Follitropin α, lutropin α.
Each vial contains follitropin α (r-hFSH) 150 IU (equivalent to 11 mcg) and lutropin α (r-hLH) 75 IU (equivalent to 3 mcg).
Each mL of the reconstituted solution contains r-hFSH 150 IU and r-hLH 75 IU.
Follitropin α and lutropin α are produced in genetically engineered Chinese Hamster Ovary (CHO) cells.
Pharmacotherapeutic Group: Gonadotrophins. ATC Code: G03GA05/G03GA07.
Pharmacology: Pharmacodynamics: Pergoveris is a preparation of follicle-stimulating hormone (FSH) and luteinising hormone (LH) produced by genetically engineered Chinese Hamster Ovary (CHO) cells.
In clinical trials, the efficacy of the combination of follitropin α (r-hFSH) and lutropin α (r-hLH) 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 the administration of lutropin α is an increase in oestradiol secretion by the follicles, the growth of which is stimulated by FSH.
In 1 clinical study of women with hypogonadotropic hypogonadism and an endogenous serum LH concentration <1.2 IU/L, the appropriate dose of lutropin α was investigated. A dose of lutropin α 75 IU daily (in combination with follitropin α 150 IU) resulted in adequate follicular development and oestrogen production. A dose of lutropin α 25 IU daily (in combination with follitropin α 150 IU) resulted in insufficient follicular development. Therefore, administration of <1 vial of Pergoveris daily may provide too little LH activity to ensure adequate follicular development.
Pharmacokinetics: Follitropin α and lutropin α have shown the same pharmacokinetic profile as follitropin α and lutropin α separately.
Follitropin α: Following IV administration, follitropin α 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 1 day. The steady-state volume of distribution and total clearance are 10 L and 0.6 L/hour, respectively. One-eighth (1/8) of the follitropin α dose is excreted in the urine.
Following SC administration, the absolute bioavailability is about 70%. Following repeated administration, follitropin α accumulates 3-fold achieving a steady-state within 3 to 4 days. In women whose endogenous gonadotrophin secretion is suppressed, follitropin α has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.
Lutropin α: Following IV administration, lutropin α is rapidly distributed with an initial half-life of approximately 1 hour and eliminated from the body with a terminal half-life of 10-12 hours. The steady-state volume of distribution is around 10 to 14 L. Lutropin α shows linear pharmacokinetics, as assessed by the AUC which is directly proportional to the dose administered. Total clearance is about 2 L/hour and <5% of the dose is excreted in the urine. The mean residence time is approximately 5 hours.
Following SC administration, the absolute bioavailability is approximately 60%; the terminal half-life is slightly prolonged. The lutropin α pharmacokinetics following single and repeated administration of lutropin α are comparable and the accumulation ratio of lutropin α is minimal. There is no pharmacokinetic interaction with follitropin α when administered simultaneously.
Toxicology: Preclinical Safety Data: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity and genotoxicity.
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.
In luteinising hormone (LH) and follicle stimulating hormone (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 1 vial daily. If <1 vial of Pergoveris is used, the follicular response may be unsatisfactory because the amount of lutropin α may be insufficient (see Pharmacology under Actions).
If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7 to 14 day intervals and preferably by 37.5 to 75 IU increments using a licensed follitropin α preparation. It may be acceptable to extend the duration of stimulation in any 1 cycle to up to 5 weeks.
When an optimal response is obtained, a single injection of hCG 5000-10,000 IU should be administered 24-48 hrs 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%.
Administration: Pergoveris is intended for SC administration. The powder should be reconstituted immediately prior to use with the solvent provided.
The effects of an overdose of Pergoveris are unknown. Nevertheless, one could expect ovarian hyperstimulation syndrome to occur (see Precautions).
Hypersensitivity to follitropin α, lutropin α or to any of the excipients of Pergoveris. Case of tumours of the hypothalamus and pituitary glands; 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 eg, primary ovarian failure, malformations of sexual organs incompatible with pregnancy and fibroid tumours of the uterus.
Use in pregnancy & lactation: Pergoveris should not be used during pregnancy or lactation.
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 1st 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 1st appearance of this condition may require cessation of treatment.
Pergoveris contains sodium <1 mmol (23 mg)/dose ie, essentially "sodium-free".
Pergoveris contains sucrose 30 mg/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 α in combination with follitropin α has been shown to increase the ovarian sensitivity to gonadotrophins. 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 α 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 and 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 hrs to several days) to become a serious medical event, therefore patients should be followed for at least 2 weeks after hCG administration.
To minimise the risk of OHSS or of multiple pregnancy (see text 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 (3300 pmol/L) and by the presence of >3 follicles of ≥14 mm 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 text 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 7-10 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 2-5%, as compared to 1-1.5% 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 (eg, maternal age, sperm characteristics) and multiple pregnancies.
In women with generally recognised risk factors for thromboembolic events eg, 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 thromboembolic events.
Effects on the Ability to Drive or Operate Machinery: 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.
Frequency is defined as: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Nervous System Disorders:
Very Common: Headache. Common: Somnolence.
Respiratory, Thoracic and Mediastinal Disorders:
Very Rare: Exacerbation or worsening of asthma.
Common: Abdominal pain and gastrointestinal symptoms eg, nausea, vomiting, diarrhoea, abdominal cramps and bloating.
Very Rare: Thromboembolism, usually associated with severe ovarian hyperstimulation syndrome (OHSS).
General Disorders and Administration Site Conditions:
Very Common: Mild to severe injection site reaction (pain, redness, bruising, swelling and/or irritation at the site of injection).
Immune System Disorders:
Very Rare: Mild systemic allergic reactions (eg, mild forms of erythema, rash, facial swelling, urticaria, oedema, difficulty in breathing). Serious cases of allergic reactions, including anaphylactic reactions, have also been reported.
Reproductive System Disorders:
Very Common: Ovarian cysts. Common: Breast and pelvic pain, mild to moderate OHSS. Uncommon: Severe OHSS. Rare: Ovarian torsion, a complication of OHSS.
Pergoveris should not be administered as a mixture with other medicinal products, in the same injection except follitropin α.
Pergoveris is for single use only. It 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 α and co-administered as a single injection.
Any unused medicinal product or waste material should be disposed off in accordance with local requirements.
Instructions for Self-Administration of Pergoveris: 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 needed: 1 vial containing Pergoveris powder, 1 solvent vial, 2 alcohol swabs, 1 syringe, 1 needle for reconstitution and a fine bore needle for SC 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. Choose the site of injection (eg, tummy, front of thigh). Wipe the chosen area with an alcohol swab. Firmly pinch the skin together and insert the needle at a 45°-90° angle using a dart-like motion. Inject under the skin. 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 of 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. Protect from light.
G03GA30 - combinations ; Belongs to the class of gonadotropins. Used as ovulation stimulants.