • Anovulation (including polycystic ovarian syndrome, PCOS) in women who have been unresponsive to treatment with clomifene citrate.

g. in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)]. In adult males: • Deficient spermatogenesis due to hypogonadotrophic hypogonadism. 3

Treatment with Puregon should be initiated under the supervision of a physician experienced in the treatment of fertility problems. The first injection with Puregon should be performed under direct medical supervision. Posology Dosage in the female There are great inter- and intra-individual variations in the response of the ovaries to exogenous gonadotrophins.

This makes it impossible to set a uniform dosage scheme. The dosage should, therefore, be adjusted individually depending on the ovarian response. This requires ultrasound assessment of follicular development. The concurrent determination of serum oestradiol levels may also be useful.

When using the pen-injector, it should be realised that the pen is a precision device which accurately delivers the dose to which it is set. It was shown that on average an 18% higher amount of FSH is given with the pen compared with a conventional syringe.

This may be of particular relevance when switching between the pen-injector and a conventional syringe within one treatment cycle. Especially when switching from a syringe to the pen, small dose adjustments may be needed to prevent too high a dose being given.

1). Clinical experience with Puregon is based on up to three treatment cycles in both indications. Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter.

4 • Anovulation A sequential treatment scheme is recommended starting with daily administration of 50 IU Puregon. The starting dose is maintained for at least seven days. If there is no ovarian response, the daily dose is then gradually increased until follicle growth and/or plasma oestradiol levels indicate an adequate pharmacodynamic response.

A daily increase of oestradiol levels of 40-100% is considered to be optimal. The daily dose is then maintained until pre-ovulatory conditions are reached. Pre-ovulatory conditions are reached when there is ultrasonographic evidence of a dominant follicle of at least 18 mm in diameter and/or when plasma oestradiol levels of 300-900 picograms/mL (1,000-3,000 pmol/L) are attained.

Usually, 7 to 14 days of treatment is sufficient to reach this state. The administration of Puregon is then discontinued and ovulation can be induced by administering human chorionic gonadotrophin (hCG). e. more than a daily doubling for oestradiol for two or three consecutive days, the daily dose should be decreased.

Since follicles of over 14 mm may lead to pregnancies, multiple pre-ovulatory follicles exceeding 14 mm carry the risk of multiple gestations. In that case hCG should be withheld and pregnancy should be avoided to prevent multiple gestations.

• Controlled ovarian hyperstimulation in medically assisted reproduction programs Various stimulation protocols are applied. A starting dose of 100-225 IU is recommended for at least the first four days. Thereafter, the dose may be adjusted individually, based upon ovarian response.

In clinical studies it was shown that maintenance dosages ranging from 75-375 IU for six to twelve days are sufficient, although longer treatment may be necessary. Puregon can be given either alone, or, to prevent premature luteinisation, in combination with a GnRH agonist or antagonist.

When using a GnRH agonist, a higher total treatment dose of Puregon may be required to achieve an adequate follicular response. Ovarian response is monitored by ultrasound assessment. The concurrent determination of serum oestradiol levels may also be useful.

When ultrasound assessment indicates the presence of at least three follicles of 16-20 mm, and there is evidence of a good oestradiol response (plasma levels of about 300-400 picograms/mL (1,000-1,300 pmol/L) for each follicle with a diameter greater than 18 mm), the final phase of maturation of the follicles is induced by administration of hCG.

Oocyte retrieval is performed 34-35 hours later. Dosage in the male Puregon should be given at a dosage of 450 IU/week, preferably divided in 3 dosages of 150 IU, concomitantly with hCG. Treatment with Puregon and hCG should be continued for at least 3 to 4 months before any improvement in spermatogenesis can be expected.

To assess the response, semen analysis is recommended 4 to 6 months after the beginning of treatment. If a patient has not responded after this period, the combination therapy may be continued; current clinical experience indicates that treatment for up to 18 months or longer may be necessary to achieve spermatogenesis.

Paediatric population There is no relevant use of Puregon in the paediatric population for the approved indication. Method of administration Puregon solution for injection in cartridges has been developed for use in the Puregon Pen and should be administered subcutaneously.

The injection site should be alternated to prevent lipoatrophy. Using the pen, injection of Puregon can be carried out by the patient, provided that proper instructions are given by the physician. Before using the pen, the instructions for use must be read carefully.

Clinical use of Puregon by the intramuscular or subcutaneous routes may lead to local reactions at the site of injection (3% of all patients treated). The majority of these local reactions are mild and transient in nature. 2% of all patients treated with follitropin beta).

Cases of anaphylactic reactions (including those requiring hospitalisation) have been reported in the post-marketing setting. 4). Adverse 8 reactions related to this syndrome include pelvic pain and/or congestion, abdominal pain and/or distension, breast complaints and ovarian enlargement.

The table below lists the adverse reactions with follitropin beta reported in clinical trials and post- marketing surveillance in females, according to system organ class and frequency; common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and not known (cannot be estimated from available data).

SOC Frequency Adverse reaction Immune system disorders Not known Anaphylactic reactions Nervous system disorders Common Headache Gastrointestinal disorders Common Abdominal distension Abdominal pain Uncommon Abdominal discomfort Constipation Diarrhoea Nausea Reproductive system and breast disorders Common OHSS Pelvic pain Uncommon Breast complaints1 Metrorrhagia Ovarian cyst Ovarian enlargement Ovarian torsion Uterine enlargement Vaginal haemorrhage General disorders and administration site conditions Common Injection site reaction2 Uncommon Generalised hypersensitivity reaction3 1.

Breast complaints include tenderness, pain and/or engorgement and nipple pain. 2. Local reactions at the site of injection include: bruising, pain, redness, swelling and itching. 3. Generalised hypersensitivity reaction include erythema, urticaria, rash and pruritus.

In addition, ectopic pregnancy, miscarriage 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 follitropin beta /hCG therapy as with other gonadotrophins.

Treatment of males:

The table below lists the adverse reactions with follitropin beta reported in a clinical trial in males (30 patients dosed) and post-marketing surveillance, according to system organ class and frequency; common (≥ 1/100 to < 1/10) and not known (cannot be estimated from available data).

SOC Frequency1 Adverse reaction Immune system disorders Not known Anaphylactic reactions Nervous system disorders Common Headache Skin and subcutaneous tissue disorders Common Acne Rash Reproductive system and breast disorders Common Epididymal cyst Gynaecomastia General disorders and administration site conditions Common Injection site reaction2 1.

Adverse reactions that are reported only once are listed as common because a single report raises the frequency above 1%. 2. Local reactions at the site of injection include induration and pain. 9 Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

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

1. • Tumours of the ovary, breast, uterus, testis, pituitary or hypothalamus. • Primary gonadal failure. 5 Additionally for females • Undiagnosed vaginal bleeding. • Ovarian cysts or enlarged ovaries, not related to polycystic ovarian syndrome (PCOS).

• Malformations of the reproductive organs incompatible with pregnancy. • Fibroid tumours of the uterus incompatible with pregnancy.

In female:

PUREGON® (follitropin beta) is indicated for: • Development of multiple follicles in ovulatory patients participating in an Assisted Reproduction Technology (ART) program. • Induction of ovulation and pregnancy in anovulatory infertile females in whom the cause of infertility is functional and not due to primary ovarian failure.

In male:

PUREGON® is indicated for: • Deficient spermatogenesis due to hypogonadotrophic hypogonadism. 1 Pediatrics The safety and efficacy of PUREGON® has not been established in women under the age of 18 years. Use of this product before menarche is not indicated.

2 Geriatrics PUREGON® is not indicated in postmenopausal women.

4 Administration 02/2024 TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed. RECENT MAJOR LABEL CHANGES .............................................................................................

2 TABLE OF CONTENTS ............................................................................................................... 2 PART I: HEALTH PROFESSIONAL INFORMATION .......................................................................

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

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

4 4 DOSAGE AND ADMINISTRATION .................................................................................. 1 Dosing Considerations ............................................................................................. 2 Recommended Dose and Dosage Adjustment ........................................................

4 Administration ......................................................................................................... 5 Missed Dose ............................................................................................................

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

1 Adverse Reaction Overview The most frequently reported adverse drug reactions (≥1%) with Puregon in clinical trials were ovarian hyperstimulation syndrome (OHSS), ectopic pregnancy, vaginal hemorrhage, miscarriage, abdominal pain and injection site pain.

2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, 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 may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

In Females:

The following adverse events, listed by body system, have been reported in clinical studies evaluating the efficacy and safety of PUREGON® in women. 2 † Related: definitely, probably, or possibly related to the study drug In Males: The safety of PUREGON® was examined in a clinical trial that enrolled 49 male patients for the indication of spermatogenesis, of whom 30 received PUREGON®.

Two subjects in the treatment period each reported one serious event, which were judged not related to study drug by the investigator. The events involved are pilonidal cyst and hemorrhoids. Both subjects recovered from these adverse events.

In the PUREGON® treatment phase, no patients discontinued due to an adverse event. In total, 21 patients in the treatment phase experienced at least one adverse event. Ten were reported by the investigator to be possibly related to study drug.

These include: two cases of acne, two cases of injection site bruising, two cases of injection site pain, and single cases of varicose veins, gynecomastia, injection site induration, and dermoid cyst. 3 Less Common Clinical Trial Adverse Reactions In Females: Body as a Whole, General Disorders: back pain, feeling unwell, influenza-like symptoms, face edema, lumbar pain, pain, sepsis, tooth disorder, Gastrointestinal: bloating, constipation, gastroesophageal reflux, vomiting, increased bilirubin, swollen abdomen.

Nervous System: hyperemesis, hot flashes, syncope Reproductive Disorder Women: premature labour, menorrhagia, ovarian disorder, vaginal discharge, vulvovaginitis, genital infection, genital herpes, hydatidiform mole. Respiratory System: dyspnea, otitis media Skin and Appendages: eczema, itching, rash, hematoma, abscess, Herpes zoster.

PUREGON® (follitropin beta) Page 18 of 39 Urinary System: dysuria, cystitis, frequent micturition. 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings In Females: Post-treatment sera were analysed following three treatment cycles and no evidence of induction of anti-FSH or anti-CHO cell-derived […]

For males and females: • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING. • Tumours of the ovary, breast, uterus, testis, pituitary gland or hypothalamus.

• A high circulating FSH level indicating primary gonadal failure. For females: • Patients who exhibit uncontrolled thyroid or adrenal dysfunction. • Patients who are pregnant or are breast-feeding. • Patients who exhibit heavy or irregular vaginal bleeding of undetermined origin.

• Patients who exhibit ovarian cysts or enlargement not due to polycystic ovary syndrome (PCOS). g. malformation of reproductive organs or PUREGON® (follitropin beta) Page 5 of 39 fibroid tumours of the uterus). PUREGON® is contraindicated in children.