Follitropin alfa, lutropin alfa.
One vial contains 150 IU (equivalent to 11 micrograms) of follitropin alfa (r-hFSH) and 75 IU (equivalent to 3.0 micrograms) of lutropin alfa (r-hLH). The reconstituted solution contains 150 IU r-hFSH and 75 IU r-hLH per milliliter. Follitropin alfa and lutropin alfa are produced in genetically engineered Chinese Hamster Ovary (CHO) cells.
Solvent: clear colourless solution.
Pharmacotherapeutic group: Gonadotrophins. ATC code: G03GA05/G03GA07.
Pharmacology: Pharmacodynamics: Pergoveris is a preparation of follicle stimulating hormone and luteinising hormone produced by genetically engineered Chinese Hamster Ovary (CHO) cells.
In clinical trials the efficacy of the combination of follitropin alfa and lutropin alfa has been demonstrated in women with hypogonadotropic hypogonadism.
In the stimulation of follicular development in anovulatory women deficient in LH and FSH, the primary effect resulting from administration of lutropin alfa is an increase in oestradiol secretion by the follicles, the growth of which is stimulated by FSH.
In one clinical study of women with hypogonadotrophic hypogonadism and an endogenous serum LH concentration below 1.2 IU/L the appropriate dose of r-hLH (lutropin alfa) was investigated. A dose of 75 IU r-hLH daily (in combination with 150 IU follitropin alfa (r-hFSH)) resulted in adequate follicular development and oestrogen production. A dose of 25 IU r-hLH daily (in combination with 150 IU follitropin alfa) resulted in insufficient follicular development. Therefore, administration of less than one vial of Pergoveris daily may provide too little LH-activity to ensure adequate follicular development.
Pharmacokinetics: Follitropin alfa and lutropin alfa have shown the same pharmacokinetic profile as follitropin alfa and lutropin alfa separately.
Follitropin alfa: 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 gonadotrophin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.
Lutropin alfa: Following intravenous administration, lutropin alfa is rapidly distributed with an initial half-life of approximately one hour and eliminated from the body with a terminal half-life of about 10-12 hours. The steady state volume of distribution is around 10-14 l. Lutropin alfa shows linear pharmacokinetics, as assessed by AUC which is directly proportional to the dose administered. Total clearance is about 2 l/h, and less than 5% of the dose is excreted in the urine. The mean residence time is approximately 5 hours.
Following subcutaneous administration, the absolute bioavailability is approximately 60%; the terminal half-life is slightly prolonged. The lutropin alfa pharmacokinetics following single and repeated administration of lutropin alfa are comparable and the accumulation ratio of lutropin alfa is minimal. There is no pharmacokinetic interaction with follitropin alfa when administered simultaneously.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Pergoveris is indicated for the stimulation of follicular development in women with severe Luteinising Hormone LH and Follicle Stimulating Hormone FSH deficiency.
In clinical trials, these patients were defined by an endogenous serum LH level < 1.2 IU/l.
Treatment with Pergoveris should be initiated under the supervision of a physician experienced in the treatment of fertility problems.
Pergoveris is intended for subcutaneous administration.
The powder should be reconstituted immediately prior to use with the solvent provided.
In LH and FSH deficient women (hypogonadotrophic hypogonadism), the objective of Pergoveris therapy is to develop a single mature Graafian follicle from which the oocyte will be liberated after the administration of human chorionic gonadotrophin (hCG). Pergoveris should be given as a course of daily injections. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time.
Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and oestrogen response. A recommended regimen commences with one vial of Pergoveris daily. If less than one vial of Pergoveris daily is used, the follicular response may be unsatisfactory because the amount of lutropin alfa may be insufficient (see Pharmacology: Pharmacodynamics under Actions). 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 using a licensed follitropin alfa preparation. 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 to 10,000 IU hCG should be administered 24-48 hours after the last Pergoveris injection. The patient is recommended to have coitus on the day of, and on the day following, hCG administration. Alternatively, intrauterine insemination (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.
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 these trials the ovulation rate per cycle was 70-75%.
The effects of an overdose of Pergoveris are unknown. Nevertheless one could expect ovarian hyperstimulation syndrome to occur, which is further described in Precautions.
Pergoveris is contraindicated in patients with: hypersensitivity to the active substances follitropin alfa and lutropin alfa or to any of the excipients; case of tumours of the hypothalamus and pituitary gland; ovarian enlargement or cyst not due to polycystic ovarian disease; gynaecological haemorrhages of unknown aetiology; ovarian, uterine or mammary carcinoma.
Pergoveris must not be used when an effective response cannot be obtained, such as: primary ovarian failure, malformations of sexual organs incompatible with pregnancy, fibroid tumours of the uterus incompatible with pregnancy.
Pergoveris contains potent gonadotrophic substances 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. Gonadotrophin 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 Pergoveris 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/LH administration, with a poor response to FSH/LH in some patients. The lowest effective dose in relation to the treatment objective should be used in women.
Self-administration of Pergoveris should only be performed by patients who are well motivated, adequately trained and with access to expert advice.
The first injection of Pergoveris should be performed under direct medical supervision.
Patients with porphyria or a family history of porphyria should be closely monitored during treatment with Pergoveris. Deterioration or a first appearance of this condition may require cessation of treatment.
Pergoveris contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially "sodium-free".
Pergoveris contains sucrose 30 mg per dose. This should be taken into account in patients with diabetes mellitus.
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 the following: hypothyroidism, adrenocortical deficiency, hyperprolactinemia and pituitary or hypothalamic tumours.
Appropriate specific treatment should be given.
Patients undergoing stimulation of follicular growth are at an increased risk of developing hyperstimulation in view of possible excessive oestrogen response and multiple follicular development.
In clinical trials, lutropin alfa in combination with follitropin alfa has been shown to increase the ovarian sensitivity to gonadotropins. 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 using a licensed follitropin alfa preparation.
Ovarian Hyperstimulation Syndrome (OHSS) is a medical event distinct from uncomplicated ovarian enlargement. OHSS is a syndrome 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, acute pulmonary distress, and thromboembolic events.
Very rarely, severe OHSS may be complicated by pulmonary embolism, ischemic stroke and myocardial infarction.
Excessive ovarian response seldom gives rise to significant hyperstimulation unless hCG is administered to induce ovulation. Therefore in cases of ovarian hyperstimulation it is prudent to withhold hCG in such cases and advise the patient to refrain from coitus or use barrier methods for at least 4 days. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event, therefore patients should be followed for at least two weeks after hCG administration.
To minimise the risk of OHSS or of multiple pregnancy (see as follows), ultrasound scans as well as oestradiol measurements are recommended. In anovulation the risk of OHSS is increased by a serum oestradiol level > 900 pg/ml (3,300 pmol/l) and by the presence of more than 3 follicles of 14 mm or more in diameter.
Adherence to recommended Pergoveris and FSH dosage and regimen of administration and careful monitoring of therapy will minimise the incidence of ovarian hyperstimulation and multiple pregnancy (see as follows).
OHSS may be more severe and more protracted if pregnancy occurs. Most often, OHSS occurs after hormonal treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses.
If severe OHSS occurs, gonadotrophin treatment should be stopped if still ongoing. The patient should be hospitalised and specific therapy for OHSS started.
This syndrome occurs with higher incidence in patients with polycystic ovarian disease. In patients undergoing induction of ovulation, the incidence of multiple pregnancies and births is increased compared with natural conception. The majority of multiple conceptions are twins. To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.
The patients should be advised of the potential risk of multiple births before starting treatment.
The incidence of pregnancy wastage by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction than in the normal population.
When risk of OHSS or multiple pregnancies is assumed, treatment discontinuation should be considered. 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 IVF was reported to be 2 to 5%, as compared to 1 to 1.5% in the general population.
There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. It is not yet established whether or not treatment with gonadotrophins increases the baseline risk of these tumours in infertile women.
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.
In women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotrophins may further increase the risk.
In these women, the benefits of gonadotrophin administration need to be weighed against the risks. It should be noted however, that pregnancy itself 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.
Pergoveris should not be used during pregnancy or lactation.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See table.)
Click on icon to see table/diagram/image
Pergoveris should not be administered as a mixture with other medicinal products, in the same injection, except follitropin alfa.
Incompatibilities: This medicinal product must not be mixed with other medicinal products except follitropin alfa.
Special precautions for disposal and other handling: For single use only.
Pergoveris must be reconstituted with the solvent before use.
The reconstituted solution should not be administered if it contains particles or is not clear.
Pergoveris may be mixed with follitropin alfa and coadministered as a single injection.
Any unused medicinal product or waste material should be disposed off in accordance with local requirements.
If administering Pergoveris to oneself, please carefully read the following instructions: Wash hands. It is important that hands and the items to be used are as clean as possible.
Assemble and lay out on a clean surface everything the patient needs: one vial containing Pergoveris powder, one solvent vial, two alcohol swabs, one syringe, one needle for reconstitution and a fine bore needle for subcutaneous injection, sharp container.
Remove the protective cap from the solvent vial. Attach the reconstitution needle to the syringe and draw up some air into the syringe by pulling the plunger to approximately the 1 ml mark. Then, insert the needle into the vial, push the plunger to expel the air, turn the vial upside down and gently draw up all the solvent. Set the syringe down carefully on the work-surface taking care not to touch the needle.
Prepare the injection solution: Remove the protective cap from the Pergoveris powder vial, pick up the syringe and slowly inject the solvent into the vial of powder. Swirl gently without removing the syringe. Do not shake. After the powder has dissolved (which usually occurs immediately), check that the resulting solution is clear and does not contain any particles. Turn the vial upside down, gently draw the solution back into the syringe.
Change the needle for the fine bore needle and remove any air bubbles: If air bubbles are seen in the syringe, hold the syringe with the needle pointing upwards and gently flick the syringe until all the air collects at the top. Push the plunger until the air bubbles are gone.
Immediately inject the solution: The doctor or nurse will have already advised where to inject (e.g. tummy, front of thigh). Wipe the chosen area with an alcohol swab. Firmly pinch the skin together and insert the needle at a 45° to 90° angle using a dart-like motion. Inject under the skin, as were taught. Do not inject directly into a vein. Inject the solution by pushing gently on the plunger. Take as much time as needed to inject all the solution. Immediately withdraw the needle and clean the skin with an alcohol swab using a circular motion.
Dispose off all used items: Once finished with the injection, immediately discard all needles and empty glass containers in the sharp container provided. Any unused solution must be discarded.
Do not store above 25°C.
Store in the original package in order to protect from light.
G03GA30 - combinations ; Belongs to the class of gonadotropins. Used as ovulation stimulants.
Powd for inj (white lyophilised pellet in a vial) x 1's.