Ovaleap

Treatment with GONAL-f should be initiated under the supervision of a physician experienced in the treatment of fertility disorders.

Posology

The dose recommendations given for GONAL-f are those in use for urinary FSH. Clinical assessment of GONAL-f indicates that its daily doses, regimens of administration, and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing medicinal products. It is advised to adhere to the recommended starting doses indicated below.

Comparative clinical studies have shown that on average patients require a lower cumulative dose and shorter treatment duration with GONAL-f compared with urinary FSH.

Bioequivalence has been demonstrated between equivalent doses of the monodose presentation and the multidose presentation of GONAL-f.

The following table states the volume to be administered to deliver the prescribed dose:

The next injection should be done at the same time the next day.

Women with anovulation (including polycystic ovarian syndrome)

GONAL-f may be given as a course of daily injections. In menstruating women treatment should commence within the first 7 days of the menstrual cycle.

A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and/or oestrogen secretion. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should undergo further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned cycle.

When an optimal response is obtained, a single injection of 250 micrograms recombinant human choriogonadotropin alfa (r-hCG) or 5,000 IU, up to 10,000 IU hCG should be administered 24-48 hours after the last GONAL-f injection. The patient is recommended to have coitus on the day of, and the day following, hCG administration. Alternatively intrauterine insemination (IUI) may be performed.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose lower than that of the previous cycle.

Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies.

A commonly used regimen for superovulation involves the administration of 150-225 IU of GONAL-f daily, commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum oestrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days).

A single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24-48 hours after the last GONAL-f injection to induce final follicular maturation.

Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, GONAL-f is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks of treatment with an agonist, 150-225 IU GONAL-f are administered for the first 7 days. The dose is then adjusted according to the ovarian response.

Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter.

Women with anovulation resulting from severe LH and FSH deficiency.

In LH and FSH deficient women (hypogonadotrophic hypogonadism), the objective of GONAL-f therapy in association with lutropin alfa is to develop a single mature Graafian follicle from which the oocyte will be liberated after the administration of human chorionic gonadotropin (hCG). GONAL-f should be given as a course of daily injections simultaneously with lutropin alfa. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time.

A recommended regimen commences at 75 IU of lutropin alfa daily with 75-150 IU FSH. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and oestrogen response.

If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks.

When an optimal response is obtained, a single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last GONAL-f and lutropin alfa injections. The patient is recommended to have coitus on the day of, and on the day following, hCG administration.

Alternatively, IUI may be performed.

Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle.

Men with hypogonadotrophic hypogonadism

GONAL-f should be given at a dose of 150 IU three times a week, concomitantly with hCG, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued; current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis.

Special population

Older people

There is no relevant use of GONAL-f in the elderly population. Safety and effectiveness of GONAL-f in elderly patients have not been established.

Renal or hepatic impairment

Safety, efficacy and pharmacokinetics of GONAL-f in patients with renal or hepatic impairment have not been established.

Paediatric population

There is no relevant use of GONAL-f in the paediatric population.

Method of administration

GONAL-f is intended for subcutaneous use. The first injection of GONAL--f should be performed under direct medical supervision. Self-administration of GONAL-f should only be performed by patients who are well motivated, adequately trained and have access to expert advice.

As GONAL-f multidose is intended for several injections, clear instructions should be provided to the patients to avoid misuse of the multidose presentation.

Due to a local reactivity to benzyl alcohol, the same site of injection should not be used on consecutive days.

Individual reconstituted vials should be for single patient use only.

Special requirements

Treatment with Ovaleapin alfa should be initiated under the supervision of a physician experienced in the treatment of fertility disorders.

Posology

The dose recommendations given for Ovaleapin alfa are those in use for urinary FSH. Clinical assessment of Ovaleapin alfa indicates that its daily doses, regimens of administration and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing medicinal products. It is advised to adhere to the recommended starting doses indicated below.

Comparative clinical studies have shown that on average patients require a lower cumulative dose and shorter treatment duration with Ovaleapin alfa compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dose of Ovaleapin alfa than generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation.

Women with anovulation (including polycystic ovarian syndrome)

Ovaleapin alfa may be given as a course of daily injections. In menstruating women treatment should commence within the first 7 days of the menstrual cycle.

A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and/or oestrogen secretion. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should undergo further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned cycle.

When an optimal response is obtained, a single injection of 250 micrograms recombinant human choriogonadotropin alfa (r-hCG) or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last Ovaleapin alfa injection. The patient is recommended to have coitus on the day of, and the day following, hCG administration. Alternatively intrauterine insemination (IUI) may be performed.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose lower than that of the previous cycle.

Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other ART

A commonly used regimen for superovulation involves the administration of 150-225 IU of Ovaleapin alfa daily, commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum oestrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days).

A single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24-48 hours after the last Ovaleapin alfa injection to induce final follicular maturation.

Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, Ovaleapin alfa is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks of treatment with an agonist, 150-225 IU Ovaleapin alfa are administered for the first 7 days. The dose is then adjusted according to the ovarian response.

Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter.

Women with anovulation resulting from severe LH and FSH deficiency

In LH and FSH deficient women (hypogonadotropic hypogonadism), the objective of Ovaleapin alfa therapy in association with lutropin alfa is to develop a single mature Graafian follicle from which the oocyte will be liberated after the administration of hCG. Ovaleapin alfa should be given as a course of daily injections simultaneously with lutropin alfa. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time.

A recommended regimen commences at 75 IU of lutropin alfa daily with 75-150 IU FSH. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and oestrogen response.

If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks.

When an optimal response is obtained, a single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last Ovaleapin alfa and lutropin alfa injections. The patient is recommended to have coitus on the day of, and on the day following, hCG administration. Alternatively, IUI may be performed.

Luteal phase support may be considered since lack of substances with luteotropic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle.

Men with hypogonadotropic hypogonadism

Ovaleapin alfa should be given at a dose of 150 IU three times a week, concomitantly with hCG, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued; current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis.

Special population

Elderly population

There is no relevant use of Ovaleapin alfa in the elderly population. Safety and effectiveness of Ovaleapin alfa in elderly patients have not been established.

Renal or hepatic impairment

Safety, efficacy and pharmacokinetics of Ovaleapin alfa in patients with renal or hepatic impairment have not been established.

Paediatric population

There is no relevant use of Ovaleapin alfa in the paediatric population.

Method of administration

Ovaleap is intended for subcutaneous administration. The first injection of Ovaleap should be performed under direct medical supervision. Self-administration of Ovaleap should only be performed by patients who are well motivated, adequately trained and have access to expert advice.

As the Ovaleap multidose cartridge is intended for several injections, clear instructions should be provided to the patients to avoid misuse of the multidose presentation.

The Ovaleap cartridge is designed for use in conjunction with the Ovaleap Pen only, which is separately available.

Special requirements

Treatment with follitropin alfa should be initiated under the supervision of a physician experienced in the treatment of fertility disorders.

Posology

The dose recommendations given for follitropin alfa are those in use for urinary FSH. Clinical assessment of follitropin alfa indicates that its daily doses, regimens of administration and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing medicinal products. It is advised to adhere to the recommended starting doses indicated below.

Comparative clinical studies have shown that on average patients require a lower cumulative dose and shorter treatment duration with follitropin alfa compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dose of follitropin alfa than generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation.

Women with anovulation (including polycystic ovarian syndrome)

Follitropin alfa may be given as a course of daily injections. In menstruating women treatment should commence within the first 7 days of the menstrual cycle.

A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and/or oestrogen secretion. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should undergo further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned cycle.

When an optimal response is obtained, a single injection of 250 micrograms recombinant human choriogonadotropin alfa (r-hCG) or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa injection. The patient is recommended to have coitus on the day of, and the day following, hCG administration. Alternatively intrauterine insemination (IUI) may be performed.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose lower than that of the previous cycle.

Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other ART

A commonly used regimen for superovulation involves the administration of 150-225 IU of follitropin alfa daily, commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum oestrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days).

A single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24-48 hours after the last follitropin alfa injection to induce final follicular maturation.

Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, follitropin alfa is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks of treatment with an agonist, 150-225 IU follitropin alfa are administered for the first 7 days. The dose is then adjusted according to the ovarian response.

Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter.

Women with anovulation resulting from severe LH and FSH deficiency

In LH and FSH deficient women (hypogonadotropic hypogonadism), the objective of follitropin alfa therapy in association with lutropin alfa is to develop a single mature Graafian follicle from which the oocyte will be liberated after the administration of hCG. Follitropin alfa should be given as a course of daily injections simultaneously with lutropin alfa. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time.

A recommended regimen commences at 75 IU of lutropin alfa daily with 75-150 IU FSH. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and oestrogen response.

If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks.

When an optimal response is obtained, a single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last follitropin alfa and lutropin alfa injections. The patient is recommended to have coitus on the day of, and on the day following, hCG administration. Alternatively, IUI may be performed.

Luteal phase support may be considered since lack of substances with luteotropic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle.

Men with hypogonadotropic hypogonadism

Follitropin alfa should be given at a dose of 150 IU three times a week, concomitantly with hCG, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued; current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis.

Special population

Elderly population

There is no relevant use of follitropin alfa in the elderly population. Safety and effectiveness of follitropin alfa in elderly patients have not been established.

Renal or hepatic impairment

Safety, efficacy and pharmacokinetics of follitropin alfa in patients with renal or hepatic impairment have not been established.

Paediatric population

There is no relevant use of follitropin alfa in the paediatric population.

Method of administration

Ovaleap is intended for subcutaneous administration. The first injection of Ovaleap should be performed under direct medical supervision. Self-administration of Ovaleap should only be performed by patients who are well motivated, adequately trained and have access to expert advice.

As the Ovaleap multidose cartridge is intended for several injections, clear instructions should be provided to the patients to avoid misuse of the multidose presentation.

The Ovaleap cartridge is designed for use in conjunction with the Ovaleap Pen only, which is separately available.

General Dosing Information

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
• Administer BRAVELLE® subcutaneously in the abdomen or intramuscularly as described in Instructions for Use.
• A healthcare provider should administer BRAVELLE® intramuscularly.

Recommended Dosing For Induction Of Ovulation

The dosing scheme is stepwise and is individualized for each woman.

• For women who have received GnRH agonist or antagonist pituitary suppression, a starting dose of 150 International Units per day of BRAVELLE® is administered subcutaneously or intramuscularly for 5 days in the first cycle of treatment.
• In subsequent cycles of treatment, the starting dose (and dosage adjustments) of BRAVELLE® should be determined based on the history of the ovarian response to BRAVELLE®.
• The following should be considered when planning the woman's individualized dose of BRAVELLE®:
  • Appropriate BRAVELLE® dose adjustment(s), based on clinical monitoring (including serum estradiol levels and vaginal ultrasound results), should be used to prevent multiple follicular growth and cycle cancellation.
  • Do not make adjustments in dose more frequently than once every 2 days and do not exceed more than 75 to 150 International Units per adjustment.
  • Use the lowest dose of BRAVELLE® that will achieve desired results.
  • The maximum, individualized, daily dose of BRAVELLE® is 450 International Units per day.
  • In general, do not exceed 12 days of treatment.
• When pre-ovulatory conditions are reached, administer human chorionic gonadotropin (hCG) to induce final oocyte maturation and ovulation.
• Withhold hCG in cases where the ovarian monitoring on the last day of BRAVELLE® treatment suggests an increased risk of ovarian hyperstimulation syndrome (OHSS).
• Encourage the woman and her partner to have intercourse daily, beginning on the day prior to the administration of hCG and until ovulation becomes apparent.

Discourage intercourse when the risk for OHSS is increased.

Recommended Dosing For Assisted Reproduction Technology

The recommended dosing scheme for patients undergoing IVF follows a stepwise approach and is individualized for each woman. The recommended initial dose of BRAVELLE® for women who have received a GnRH agonist for pituitary suppression is 225 International Units. BRAVELLE® may be administered together with MENOPUR® (menotropins for injection, USP), and the total initial dose when the products are combined should not exceed 225 International Units (150 International Units of BRAVELLE® and 75 International Units of MENOPUR® or 75 International Units of BRAVELLE® and 150 International Units of MENOPUR®).

• Beginning on cycle day 2 or 3, a starting dose of 225 International Units of BRAVELLE® is administered subcutaneously daily until sufficient follicular development, as determined by ultrasound in combination with measurement of serum estradiol levels, is attained. In most cases, therapy should not exceed 12 days.
• Adjust the dose after 5 days based on the woman's ovarian response, as determined by ultrasound evaluation of follicular growth and serum estradiol levels.
• Do not make additional dosage adjustments more frequently than every 2 days or by more than 75 -150 International Units at each adjustment.
• Continue treatment until adequate follicular development is evident, and then administer hCG.
• Withhold the administration of hCG in cases where the ovarian monitoring suggests an increased risk of OHSS on the last day of BRAVELLE® therapy.
• Do not administer daily doses of BRAVELLE® or BRAVELLE® in combination with MENOPUR® that exceed 450 International Units.

GONAL-f is a potent gonadotrophic 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.

Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of GONAL-f calls for monitoring of ovarian response with ultrasound, alone or preferably in combination with measurement of serum oestradiol levels, on a regular basis. There may be a degree of inter-patient variability in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women.

Porphyria

Patients with porphyria or a family history of porphyria should be closely monitored during treatment with GONAL-f. Deterioration or a first appearance of this condition may require cessation of treatment.

Treatment in women

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, adrenocortical deficiency, hyperprolactinemia and appropriate specific treatment given.

Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended GONAL-f dose and regimen of administration and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests.

In clinical trials, an increase of the ovarian sensitivity to GONAL-f was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments.

No direct comparison of GONAL-f/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with GONAL-f/LH is similar to that obtained with hMG.

Ovarian Hyperstimulation Syndrome (OHSS)

A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women 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.

The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction.

Independent risk factors for developing OHSS include polycystic ovarian syndrome high absolute or rapidly rising serum oestradiol levels (e.g. > 900 pg/mL or > 3,300 pmol/L in anovulation; > 3,000 pg/mL or > 11,000 pmol/L in ART) and large number of developing ovarian follicles (e.g. > 3 follicles of > 14 mm in diameter in anovulation; > 20 follicles of > 12 mm in diameter in ART).

Adherence to recommended GONAL-f dose and regimen of administration can minimise the risk of ovarian hyperstimulation. Monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to early identify risk factors.

There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur such as serum oestradiol level > 5,500 pg/mL or > 20,200 pmol/L and/or > 40 follicles in total, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or to use barrier contraceptive methods for at least 4 days. OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event. It most often occurs after hormonal treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Therefore patients should be followed for at least two weeks after hCG administration.

In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.

Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started.

Multiple pregnancy

In patients undergoing ovulation induction, the incidence of multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes.

To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.

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.

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 stimulation of follicular growth for ovulation induction or 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, was reported to be higher than in the general population.

Reproductive system neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women.

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 pregnancies.

Thromboembolic events

In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, 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.

Treatment in men

Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to GONAL-f/hCG therapy. GONAL-f should not be used when an effective response cannot be obtained.

Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response.

Sodium content

GONAL-f contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

Ovaleapin alfa is 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.

Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of Ovaleapin alfa calls for monitoring of ovarian response with ultrasound, alone or preferably in combination with measurement of serum oestradiol levels, on a regular basis. There may be a degree of interpatient variability in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women.

Porphyria

Patients with porphyria or a family history of porphyria should be closely monitored during treatment with Ovaleapin alfa. Deterioration or a first appearance of this condition may require cessation of treatment.

Treatment in women

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, adrenocortical deficiency, hyperprolactinemia and appropriate specific treatment given.

Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended Ovaleapin alfa dose and regimen of administration and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests.

In clinical trials, an increase of the ovarian sensitivity to Ovaleapin alfa was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments.

No direct comparison of Ovaleapin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with Ovaleapin alfa/LH is similar to that obtained with hMG.

Ovarian Hyperstimulation Syndrome (OHSS)

A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women 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.

The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction.

Independent risk factors for developing OHSS include polycystic ovarian syndrome high absolute or rapidly rising serum oestradiol levels (e.g. > 900 pg/mL or > 3,300 pmol/L in anovulation; > 3,000 pg/mL or > 11,000 pmol/L in ART) and large number of developing ovarian follicles (e.g. > 3 follicles of > 14 mm in diameter in anovulation; > 20 follicles of > 12 mm in diameter in ART).

Adherence to recommended Ovaleapin alfa dose and regimen of administration can minimise the risk of ovarian hyperstimulation. Monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to early identify risk factors.

There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur such as serum oestradiol level > 5,500 pg/mL or > 20,200 pmol/L and/or > 40 follicles in total, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or to use barrier contraceptive methods for at least 4 days. OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event. It most often occurs after hormonal treatment has been discontinued and reaches its maximum at about 7 to 10 days following treatment. Therefore, patients should be followed for at least 2 weeks after hCG administration.

In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.

Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing and that the patient be hospitalised and appropriate therapy be started.

Multiple pregnancy

In patients undergoing ovulation induction, the incidence of multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes.

To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.

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.

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 stimulation of follicular growth for ovulation induction or 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, was reported to be higher than in the general population.

Reproductive system neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women.

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 pregnancies.

Thromboembolic events

In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, 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.

Treatment in men

Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to Ovaleapin alfa/hCG therapy. Ovaleapin alfa should not be used when an effective response cannot be obtained.

Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response.

Sodium content

Ovaleap contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

Follitropin alfa is 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.

Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of follitropin alfa calls for monitoring of ovarian response with ultrasound, alone or preferably in combination with measurement of serum oestradiol levels, on a regular basis. There may be a degree of interpatient variability in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women.

Porphyria

Patients with porphyria or a family history of porphyria should be closely monitored during treatment with follitropin alfa. Deterioration or a first appearance of this condition may require cessation of treatment.

Treatment in women

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, adrenocortical deficiency, hyperprolactinemia and appropriate specific treatment given.

Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended follitropin alfa dose and regimen of administration and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests.

In clinical trials, an increase of the ovarian sensitivity to follitropin alfa was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments.

No direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG.

Ovarian Hyperstimulation Syndrome (OHSS)

A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women 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.

The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction.

Independent risk factors for developing OHSS include polycystic ovarian syndrome high absolute or rapidly rising serum oestradiol levels (e.g. > 900 pg/mL or > 3,300 pmol/L in anovulation; > 3,000 pg/mL or > 11,000 pmol/L in ART) and large number of developing ovarian follicles (e.g. > 3 follicles of > 14 mm in diameter in anovulation; > 20 follicles of > 12 mm in diameter in ART).

Adherence to recommended follitropin alfa dose and regimen of administration can minimise the risk of ovarian hyperstimulation. Monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to early identify risk factors.

There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur such as serum oestradiol level > 5,500 pg/mL or > 20,200 pmol/L and/or > 40 follicles in total, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or to use barrier contraceptive methods for at least 4 days. OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event. It most often occurs after hormonal treatment has been discontinued and reaches its maximum at about 7 to 10 days following treatment. Therefore, patients should be followed for at least 2 weeks after hCG administration.

In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.

Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing and that the patient be hospitalised and appropriate therapy be started.

Multiple pregnancy

In patients undergoing ovulation induction, the incidence of multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes.

To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.

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.

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 stimulation of follicular growth for ovulation induction or 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, was reported to be higher than in the general population.

Reproductive system neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women.

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 pregnancies.

Thromboembolic events

In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, 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.

Treatment in men

Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained.

Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response.

Sodium content

Ovaleap contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

BRAVELLE® should only be used by physicians who are experienced in infertility treatment. BRAVELLE® contains gonadotropic substances capable of causing in women, Ovarian Hyperstimulation Syndrome [OHSS] with or without pulmonary or vascular complications and multiple births. Gonadotropin therapy requires the availability of appropriate monitoring facilities. Use the lowest effective dose.

Hypersensitivity And Anaphylactic Reactions

Hypersensitivity/anaphylactic reactions associated with urofollitropins for injection, purified administration have been reported in some patients. These reactions presented as generalized urticaria, facial edema, angioneurotic edema, and/or dyspnea suggestive of laryngeal edema. The relationship of these symptoms to uncharacterized urinary proteins is uncertain.

Abnormal Ovarian Enlargement

In order to minimize the hazard associated with abnormal ovarian enlargement that may occur with BRAVELLE® therapy, the lowest effective dose should be used. Use of ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels is important to minimize the risk of ovarian stimulation.

If the ovaries are abnormally enlarged on the last day of BRAVELLE® therapy, hCG should not be administered in order to reduce the chances of development of the Ovarian Hyperstimulation Syndrome. Prohibit intercourse in women with significant ovarian enlargement because of the danger of hemoperitoneum resulting from rupture of ovarian cysts.

Ovarian Hyperstimulation Syndrome (OHSS)

OHSS: OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS may progress rapidly to become a serious medical event. It is characterized by an apparent dramatic increase in vascular permeability, which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium. The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain. Abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria have been reported with OHSS. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events. 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 OHSS.

OHSS occurs after treatment has been discontinued and reaches its maximum at about 7 to 10 days after treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration, the hCG must be withheld.

Cases of OHSS are more common, more severe and more protracted if pregnancy occurs. OHSS develops rapidly; therefore patients should be followed for at least two weeks after hCG administration.

If severe OHSS occurs, gonadotropins, including hCG, must be stopped and consideration should be given as to whether the woman needs be hospitalized. Treatment is primarily symptomatic and overall should consist of bed rest, fluid and electrolyte management, and analgesics (if needed). Because the use of diuretics can accentuate the diminished intravascular volume, diuretics should be avoided except in the late phase of resolution as described below. The management of OHSS may be divided into three phases as follows:

• Acute Phase:
  Management should be directed at preventing hemoconcentration due to loss of intravascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage. Fluid intake and output, weight, hematocrit, serum and urinary electrolytes, urine specific gravity, BUN and creatinine, total proteins with albumin: globulin ratio, coagulation studies, electrocardiogram to monitor for hyperkalemia, and abdominal girth should be thoroughly assessed daily or more often based on the clinical need. Treatment, consisting of limited intravenous fluids, electrolytes, human serum albumin, is intended to normalize electrolytes while maintaining an acceptable but somewhat reduced intravascular volume. Full correction of the intravascular volume deficit may lead to an unacceptable increase in the amount of third space fluid accumulation.
• Chronic Phase:
  After the acute phase is successfully managed as above, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium, and fluid restriction.
• Resolution Phase:
  As third space fluid returns to the intravascular compartment, a fall in hematocrit and increasing urinary output are observed in the absence of any increase in intake. Peripheral and/or pulmonary edema may result if the kidneys are unable to excrete third space fluid as rapidly as it is mobilized. Diuretics may be indicated during the resolution phase, if necessary, to combat pulmonary edema.

Do not remove ascitic, pleural, and pericardial fluid unless there is the necessity to relieve symptoms such as pulmonary distress or cardiac tamponade.

OHSS increases the risk of injury to the ovary. Pelvic examination or intercourse may cause rupture of an ovarian cyst, which may result in hemoperitoneum, and should be avoided.

If bleeding occurs and requires surgical intervention, the clinical objective should be to control the bleeding and retain as much ovarian tissue as possible. A physician experienced in the management of this syndrome, or who is experienced in the management of fluid and electrolyte imbalances, should be consulted.

In a clinical study of induction of ovulation indication, 6 of 72 (8.33%) BRAVELLE® treated women developed OHSS and 2 were classified as severe. In a clinical study for the development of multiple follicles as part of an IVF cycle, 3 of 60 women treated with BRAVELLE® developed OHSS and 1 was classified as severe.

Pulmonary And Vascular Complications

Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome) have been reported in women treated with gonadotropins. In addition, thromboembolic events both in association with, and separate from, the Ovarian Hyperstimulation Syndrome have been reported in women treated with gonadotropins. Intravascular thrombosis and embolism, which may originate in venous or arterial vessels, can result in reduced blood flow to critical organs or the extremities. Women with generally recognized risk factors for thrombosis, such as personal or family history, severe obesity, or thrombophilia, may have an increased risk of venous or arterial thromboembolic events during or following treatment with gonadotropins. Sequelae of such reactions have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb and rarely in myocardial infarctions. In rare cases, pulmonary complications and/or thromboembolic events have resulted in death. In women with recognized risk factors, the benefits of ovulation induction and assisted reproductive technology need to be weighed against the risks. Pregnancy also carries an increased risk of thrombosis.

Ovarian Torsion

Ovarian torsion has been reported after treatment with gonadotropins. This may be related to 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.

Multi-fetal Gestation And Birth

Multi-fetal gestation and births have been reported with all gonadotropin therapy including therapy with BRAVELLE®.

In a controlled study of 72 patients undergoing induction of ovulation, 66.7% of pregnancies of women treated with subcutaneous BRAVELLE® were multiples, while 28.6% of pregnancies in women treated with intramuscular BRAVELLE® were multiples.

In a controlled study of 60 patients undergoing IVF, 34.8% of pregnancies of women treated with subcutaneous BRAVELLE® were multiples. Before beginning treatment with BRAVELLE®, advise the woman and her partner of the potential risk of multi-fetal gestation and birth.

Congenital Malformations

The incidence of congenital malformations after some ART [specifically in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)] may be slightly higher than after spontaneous conception. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g., maternal age, maternal and paternal genetic background, sperm characteristics) and to the higher incidence of multi-fetal gestations after IVF or ICSI. There are no indications that the use of gonadotropins during IVF or ICSI is associated with an increased risk of congenital malformations.

Ectopic Pregnancy

Since infertile women undergoing ART often have tubal abnormalities, the incidence of ectopic pregnancy may be increased. Early confirmation of intrauterine pregnancy should be determined by β-hCG testing and transvaginal ultrasound.

Spontaneous Abortion

The risk of spontaneous abortion (miscarriage) is increased with gonadotropin products. However, causality has not been established. The increased risk may be a factor of the underlying infertility.

Ovarian Neoplasms

There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have had multiple drug therapy for controlled ovarian stimulation; however, a causal relationship has not been established.

Laboratory Tests

In most instances, treatment of women with BRAVELLE® will result only in follicular growth and maturation. In the absence of an endogenous LH surge, hCG is given when monitoring of the woman indicates that sufficient follicular development has occurred. This may be estimated by ultrasound alone or in combination with measurement of serum estradiol levels. The combination of both ultrasound and serum estradiol measurement are useful for monitoring follicular growth and maturation, timing of the ovulatory trigger, detecting ovarian enlargement and minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestation.

The clinical confirmation of ovulation is obtained by direct or indirect indices of progesterone production as well as sonographic evidence of ovulation.

Direct or indirect indices of progesterone production:

• Urinary or serum luteinizing hormone (LH) rise
• A rise in basal body temperature
• Increase in serum progesterone
• Menstruation following the shift in basal body temperature

Sonographic evidence of ovulation:

• Collapsed follicle
• Fluid in the cul-de-sac
• Features consistent with corpus luteum formation
• Secretory endometrium

Patient Counseling Information

See FDA-approved patient labeling (Patient Information and Instructions for Use)

Dosing and Use

Instruct women on the correct usage and dosing of MENOPUR®. Caution women not to change the dosage or the schedule of administration unless she is told to do so by her healthcare provider.

Duration and Monitoring Required

Prior to beginning therapy with BRAVELLE®, inform women about the time commitment and monitoring procedures necessary for treatment.

Instructions Regarding a Missed

Dose Inform the woman that if she misses or forgets to take a dose of BRAVELLE®, the next dose should not be doubled and she should call her healthcare provider for further dosing instructions.

Ovarian Hyperstimulation Syndrome (OHSS)

Inform women regarding the risks of OHSS and OHSS-associated symptoms including lung and blood vessel problems and ovarian torsion with the use of BRAVELLE®.

Multi-fetal Gestation and Birth

Inform women regarding the risk of multi-fetal gestation and birth with the use of BRAVELLE®.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term toxicity studies in animals and in vitro mutagenicity tests have not been performed to evaluate the carcinogenic potential of urofollitropin for injection, purified.

Use In Specific Populations

Pregnancy

Teratogenic effects

Pregnancy Category X.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from BRAVELLE®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Renal and Hepatic Insufficiency

Safety and effectiveness in women with renal and hepatic sufficiency have not been established.

The effects of an overdose of GONAL-f are unknown, nevertheless, there is a possibility that OHSS may occur.

The effects of an overdose of Ovaleapin alfa are unknown, nevertheless, there is a possibility that OHSS may occur.

The effects of an overdose of follitropin alfa are unknown, nevertheless, there is a possibility that OHSS may occur.

Aside from possible ovarian hyperstimulation and multiple gestations , little is known concerning the consequences of acute overdosage with BRAVELLE®.

Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05.

In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the object of GONAL-f therapy is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG.

Clinical efficacy and safety in women

In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.

In clinical studies comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table below) and in ovulation induction, GONAL-f was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.

In ART, GONAL-f at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH.

Table: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of GONAL-f with urinary FSH in assisted reproduction technologies)

Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed.

Clinical efficacy and safety in men

In men deficient in FSH, GONAL-f administered concomitantly with hCG for at least 4 months induces spermatogenesis.

Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05.

Ovaleap is a biosimilar medicinal product.Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Pharmacodynamic effects

In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the object of Ovaleapin alfa therapy is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG.

Clinical efficacy and safety in women

In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.

In clinical studies comparing r-hFSH (Ovaleapin alfa) and urinary FSH in ART (see table 3 below) and in ovulation induction, Ovaleapin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.

In ART, Ovaleapin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH.

Clinical efficacy and safety in men

In men deficient in FSH, Ovaleapin alfa administered concomitantly with hCG for at least 4 months induces spermatogenesis.

Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05.

Ovaleap is a biosimilar medicinal product.Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Pharmacodynamic effects

In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the object of follitropin alfa therapy is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG.

Clinical efficacy and safety in women

In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.

In clinical studies comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table 3 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.

In ART, follitropin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH.

Clinical efficacy and safety in men

In men deficient in FSH, follitropin alfa administered concomitantly with hCG for at least 4 months induces spermatogenesis.

Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 l and 0.6 l/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine.

Following subcutaneous administration, the absolute bioavailability is about 70 %. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steady-state within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.

Following intravenous administration, Ovaleapin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 L and 0.6 L/h, respectively. One-eighth of the Ovaleapin alfa dose is excreted in the urine.

Following subcutaneous administration, the absolute bioavailability is about 70 %. Following repeated administration, Ovaleapin alfa accumulates 3-fold achieving a steady-state within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, Ovaleapin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.

Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 L and 0.6 L/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine.

Following subcutaneous administration, the absolute bioavailability is about 70 %. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steady-state within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.

Single doses of 225 International Units and multiple daily doses (7 days) of 150 International Units of BRAVELLE® were administered to healthy volunteer female subjects while their endogenous FSH was suppressed. Sixteen subjects received BRAVELLE® subcutaneously and 12 received the drug intramuscularly. Serum FSH concentrations were determined. Based on the steady state ratio of FSH C max and AUC, subcutaneous and intramuscular administration of BRAVELLE® were not bioequivalent. Multiple doses of BRAVELLE® intramuscular resulted in C max and AUC of 77.7% and 81.8% compared to multiple doses of BRAVELLE® subcutaneous. The FSH pharmacokinetic parameters for single and multiple dose BRAVELLE®, administered subcutaneously and intramuscularly are in Table 3.

Table 3: FSH Pharmacokinetic Parameters (Mean ± SD) Following BRAVELLE® Administration

Absorption

The subcutaneous route of administration trends toward greater bioavailability than the IM route for single and multiple doses of BRAVELLE®.

Distribution

Human tissue or organ distribution of FSH has not been studied for BRAVELLE®.

Metabolism

Metabolism of FSH has not been studied for BRAVELLE® in humans.

Elimination

The mean elimination half-lives of FSH for subcutaneous and intramuscular single dosing are 31.8 and 37 hours, respectively. However, following multiple dosing (X 7 days) they are 20.6 and 15.2 hours for SC and IM, respectively.

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity additional to that already stated in other sections of this SmPC.

In rabbits, the formulation reconstituted with 0.9 % benzyl alcohol and 0.9 % benzyl alcohol alone, both resulted in a slight haemorrhage and subacute inflammation after single subcutaneous injection or mild inflammatory and degenerative changes after single intramuscular injection respectively.

Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa (> 40 IU/kg/day) for extended periods, through reduced fecundity.

Given in high doses (> 5 IU/kg/day) follitropin alfa caused a decrease in the number of viable foetuses without being a teratogen, and dystocia similar to that observed with urinary Menopausal Gonadotropin (hMG). However, since GONAL-f is not indicated in pregnancy, these data are of limited clinical relevance.

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity additional to that already stated in other sections of this SmPC.

Impaired fertility has been reported in rats exposed to pharmacological doses of Ovaleapin alfa (> 40 IU/kg/day) for extended periods, through reduced fecundity.

Given in high doses (> 5 IU/kg/day) Ovaleapin alfa caused a decrease in the number of viable foetuses without being a teratogen and dystocia similar to that observed with urinary Menopausal Gonadotropin (hMG). However, since Ovaleap is not indicated in pregnancy, these data are of limited clinical relevance.

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity additional to that already stated in other sections of this SmPC.

Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa (> 40 IU/kg/day) for extended periods, through reduced fecundity.

Given in high doses (> 5 IU/kg/day) follitropin alfa caused a decrease in the number of viable foetuses without being a teratogen and dystocia similar to that observed with urinary Menopausal Gonadotropin (hMG). However, since Ovaleap is not indicated in pregnancy, these data are of limited clinical relevance.