Pergoveris

Each vial contains follitropin α (r-hFSH) 150 IU (equivalent to 11 mcg), lutropin α (r-hLH) 75 IU (equivalent to 3 mcg).
It also contains the following excipients: Powder: Sucrose, polysorbate 20, methionine, disodium phosphate dihydrate, sodium dihydrogen phosphate monohydrate, phosphoric acid, sodium hydroxide for pH adjustment.
Solvent: Water for injection.
The reconstituted solution contains r-hFSH 150 IU and r-hLH 75 IU per mL. These 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 luteinizing hormone (LH) produced by genetically engineered Chinese Hamster ovary (CHO) cells.
In clinical trials, the efficacy of the combination of follitropin α and lutropin α 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 α is an increase in oestradiol secretion by the follicles, the growth of which is stimulated by follitropin α.
In 1 clinical study of women with hypogonadotrophic 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 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 Pergoveris <75 IU daily may provide inadequate LH-activity to ensure satisfactory 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 (t_½) of around 2 hrs and eliminated from the body with a terminal t_½ of about 1 day. The steady state volume of distribution and total clearance are 10 L/hr and 0.6 L/hr, 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 3-4 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 t_½ of approximately 1 hr and eliminated from the body with a terminal t_½ of about 10-12 hrs. The steady state volume of distribution is approximately 10-14 L. Lutropin α shows linear pharmacokinetics, as assessed by AUC which is directly proportional to the dose administered. Total clearance is around 2 L/hr and <5% of the dose is excreted in the urine. The mean residence time is approximately 5 hrs.
Following SC administration, the absolute bioavailability is approximately 60%; the terminal t_½ 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 lutropin α when administered simultaneously.
Preclinical Safety Data: Nonclinical 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 luteinizing 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 disorders.
Pergoveris is intended for SC administration. The injection site should be alternated daily. 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 1 vial of Pergoveris daily.
If <1 vial of Pergoveris daily 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 7-14 day intervals and preferably by 37.5-75 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 choriogonadotropin α (r-hCG) 250 mcg or 5000 IU-10,000 IU hCG 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 hormones 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 recommend 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 α and lutropin α or to any of the excipients of Pergoveris.
Case of hypothalamus and pituitary gland tumours; 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 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 and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used.
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, Pergoveris may increase the risk of an acute attack. Deterioration or a 1st appearance of this condition may require cessation of treatment. Pergoveris contains <1 mmol sodium (23 mg) per 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. 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 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 α preparation.
Ovarian hyperstimulation syndrome (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.
Mild manifestations of OHSS include abdominal pain, abdominal discomfort and distension, and enlarged ovaries. Moderate OHSS may additionally present with nausea, vomiting, ultrasound evidence of ascites and marked ovarian enlargement.
Severe OHSS further includes symptoms eg, severe ovarian enlargement, weight gain, dyspnoea or oliguria. Clinical evaluation may reveal signs eg, hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, pleural effusions, or acute pulmonary distress and thromboembolic events, haemoperitonium, hydrothorax.
Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events eg, pulmonary embolism, ischemic stroke and myocardial infarction.
Excessive ovarian response seldom gives rise to significant hyperstimulation unless hCG is administered to induce ovulation. Therefore, if signs of ovarian hyperstimulation occur, it is recommended that hCG be withheld 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 wks after hCG administration.
To minimize the risk of OHSS or of multiple pregnancy (see texts on Multiple Pregnancies as follows), monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to early identify risk factors. 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 can minimize the risk of ovarian hyperstimulation (see Dosage & Administration).
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, it is recommended that gonadotrophin treatment be stopped if still ongoing. The patient should be hospitalized and specific therapy for OHSS started.
This syndrome occurs with higher incidence in patients with polycystic ovarian disease.
Multiple Pregnancies: In patients undergoing induction of ovulation, the incidence of multiple pregnancies is increased compared with natural conception. The majority of multiple conceptions are twins. To minimize 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.
Pregnancy Loss: The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction than following natural conception. When risk of OHSS or multiple pregnancies is assumed, treatment discontinuation should be considered.
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 drug regimens for infertility treatment. It is not yet established whether or not treatment with gonadotrophins increases the risk of these tumours in infertile women.
Congenital Anomalies: The prevalence of congenital anomalies after the use of assisted reproductive technology (ART) may be slightly higher than after spontaneous conceptions although it is unclear whether this is related to factors inherent to the couple's infertility or the ART procedures. Based on clinical trials and post-marketing data, there is no evidence that gonadotropin use increase the risk of congenital anomalies in the offspring of the patients receiving infertility treatments.
Thromboembolic Events: In women with recent or ongoing thromboembolic disease or women with generally recognized risk factors for thromboembolic events eg, personal or family history, treatment with gonadotrophins may further increase the risk for aggravation or occurrence of such events. 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 Ability to Drive and Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed.
Use in pregnancy & lactation: Pergoveris should not be used during pregnancy or lactation.

Pergoveris should not be used during pregnancy or lactation.

The following definitions apply to the frequency terminology used hereafter: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), and very rare (<1/10,000). Frequency not known (cannot be estimated from the available data).
Immune System Disorders: Very Rare: Mild to severe systemic allergic hypersensitivity reaction (eg, mild forms of erythema, rash, facial swelling, urticaria, oedema, difficulty breathing). Serious cases of allergic reactions, including anaphylactic reactions, have also been reported.
Nervous System Disorders: Very Common: Headache. Common: Somnolence.
Vascular Disorders: Very Rare: Thromboembolism, usually associated with severe ovarian hyperstimulation syndrome (OHSS).
Respiratory, Thoracic and Mediastinal Disorders: Very Rare: Exacerbation or worsening of asthma.
Gastrointestinal Disorders: Common: Abdominal pain and gastrointestinal symptomps eg, nausea, vomiting, diarrhea, abdominal cramps and bloating.
Reproductive System and Breast Disorders: Very Common: Ovarian cysts. Common: Mild or moderate OHSS (including associated symptomatology), breast pain, pelvic pain. Uncommon: Severe OHSS (including associated symptomatology). Rare: Complication of severe OHSS, ovarian torsion.
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).

Pergoveris must not be administered as a mixture with other medicinal products, in the same injection, except follitropin α. No other clinically significant drug interaction has been reported during Pergoveris therapy.
Incompatibilities: This medicinal product must not be mixed with other medicinal products except follitropin α.

Instructions for Use and 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 α and co-administration as a single injection.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
If Pergoveris is for self-administration, please carefully read the following instructions: Wash hands. It is important that hands and the items to be used is clean as possible.
Assemble and lay out on a clean surface all things 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 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 you see air bubbles 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: 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, as advised by the doctor or nurse (eg, tummy, front of thigh). Do not inject directly into a vein. Inject the solution by pushing gently on the plunger. Take as much time as you need 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 from 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.
Shelf-Life: 3 years.

Trophic Hormones & Related Synthetic Drugs

G03GA30 - combinations ; Belongs to the class of gonadotropins. Used as ovulation stimulants.

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