Folisan

Recombinant-human FSH.

Each vial contains Recombinant-Human Follicle Stimulating Hormone 75 IU.
Powder and solvent for solution for injection.
Excipients/Inactive Ingredients: Sucrose B.P., Di-sodium Hydrogen Phosphate B.P., Mannitol B.P., Tween 20 B.P. and Methionine B.P.

Pharmacotherapeutic group: gonadotrophins.
Pharmacology: Pharmacodynamics: FOLISAN (r-hFSH) is a preparation of follicle stimulating hormone produced by genetically engineered Chinese Hamster Ovary (CHO) cells. In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. Patients with severe FSH and LH deficiency were defined by an endogenous serum LH level <1.2 IU/l as measured in laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.
Pharmacokinetics: Following intravenous administration, FOLISAN (r-hFSH) is distributed to the extra cellular 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 FOLISAN (r-hFSH) dose is excreted in the urine. Following subcutaneous administration, the absolute bioavailability is about 70%. Following repeated administration, FOLISAN (r-hFSH) accumulates 3-fold achieving a steady state within 3-4 days. In women whose endogenous gonadotrophin secretion is suppressed, FOLISAN (r-hFSH) has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite un-measurable LH levels.

Anovulation (including polycystic ovarian syndrome) in women who have been unresponsive to treatment with clomiphene citrate.
Stimulation of multifollicular development in patients undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian transfer (GIFT) and zygote intra-fallopian transfer (ZIFT).
FOLISAN (r-hFSH) in association with a luteinising hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency.

Treatment with FOLISAN (r-hFSH) should be initiated under the supervision of a physician experienced in the treatment of fertility disorders.
FOLISAN (r-hFSH) is intended for subcutaneous administration. The powder should be reconstituted immediately prior to use with the solvent provided. In order to avoid the injection of large volumes, up to 3 vials of product may be dissolved in 0.5ml of solvent.
Posology: The dosage recommendations given for FOLISAN (r-hFSH) are those in use for urinary FSH. Clinical assessment of FOLISAN (r-hFSH) 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. However, the study reports conclude that FOLISAN (r-hFSH) is more effective than urinary FSH in terms of a lower total dose and shorter treatment period needed to achieve pre-ovulatory. It is advised to adhere to the recommended starting doses indicated as follows.
Women with anovulation (including polycystic ovarian syndrome): FOLISAN (r-hFSH) may be given as a course of daily injections. In menstruating patients treatment should commence within the first 7 days of the menstrual cycle.
Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and/or oestrogen secretion. 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. 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 5,000 IU, up to 10,000 IU HCG should be administered 24-48 hours after the last FOLISAN (r-hFSH) 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 (see Special warnings and precautions for use under Precautions). Treatment should recommence in the next cycle at a dose lower than that of the previous cycle.
Women undergoing ovarian stimulation for multiple follicular developments prior to in vitro fertilisation or other assisted reproductive technologies: A commonly used regimen for superovulation involves the administration of 150-225 IU of FOLISAN (r-hFSH) 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 up to 10,000 IU HCG is administered 24-48 hours after the last FOLISAN (r-hFSH) 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, FOLISAN (r-hFSH) 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 FOLISAN (r-hFSH) 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 FOLISAN (r-hFSH) 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). FOLISAN (r-hFSH) 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 anytime.
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 5,000 IU up to 10,000 IU HCG should be administered 24-48 hours after the last FOLISAN (r-hFSH) 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.
Special Population: Elderly population: There is no relevant use of FOLISAN (r-hFSH) in the elderly population. Safety and effectiveness of FOLISAN (r-hFSH) in elderly patients have not been established.
Renal or hepatic impairment: Safety, efficacy and pharmacokinetics of FOLISAN (r-hFSH) in patients with renal or hepatic impairment have not been established.
Paediatric population: There is no relevant use of FOLISAN (r-hFSH) in the paediatric population.
Method of administration: FOLISAN (r-hFSH) is intended for subcutaneous administration. The first injection of FOLISAN (r-hFSH) should be performed under direct medical supervision. Self-administration of FOLISAN (r-hFSH) should only be performed by patients who are well motivated, adequately trained and have access to expert advice.
The injection site should be alternated daily.

The effects of an overdose of FOLISAN (r-hFSH) are unknown, nevertheless, there is a possibility that OHSS may occur (see Special warnings and precautions for use under Precautions).

Hypersensitivity to follitropin alfa or to any of the excipients.
Tumours of the hypothalamus and pituitary gland.
Ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome.
Gynaecological haemorrhages of unknown aetiology.
Ovarian, uterine or mammary carcinoma.
FOLISAN (r-hFSH) should not be used when an effective response cannot be obtained, such as: Primary ovarian failure; Malformations of sexual organs incompatible with pregnancy; Fibroid tumours of the uterus incompatible with pregnancy.

Special warnings and precautions for use: FOLISAN (r-hFSH) 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 FOLISAN (r-hFSH) 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 women.
Self-administration of FOLISAN (r-hFSH) should only be performed by patients who are well motivated. Adequately trained and with access to expert advice. The first injection of FOLISAN (r-hFSH) should be performed under direct medical supervision. 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 pituitary or hypothalamic tumors, and appropriate specific treatment given. Patients undergoing stimulation of follicular growth, whether in the frame of a treatment for anovulatory infertility or ART procedures may experience ovarian enlargement or develop hyper stimulation. Adherence to recommended FOLISAN (r-hFSH) dosage and regimen of administration, and careful monitoring of therapy will minimize the incidence of such events. Acute interpretation of the indices of follicle development and maturation require a physician who is experienced in the interpretation of the relevant tests.
Porphyria: Patients with porphyria or a family history of porphyria should be closely monitored during treatment with FOLISAN (r-hFSH). 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 FOLISAN (r-hFSH) 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 FOLISAN (r-hFSH) 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 r-hFSH/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with FOLISAN/LH is similar to what can be 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.
OHSS is a medical event distinct from 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 and thromboembolic events. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction.
To minimize the risk of OHSS or of multiple pregnancy, ultrasound scans as well as oestradiol measurements are recommended. In anovulation the risk of OHSS and multiple pregnancy is increased by a serum oestradiol > 900 pg/ml (3,300 pmol/l) and more than 3 follicles of 14 mm or more in diameter. In ART there is an increased risk of OHSS with a serum oestradiol > 3,000 pg/ml (11,000 pmol/l) and 20 or more follicles of 12 mm or more in diameter. When the oestradiol level is > 5,500 pg/ml (20,200 pmol/l) and where there are 40 or more follicles in total, it may be necessary to withhold HCG administration.
Adherence to recommended FOLISAN (r-hFSH) dosage and regimen of administration will minimise the incidence of ovarian and multiple pregnancy. 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 maybe 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 usually OHSS 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 thrombo-embolic 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 carries an increased risk of thrombo-embolic events.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.

Pregnancy: There is no indication for use of FOLISAN (r-hFSH) during pregnancy. No teratogenic risk has been reported, following controlled ovarian hyper stimulation, in clinical use with gonadotrophins. However to date, no particular malformative effect has been reported.
In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of FOLISAN (r-hFSH).
Breastfeeding: FOLISAN (r-hFSH) is not indicated during breastfeeding. During lactation, the secretion of prolactin can result in a poor prognosis of ovarian stimulation.

Treatment in women: Very Common(> 1/10): Ovarian cysts; Mild to severe injection site reaction (pain, redness, bruising, swelling and/or irritation at the site of injection); Headache.
Common(1/100 1/10): Mild to moderate OHSS; Abdominal pain and gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal cramps and bloating.
Uncommon(1/1,000 1/100): Severe OHSS.
Rare (1/10,000 1/1,000): Ovarian torsion, a complication of OHSS.
Very rare(< 1/10,000): Thromboembolism usually associated with severe OHSS; Mild systemic allergic reactions (erythema, rash or facial swelling).

Applies only to single presentation forms: FOLISAN (r-hFSH) must not be administered as a mixture with other medicinal products in the same injection, except lutropin alfa or combination of lutropin alfa and follitropin alfa for which studies have shown that co-administration does not significantly alter the activity, stability, pharmacokinetics nor pharmacodynamic properties of the active substances.
Applies to all presentation forms: Concomitant use of FOLISAN (r-hFSH) with other medicinal products used to stimulate ovulation (e.g. HCG, clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dose of FOLISAN (r-hFSH) needed to elicit an adequate ovarian response. No other clinically significant medicinal product interaction has been reported during FOLISAN (r-hFSH) therapy.

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

Store between 2°-8°C. Do not freeze. Protect from light. Store in the original package.
For immediate and single use following first opening and reconstitution.

Trophic Hormones & Related Synthetic Drugs

G03GA05 - follitropin alfa ; Belongs to the class of gonadotropins. Used as ovulation stimulants.

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