Puregon (Organon Canada) Product Monograph

RECENT MAJOR LABEL CHANGES

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 ................................................................................................................ 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................................................................................................ 12

7.1.1 Pregnant Women ............................................................................................ 12

7.1.2 Breast-feeding ................................................................................................. 12

7.1.3 Pediatrics ......................................................................................................... 13

8 ADVERSE REACTIONS ................................................................................................. 13

8.1 Adverse Reaction Overview ................................................................................... 13

8.2 Clinical Trial Adverse Reactions ............................................................................. 13

8.3 Less Common Clinical Trial Adverse Reactions ...................................................... 17

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................ 18

8.5 Post-Market Adverse Reactions ............................................................................ 18

9 DRUG INTERACTIONS ................................................................................................. 20

9.2 Drug Interactions Overview ................................................................................... 20

9.5 Drug-Food Interactions .......................................................................................... 20

9.6 Drug-Herb Interactions .......................................................................................... 20

9.7 Drug-Laboratory Test Interactions ......................................................................... 20

10 CLINICAL PHARMACOLOGY ........................................................................................ 20

10.1 Mechanism of Action ....................................................................................... 20

10.2 Pharmacodynamics ......................................................................................... 20

10.3 Pharmacokinetics ............................................................................................ 21

11 STORAGE, STABILITY AND DISPOSAL .......................................................................... 23

12 SPECIAL HANDLING INSTRUCTIONS ............................................................................ 23

PART II: SCIENTIFIC INFORMATION ........................................................................................ 24

13 PHARMACEUTICAL INFORMATION ............................................................................. 24

14 CLINICAL TRIALS ......................................................................................................... 24

14.1 Clinical Trials by Indication .............................................................................. 24

15 MICROBIOLOGY ......................................................................................................... 31

16 NON-CLINICAL TOXICOLOGY ...................................................................................... 31

PATIENT MEDICATION INFORMATION ................................................................................... 32

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

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.

1.1 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.

1.2 Geriatrics

PUREGON^® is not indicated in postmenopausal women.

2 CONTRAINDICATIONS

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).

• Conditions incompatible with pregnancy (e.g. malformation of reproductive organs or

PUREGON^® is contraindicated in children.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

PUREGON^® may be given alone, or in combination with clomiphene citrate to stimulate the endogenous production of gonadotropins or in combination with a GnRH agonist to prevent premature luteinisation (see 9 DRUG INTERACTIONS).

4.2 Recommended Dose and Dosage Adjustment

In Female:

There are great inter- and intra-individual variations in the response of the ovaries to exogenous gonadotropins. 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 estradiol levels may also be useful.

In comparative clinical studies with PUREGON^® and urinary FSH it was shown that PUREGON^® is more effective than urinary FSH in terms of a lower total dose and a shorter treatment period needed to achieve pre-ovulatory conditions. Therefore, it is considered appropriate to give a lower dosage of PUREGON^® than generally used for urinary FSH, not only in order to optimize follicular development but also to reduce the risk of unwanted ovarian hyperstimulation.

After pituitary desensitization induced by GnRH agonist a higher dose of PUREGON^® may be necessary to achieve an adequate follicular response. 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.

Ovulation Induction:

A sequential treatment scheme is recommended starting with daily administration of 50 IU PUREGON^®. The starting dose is maintained for at least 7 days. If there is no ovarian response, the daily dose is then gradually increased until follicle growth and/or plasma estradiol levels indicate an adequate pharmacodynamic response. A daily increase of estradiol 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 estradiol levels of 300-900 picograms/ml (1000-3000 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 gonadotropin (hCG).

If the number of responding follicles is too high or estradiol levels increase too rapidly, i.e. more than a daily doubling for estradiol for 2 or 3 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 in order to prevent multiple gestations.

Controlled Ovarian Hyperstimulation in Medically Assisted Reproduction Programs:

The dosage regimen may vary according to the physician's preference or the patient's response. In general, stimulation of follicular growth is achieved by starting with daily s.c. or i.m administration (see 4.3 Administration) of 150-225 IU PUREGON^® for a period of 4 days. Thereafter, the dose may be adjusted according to the individual’s ovarian response.

Maturation of follicles is monitored by pelvic ultrasound assessment. The concurrent determination of serum estradiol levels may also be useful. In responding patients, daily maintenance doses of 75 to 300 IU for 6 to 12 days are usually sufficient, although longer treatment may be necessary. The maximum individualized daily dose safely used in clinical studies was 450 IU. There is limited experience with higher doses. When ultrasonic evaluation indicates the presence of at least three follicles of sufficient size and there is evidence of a good estradiol response, the final phase of maturation of the follicles is induced by administration of hCG. HCG is given 30-40 hours after the last administration of PUREGON^® in a dose of 5000-10000 IU.

After embryo transfer, up to three repeat injections of 1000 to 3000 IU hCG each, may be given within the following 9 days to provide luteal phase support.

In Male:

PUREGON^® should be given at a dosage of 450 IU/week, preferably divided in 3 dosages of 150 IU (two doses of 225 IU per week is considered to be equivalent) concomitantly with hCG. Please note that the intramuscular route of administration of PUREGON^® in males has not been evaluated. 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. The efficacy and safety of PUREGON^® have not been established beyond a treatment period of 48 weeks. Clinical experience with other gonadotropins suggests that treatment for up to 18 months or longer may be necessary to achieve spermatogenesis.

4.4 Administration

PUREGON^® solution for injection in cartridges has been developed for use with the PUREGON PEN^® (a pen-injector) and should be administered subcutaneously. The injection site should be alternated to prevent lipoatrophy.

When using the pen-injector, it should be realized 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. Since the daily dose of PUREGON^® is determined by the patient’s individual ovarian response, the slightly higher dose delivered by the PUREGON PEN^® is unlikely to affect clinical outcome. It may however be of relevance when switching between the pen-injector and a conventional syringe within one treatment cycle. Especially when switching from a syringe to the PUREGON PEN^®, small dose adjustments may be needed to prevent too high of a dose being given.

In view of loss of the active ingredient because of priming and dead volume, the 300 IU/0.36 mL cartridge contains a minimum of 400 IU / 0.48 mL which is sufficient for a net deliverable dose of 300 IU The 600 IU/0.72 mL cartridge contains a minimum of 700 IU / 0.84mL which is sufficient for a net deliverable dose of 600 IU and the 900 IU/1.08 mL cartridge contains a minimum of 1025 IU / 1.23mL which is sufficient for a net deliverable dose of 900 IU.

The net deliverable dose of 300 IU, 600 IU and 900 IU are based upon a maximum of six 50 IU injections, six 100 IU injections and nine 100 IU injections respectively.

When more injections are given, the net total dose of active ingredient may be lowered, because each injection has to be preceded by an air shot.

The instructions for using the pen must be followed carefully.

4.5 Missed Dose

If a dose is missed or forgotten, the next dose should not be doubled and the patient should call the healthcare provider for further dosing instructions.

5 OVERDOSAGE

The acute toxicity of gonadotropin preparations has been shown to be very low. However, too high a dosage for more than one day may lead to hyperstimulation of the ovaries (see 7 WARNINGS AND PRECAUTIONS, General).

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Description

Solution for injection in cartridges is clear and colourless. The cartridge is designed to be used in conjunction with a pen injector.

Composition of Solution for Injection in Cartridges:

Solution for injection in cartridges - 833 IU/mL. Cartridges contain a minimum of 400 IU FSH activity in 0.48 mL aqueous solution which is sufficient for a net deliverable dose of 300 IU, a minimum of 700 IU FSH activity in 0.84 mL aqueous solution which is sufficient for a net deliverable dose of 600 IU or a minimum of 1025 IU FSH activity in 1.23mL which is sufficient for a net dose of 900 IU.

The net deliverable dose of 300 IU, 600 IU and 900 IU are based upon a maximum of six 50 IU injections, six 100 IU injections and nine 100 IU injections respectively.

When more injections are given, the net total dose may be lowered because each injection has to be preceded by an air shot.

Packaging:

Boxes of PUREGON^® solution for injection contain 1 cartridge of PUREGON^® and 6 (300 IU and 600 IU cartridges) or 9 (900 IU cartridges) needles to be used with the PUREGON PEN^®.

The cartridges are of colourless hydrolytic (class 1) glass, with a rubber piston and an aluminium crimp-cap with a rubber inlay.

Cartridges contain 833 IU of FSH activity per mL aqueous solution. Cartridges with a net dose of 300 IU contain a minimum of 400 IU in 0.480 mL; those of 600 IU contain a minimum of 700 IU in 0.840 mL; those of 900 IU contain a minimum of 1025 IU in 1.230 mL.

7 WARNINGS AND PRECAUTIONS

General

For males and females

PUREGON^® is a potent gonadotropic agent that is capable of causing severe adverse effects. It should be used only by physicians who are experienced in the management of fertility disorders and only when facilities for appropriate clinical and endocrinologic evaluations are available.

PUREGON^® may contain traces of streptomycin and/or neomycin. These antibiotics may cause hypersensitivity reactions in susceptible persons.

Determination of serum gonadotropin concentrations should be obtained to rule out primary gonadal failure.

For females

The presence of early pregnancy should be ruled out by a biochemical pregnancy test.

A thorough gynecologic and endocrinologic evaluation must be performed prior to treatment with PUREGON^®. These evaluations may assess uterine and tubal pathology, ovulatory cycle characteristics or an endometrial biopsy. Patients should be evaluated for hypothyroidism, adrenocortical insufficiency, hyperprolactinemia and pituitary or hypothalamic tumours, and appropriate specific treatment given.

Medical conditions that contraindicate pregnancy should be evaluated before starting treatment with PUREGON^®.

Evaluation of the fertility potential of the male sexual partner should also be performed (a semen analysis) before starting PUREGON^® therapy.

Overstimulation of the Ovary During Therapy:

To minimize the risk associated with abnormal ovarian enlargement in women receiving PUREGON^® and human chorionic gonadotropin (hCG) for the induction of ovulation and pregnancy, the drugs should be administered at the lowest possible effective dosage. Since PUREGON^® may cause ovarian enlargement and/or hyperstimulation, patients should be assessed for signs of excessive ovarian stimulation during therapy and for a 2-week post-treatment period. Careful monitoring of ovarian response by ultrasound assessment (can minimize the risk of overstimulation. The concurrent determination of serum estradiol levels may also be useful.

Abnormal Ovarian Enlargement:

Hemoperitoneum may occur from ruptured ovarian cysts. This is usually the result of sexual intercourse or a vigorous pelvic examination. Should this occur and be accompanied by bleeding to the extent that surgery is necessary, partial resection of the enlarged ovary or ovaries may be required. Intercourse should be prohibited in those patients in whom significant ovarian enlargement occurs after ovulation due to the risk of hemoperitoneum resulting from ruptured ovarian cysts.

Ovarian Hyperstimulation Syndrome:

Ovarian Hyperstimulation Syndrome (OHSS) is distinct from uncomplicated ovarian enlargement in that it rarely occurs unless hCG is administered or a pregnancy occurs. Clinical signs and symptoms of mild and moderate OHSS are abdominal pain, nausea, diarrhea, 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, dyspnea, oliguria, hematological 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 human Chorionic Gonadotropin (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 during or following treatment with PUREGON^®. 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.

Follow current clinical practice for reducing the risk of OHSS during Assisted Reproductive Technology (ART). Adherence to the recommended PUREGON^® dose and treatment regimen and careful monitoring of ovarian response is important to reduce the risk of OHSS.To monitor the risk of OHSS, ultrasound assessments of follicular development should be performed prior to treatment and at regular intervals during treatment, the concurrent determination of serum estradiol 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. Patients should also be advised not to engage in unprotected sexual intercourse.

OHSS develops rapidly within 3-4 days and generally during the 2-week period following the hCG injection. If OHSS develops, standard and appropriate management of OHSS should be implemented and followed. If severe OHSS occurs, hospitalization may be needed.

Ovarian torsion:

Ovarian torsion has been reported after treatment with gonadotropins, including PUREGON^®. Ovarian torsion 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.

Liver function test abnormalities:

Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with ovarian hyperstimulation syndrome.

Carcinogenesis and Mutagenesis

PUREGON^® displays no mutagenic potential. Carcinogenicity studies have not been performed.

Cardiovascular

Thromboembolic events

Thromboembolic events, both in association with and separate from ovarian hyperstimulation syndrome, have been reported following treatment with gonadotropins, including PUREGON^®. Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. Complications resulting from thromboembolism have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, stroke, arterial occlusion necessitating limb amputation, and (rarely) death.

In women with generally recognized risk factors for thromboembolic events, such as a personal or family history, severe obesity or thrombophilia, treatment with gonadotropins, including PUREGON^®, may further increase this risk. In these women the benefits of gonadotropin administration, including PUREGON^® need to be weighed against the risks. It should be noted, however, that pregnancy itself also carries an increased risk of thrombosis.

Driving and Operating Machinery

No effects on the ability to drive and use machines have been observed.

Reproductive Health: Female and Male Potential

Multiple Pregnancy

Multiple ovulations with resulting multiple pregnancies and births can occur with all gonadotropin treatments, including PUREGON^®. Multiple gestations, especially high order, carry an increased risk of adverse maternal (pregnancy and delivery complications) and perinatal (low birth weight, preterm birth) outcomes. For anovulatory women undergoing ovulation induction, monitoring follicular development with transvaginal ultrasonography is important for minimizing the risk of multi-fetal gestations. The concurrent determination of serum estradiol levels may also be useful. The patient and her male sexual partner should be informed of the possibility and potential risks associated with multiple births before starting treatment.

In women undergoing ART procedures, the risk of a multiple pregnancy is mainly related to the number of embryos transferred.

Other Reproductive Complications

Spontaneous abortion rates have been reported from 10 to 25% of all patients following gonadotropin treatment. Increased abortion rates are more common in women over 35 years of age, in women with polycystic ovarian disease, and are more common in the infertile couple. The increased frequency of multiple pregnancy is also associated with an increased rate of abortion.

Infertile women undergoing ART have an increased incidence of ectopic pregnancies. Early ultrasound confirmation that a pregnancy is intrauterine is therefore important.

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.

The incidence of congenital malformations in infants born after ART may be higher than after spontaneous conceptions. This is thought to be related to differences in parental characteristics (e.g., maternal age, sperm characteristics) and to the higher incidence of multiple gestations after ART. There is no current evidence that the use of gonadotropins during ART is associated with an increased risk of congenital malformations.

In Males

Evaluation of the fertility potential of the male sexual partner should also be performed (a semen analysis) before starting PUREGON^® therapy.

Patients should be evaluated for hypothyroidism, adrenocortical insufficiency, hyperprolactinemia and pituitary or hypothalamic tumors, and appropriate specific treatment given.

Elevated endogenous FSH levels in men are indicative of primary testicular failure. Such patients are unresponsive to PUREGON^®/hCG therapy.

7.1 Special Populations

7.1.1 Pregnant Women

PUREGON^® is not intended for use during pregnancy.

• teratogenic effect of recombinant FSH.

7.1.2 Breast-feeding

PUREGON® is not intended for use during lactation.

7.1.3 Pediatrics

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

8 ADVERSE REACTIONS

8.1 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.

8.2 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.

Table 2 - Incidence of Most Frequently Reported Adverse Events (AEs) in Clinical Trials

† 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.

Table 3 - Number (%) of Male Subjects with at least one AE per MedDRA Body System and Preferred term Trials: P37618 (male trial)

Note: Coded with MedDRA version 8.1

8.3 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.

Urinary System: dysuria, cystitis, frequent micturition.

8.4 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 protein antibodies were found.

8.5 Post-Market Adverse Reactions

In postmarketing surveillance, anaphylactic reactions have been reported. The frequency cannot be estimated from the available data.

Post-Market Clinical Trials:

Clinical use of PUREGON^® by the intramuscular or subcutaneous routes may lead to local reactions at the site of injection: bruising, pain, redness, swelling and itching, are commonly reported (3% of all patients treated). The majority of these local reactions are mild and transient in nature. Generalized hypersensitivity reactions including erythema, urticaria, rash and pruritus have been observed uncommonly (approximately 0.2% of all patients treated with PUREGON^®).

Treatment of females

In approximately 4% of the women treated with PUREGON^® in clinical trials, signs and symptoms related to ovarian hyperstimulation syndrome (OHSS) have been reported. Undesirable effects related to this syndrome include pelvic pain and/or congestion, abdominal pain and/or distension, breast complaints (breast tenderness, pain and/or engorgement, nipple pain), ovarian enlargement, and spontaneous abortion.

A slightly increased risk of ectopic pregnancy and multiple gestations has been seen.

Other more general symptoms that have been reported include headache and nausea.

Table 4 - Number (%) of Female Subjects with at least one AE per MedDRA Body System and Preferred term Trials: all Female studies (Europe, US and Japan)

Note: Coded with MedDRA version 8.1

Less Common Adverse Drug Reactions Reported in Post-market Clinical Trials (<1%)

Gastrointestinal disorders: abdominal discomfort, constipation, diarrhea.

Reproductive system and breast disorders: metrorrhagia, ovarian cyst, ovarian torsion, uterine enlargement, vaginal hemorrhage.

Adverse reactions identified during post-marketing surveillance were consistent with those reported in clinical trials.

In Females:

In rare instances, thromboembolism has been associated with PUREGON^®/hCG treatment as with other gonadotropins.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Concurrent use of PUREGON® and clomiphene may enhance the follicular response. After pituitary desensitization effected by a GnRH agonist, a higher dose of PUREGON® may be necessary to elicit an adequate follicular response.

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

The mechanism of action of PUREGON^® is not available.

10.2 Pharmacodynamics

PUREGON^® is a sterile solution containing highly purified human follicle- stimulating hormone (hFSH) prepared by recombinant DNA technology. The active substance, follitropin beta, is a heterodimeric glycoprotein with a molecular mass of approximately 35-45kD. It is produced by a Chinese hamster ovary (CHO) cell line transfected with a plasmid containing two subunit genes encoding human FSH. Structural analysis has shown that the amino acid sequence of follitropin beta is identical to that of natural hFSH. The oligosaccharide side chains are very similar to those reported for natural hFSH but not completely identical. These small differences do not affect the degree of charge heterogeneity, receptor binding affinity and bioactivity of follitropin relative to natural hFSH. Follitropin beta, as purified from the CHO cell culture supernatant, is of high biochemical purity (≥ 99%), high specific biological activity (approximately 10,000 IU/mg protein), and devoid of luteinizing hormone (LH) activity.

Follicle-stimulating Hormone (FSH) is essential for normal female and male gamete growth and maturation, and gonadal steroid production. Deficiencies in the endogenous production of FSH may lead to infertility.

FSH is critical for the onset and duration of follicular development, and consequently for the timing and number of follicles reaching maturity in females. The primary action of follitropin beta in women with gonadal dysfunction, is the stimulation of follicular development and steroid production. Follitropin may also be used to promote multiple follicular development in medically assisted reproduction programs (i.e. IVF/ET/ISCI) and gamete or zygote intra-fallopian transfer (GIFT/ZIFT). In order to induce ovulation, in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given after follitropin beta administration once follicular maturation has occurred.

In vitro Studies

The receptor-binding affinity displayed by follitropin beta was similar to that of urinary gonadotropin preparations. Aromatase induction in Sertoli and granulosa cells, in terms of dose-dependency and maximal responses, was comparable to urinary gonadotropin preparations. A similar pattern of inhibition of induced aromatase activity by specific monoclonal antibodies confirmed the structural and functional similarity between follitropin beta and urinary gonadotropin preparations. No relevant intrinsic LH bioactivity was measured in a Leydig cell assay. The isohormone distribution of follitropin beta, ranging between pI values of 5.7 and 3.2, was slightly more basic than that of urinary FSH.

10.3 Pharmacokinetics

Table 5 - Summary of Follitropin Beta Pharmacokinetic Parameters in Female Patients

C: sub-cutaneous; IM: intramuscular

¹ taken from trial 37614 (n=13)

² taken from trial 37626 (n=22)

³ volume of distribution during terminal phase calculated as CL

Absorption

After i.m. or s.c. administration of follitropin beta, high concentrations of FSH are reached within about 12 hours. After intramuscular administration of PUREGON^®, the maximum FSH concentrations are higher and reached earlier in men as compared to women. FSH levels remain high for 24-48 hours due to follitropin beta's relatively long elimination half-life of about 40 hours (ranging from 12 to 70 hours). Plasma FSH concentrations, after repeated administration of PUREGON^®, are approximately 1.5 - 2.5 times higher than after single dose administration.

The bioavailability of PUREGON^® following subcutaneous and intramuscular administration was investigated in healthy, pituitary-suppressed, female subjects given a single 300 IU dose. After subcutaneous or intramuscular injection the apparent dose absorbed was 77.8% and 76.4%, respectively.

The subcutaneous (455.6 ± 141.4 IU• h/L) and intramuscular (455.7 ± 135.7 IU• h/L) routes of administration were equivalent with respect area under the curve (AUC) in healthy, pituitary-suppressed, female subjects given a single 300 IU dose. However, equivalence could not be established for C_max between the subcutaneous (5.41 ± 0.72 IU/L) and intramuscular (6.86 ± 2.90 IU/L) routes of administration.

The pharmacokinetics and pharmacodynamics of a single, intramuscular dose (300 IU) of PUREGON^® were also investigated in a group of gonadotropin-deficient, but otherwise healthy women. Peak (C_max) serum FSH levels in these women were 4.3 ± 1.7 IU/L (mean ± SD) and they occurred approximately 27 hours after intramuscular administration.

A multiple, dose proportionality, pharmacokinetic study of PUREGON^® was completed in healthy, pituitary-suppressed, female subjects given intramuscular doses of 75 IU, 150 IU or 225 IU for 7 days. Steady–state blood concentrations of FSH were reached with all the doses after 4 days of treatment based on the minimum concentrations of FSH just prior to dosing (C_min). Peak blood concentrations with the 75IU, 150 IU, and 225 IU dose were 4.65 ± 1.49 IU/L, 9.46 ± 2.57 IU/L and 11.30 ± 1.77 IU/L, respectively.

A multiple, dose proportionality, pharmacokinetic study of PUREGON^® was completed in healthy, pituitary-suppressed, female subjects given subcutaneous doses of 75 IU, 150 IU, or 225 IU for 7 days. Steady–state blood concentrations of FSH were reached with all the doses after 5 days of treatment based on the minimum concentrations of FSH just prior to dosing (C_min). Peak blood concentrations with the 75 IU, 150 IU, and 225 IU dose were 4.30 ± 0.60 IU/L, 8.51 ± 1.16 IU/L and 13.92 ± 1.81 IU/L, respectively.

Distribution:

The volume of distribution of PUREGON^® in healthy, pituitary-suppressed, female subjects following intravenous administration of 300IU dose was approximately 8L.

Metabolism:

The recombinant FSH in PUREGON^® is biochemically very similar to urinary FSH and it is therefore anticipated that it is metabolized in the same manner.

Elimination

The elimination half-life following a single intramuscular dose (300 IU) of PUREGON^® in female subjects was 43.9 ± 14.1 hours (mean ± SD). The elimination half–life following a 7-day intramuscular treatment with 75 IU, 150 IU or 225 IU was 26.9 ± 7.8 hours (mean ± SD), 30.1 ± 6.2 hours (mean ± SD) and 28.9 ± 6.5, respectively.

There are no significant pharmacokinetic differences between intramuscular and subcutaneous administration of PUREGON^®. Both have an absolute bioavailability of approximately 77%. Recombinant FSH is biochemically very similar to urinary human FSH and is distributed, metabolized, and excreted in the same way.

Special Populations and Conditions

No studies have been conducted with special populations and conditions.

11 STORAGE, STABILITY AND DISPOSAL

Pharmacist: Store in a refrigerator (2^oC - 8^oC). Keep the cartridge(s) in the outer carton. Do not freeze. Protect from light.

PUREGON^® Solution for Injection in Cartridges:

Once the rubber inlay of a cartridge is pierced by a needle, the product may be stored for a maximum of 28 days.

12 SPECIAL HANDLING INSTRUCTIONS

The instructions for the pen must be followed carefully (see PUREGON PEN^® booklet).

Do not use the cartridge if the solution contains particles or if the solution is not clear.

Air bubbles must be removed from the cartridge before injection (see instructions for using the pen).

Empty cartridges must not be refilled.

PUREGON^® cartridges are not designed to allow any other drug to be mixed in the cartridges.

Discard used needles immediately after injection.

Discard used cartridges (including the remaining volume) after the last injection of the treatment cycle.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Follitropin beta

Chemical name: Recombinant follicle-stimulating hormone (recFSH)

Molecular formula and molecular mass: Molecular formula is not applicable.

Molecular mass is approximately 35-45 kD

Structural formula: Not applicable

Physicochemical properties: White to off-white cake or powder.

pH is 6.5 to 8.5.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Ovulation Induction

Table 6 - Summary of patient demographics for clinical trials in ovulation induction

The efficacy and safety of PUREGON^® and urinary gonadotropin were evaluated in patients with chronic anovulation (WHO group II) who failed to ovulate and/or conceive during clomiphene citrate treatment. With PUREGON^®, ovulation was achieved with a significantly fewer number of ampoules and within a shorter treatment period, indicating a higher efficiency in ovulation induction. The higher efficiency of PUREGON^® and the fact that a greater number of follicles of ≥

12 mm were found suggest that PUREGON^® treatment may be started at a lower dose than urinary gonadotropin and maintained at this lower dose for a longer period of time.

Table 7: Mean Results on Efficacy and Efficiency Parameters for Study # 37609

nd: not determined

Controlled Ovarian Hyperstimulation in Assisted Reproduction Programs

Table 8 - Summary of patient demographics for clinical trials in controlled ovarian hyperstimulation in assisted reproduction programs

The efficacy and safety of PUREGON^® was assessed and compared to urinary gonadotropin in infertile pituitary-suppressed subjects undergoing ovarian hyperstimulation followed by in vitro fertilization (IVF) and embryo transfer (ET). The study was designed as a randomized, assessor-blind, group-comparative trial of 1027 subjects randomized to PUREGON^® or urinary gonadotropin treatment in a 3:2 ratio.

Statistical analysis showed that the PUREGON^® group required significantly (p<0.01) fewer ampoules/vials of FSH (mean 28.5) than the urinary gonadotropin group (mean 31.8), and a shorter period of treatment (10.7 vs 11.3 days).

Table 9 - Efficacy Results for Study # 37608

*Data presented are from women with oocyte pick-up

Both treatment groups were similar with respect to the number of follicles with a diameter of over 17 mm. However, there was a significantly greater number of follicles of ≥ 15 mm (7.5 for PUREGON^® and 6.7 for urinary gonadotropin, respectively, (p<0.01)). In addition, the mean maximum serum estradiol concentration was significantly higher in the PUREGON^® group [6084 vs 5179 pmol/L, (p<0.01)].

In 11 out of the 18 centres contributing to the analysis of plasma FSH, the mean immunoreactive FSH concentration just before, or on the day of human chorionic gonadotropin (hCG) administration was significantly higher in the urinary gonadotropin group than in the PUREGON^® group (12.1 vs 11.5 IU/L, p=0.03). However, the mean total number of oocytes per aspiration was consistently and significantly higher in the PUREGON^® group (difference of 1.8 oocytes, p<0.01).

Although the median fertilization rates were similar in the PUREGON^® and urinary gonadotropin groups (64.7 and 62.5 %, respectively), a significantly higher (p=0.01) mean number of high-quality (type 1 and type 2) embryos were found in the PUREGON^® group.

The two treatment groups had a similar percentage of transfers (85.5% vs 83.1% in the PUREGON^® and urinary gonadotropin group, respectively), with a similar mean number of embryos (2.4 for both groups).

The treatment cycle outcome and the mean ongoing pregnancy rates (single and multiple vital pregnancies), all expressed per attempt and per embryo transfer, are shown in the following tables:

Table 10 - Treatment cycle outcome for Study # 37608

Table 11: Mean ongoing pregnancy rates for Study # 37608

A slight, although not significant, difference in pregnancy rates in favour of the PUREGON^® group (about 4%) was found. The cumulative pregnancy rate after the first FSH treatment cycle, including frozen embryo cycles, showed a 5.3% difference (p=0.05) in favour of PUREGON^®-treated women. Results of pregnancy follow-up after the first treatment cycle, showed no statistically significant differences between the two agents. Similarly, the rate of complications during pregnancy and delivery, as well as the incidence of congenital malformations, were comparable for the two treatment groups and were not increased compared to data on routine obstetrical practice. Follow-up of children, evaluated in two studies (one year follow-up and 4-8 week follow-up, respectively) did not reveal any unexpected abnormalities and psychomotor development was normal in all children.

Data from two additional studies confirmed the superior efficacy of PUREGON^® compared with urinary gonadotropin in inducing oocyte production with a fewer number of ampoules and over shorter periods of time.

Male Infertility

Initiation / Restoration of Spermatogenesis in Hypogonadotropic Hypogonadal Men

Table 12 - Summary of patient demographics for clinical trials initiation / restoration of spermatogenesis in hypogonadotropic hypogonadal men

The efficacy and safety of PUREGON^® was assessed in hypogonadotropic hypogonadal male subjects. The study was designed as an open-label, multi-centre, efficacy and safety trial and consisted of a pre-treatment phase and treatment phase. In the pre-treatment phase subjects were treated with hCG (1500 IU, twice weekly) for 16 weeks to normalize the testosterone levels. In the treatment phase, 30 subjects received both hCG and PUREGON^® for a period of 48 weeks. The subjects were randomized in two groups and received either 150 IU PUREGON^® three times per week or 225 IU two times a week, both amounting to a total dose of 450 IU.

The average success rate (mean sperm concentration of ≥ 10⁶/mL over the last two assessments) was 43% in the 150 IU PUREGON® (three times a week) and 44% in the 225 IU PUREGON^® (two times a week) groups, respectively. If data were analyzed according to the actually followed treatment these figures were comparable (40% and 47% respectively).

A total of fourteen subjects (47%) demonstrated a sperm concentration of at least 1 million/mL during treatment. This was achieved at a median time of 165 days, ranging from 25 to 327 days. In 20 subjects (67%) receiving combination therapy, sperm appeared in the ejaculate. The percentage of morphologically normal sperm cells remained fairly constant over the whole treatment period as well as the percentage of highly motile sperm cells. For most parameters, slightly better results were obtained in the 225 IU treatment group in comparison with the 150 IU group. This may be due to a difference in subject population as reflected by higher initial testicular volume in the 225 IU treatment group. A higher testicular volume is generally regarded as a prognostic factor for positive treatment outcome in male infertility. However, in view of the small number of subject’s pre-treatment group, this may also be due to chance. Overall, the observed difference is not considered to be clinically relevant.

With respect to local tolerance no major differences were observed between the two treatment groups. Antibodies against FSH or CHO cell-derived proteins were not present.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Follitropin beta, the active ingredient in PUREGON^® prepared by recombinant DNA technology, is highly pure (≥99%), of high specific bioactivity (approximately 10 000 IU/mg protein) and devoid of LH activity. It caused no clinically significant toxic effects when administered to animals in pre-clinical studies.

General Toxicology:

Single dose i.v. and i.m. administration of follitropin beta to intact rats caused no drug-related toxicological effects.

Follitropin beta when given i.m. as a repeated daily dose for 2 weeks up to 100-fold the anticipated maximal daily human dose induced no toxicologically significant effects.

Genotoxicity:

In Ames tests using Escherichia coli and Salmonella typhimurium strains PUREGON^® showed no mutagenic potential.

Special Toxicology:

After a single i.v. injection of follitropin beta in rats no anti-recFSH antibodies were observed. However, anti-recFSH antibodies were induced in a single rat within 4 days and in the majority of rats after 7 days of i.m. administration of 500 IU/kg follitropin beta. After 2 weeks, all rats dosed at 50 or 500 IU/kg were positive for the presence of anti-recFSH antibodies. A higher titre of antibodies occurred at earlier stages in the female rats.

No anti-recFSH antibody formation was seen in dogs.

Treatment of human subjects, for up to 3 cycles, did not result in the formation of anti-recFSH or anti-CHO cell-derived protein antibodies.