Pergoveris 150 IU/75 IU powder and solvent for solution for injection follitropin alfa and lutropin alfa.

 Composition:

One vial contains 150 IU (equivalent to 11 micrograms) of follitropin alfa* (r-hFSH) and 75 IU (equivalent to 3 micrograms) of lutropin alfa* (r-hLH). *produced in genetically engineered Chinese hamster Ovary (CHO) cells.

 Indications:

Pergoveris is indicated for the stimulation of follicular development in adult women with severe LH and FSH deficiency. In clinical trials, these patients were defined by an endogenous serum LH level < 1.2 IU/l.

 

Dosage and administration:

 

Treatment should be initiated under the supervision of a physician experienced in the treatment of fertility problems. Pergoveris is intended for subcutaneous administration. The first injection of Pergoveris should be administered under direct medical supervision. The powder should be reconstituted immediately prior to use with the solvent provided. Treatment should be tailored to the individual patient’s response. A recommended regimen commences with one vial of Pergoveris daily. If a FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5 IU to 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 250 micrograms of r-hCG or 5,000 IU to 10,000 IU human chorionic gonadotrophin (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. If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should restart in the next cycle using a lower dose of FSH. Safety, efficacy, and pharmacokinetics have not been established in patients with renal or hepatic impairment.

 Contraindications:

Hypersensitivity to the active substances or to any of the excipients, tumours of the hypothalamus and pituitary gland, ovarian enlargement or ovarian cyst unrelated to polycystic ovarian disease and of unknown origin, gynaecological haemorrhages of unknown origin, ovarian, uterine or mammary carcinoma or when an effective response cannot be obtained such as: primary ovarian failure, malformation of the sexual organs incompatible with pregnancy or fibroid tumours of the uterus incompatible with pregnancy.

 Precautions:

Monitor patients for ovarian response with ultrasound alone or preferably in combination with measurement of serum oestradiol levels on a regular basis. Patients with porphyria or a family history of porphyria should be closely monitored during treatment with Pergoveris. In these patients, Pergoveris may increase the risk of an acute attack. Deterioration or first appearance of this condition may require cessation of treatment. Assess couple’s infertility and putative contraindications for pregnancy before starting treatment.

 

In particular, evaluate patients for hypothyroidism, adrenocortical deficiency, hyperprolactinaemia, and appropriate specific treatment should be given. 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, 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. Independent risk factors for developing OHSS include young age, lean body mass, polycystic ovarian syndrome, higher doses of exogenous gonadotrophins, high absolute or rapidly rising serum oestradiol level (> 900 pg/ml or > 3,300 pmol/l in anovulation), previous episodes of OHSS and large number of developing ovarian follicles (3 follicles of ≥ 14 mm in diameter in anovulation).

Adherence to recommended Pergoveris and FSH dosage 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 OHSS 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. Usually, OHSS resolves spontaneously with the onset of menses. Therefore patients should be followed for at least two weeks after hCG administration. If severe OHSS occurs, gonadotropin 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. When a risk of OHSS is assumed, treatment discontinuation should be considered.

Ovarian torsion has been reported after treatment with other gonadotropins. This may be associated with other risk factors such as OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and polycystic ovarian syndrome. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.

 

Incidence of multiple pregnancies and births is increased compared with natural conception in patients undergoing induction of ovulation. Incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction than in the normal population. Ectopic pregnancy may occur, especially in women with a history of prior tubal disease. The prevalence of ectopic pregnancy after ART was reported to be higher than in the general population. Ovarian and other reproductive system neoplasms (benign and malignant) have been reported in women who have undergone multiple regimens for infertility treatment. In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, treatment with gonadotropins may further increase the risk. 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. There is no indication for the use of Pergoveris during pregnancy. Pergoveris is not indicated during breastfeeding.

 Interactions:

Pergoveris should not be administered as a mixture with other medicinal products, in the same injection, except follitropin alfa for which studies have shown that co-administration does not significantly alter the activity, stability, pharmacokinetic nor pharmacodynamic properties of the active substances.

Side effects:

 

The frequency categories used are:

 Very common (≥1/10),

 Common (≥1/100 to <1/10),

 Uncommon (≥1/1,000 to <1/100),

 Rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

 

Very common: Headache; Ovarian cysts; Mild to severe injection site reactions (e.g. pain, erythema, haematoma, bruising, swelling and/or irritation at the site of injection)

Common: Abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea; Breast pain, pelvic pain, mild or moderate OHSS (including associated symptomatology);

Uncommon: Severe OHSS (including associated symptomatology);

Rare: Complication of severe OHSS;

Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock; Thromboembolism, usually associated with severe OHSS; Exacerbation or aggravation of asthma.

 

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