Special Warning : אזהרת שימוש

4.4       Special warnings and precautions for use

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 care 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.

Porphyria
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 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 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.

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.

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
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.

Multiple pregnancy
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. Multiple pregnancy, especially high order, carry an increased risk of adverse maternal and perinatal outcomes. 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. When risk of multiple pregnancies is assumed, treatment discontinuation should be considered.

Pregnancy loss
The 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
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 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 thromboembolic events, such as personal or family history, thrombophilia or severe obesity (body mass index > 30 kg/m2), 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 as well as OHSS also carries an increased risk of thromboembolic events.

Sodium
Pergoveris contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium- free”.


Sucrose
Pergoveris contains 30 mg of sucrose per dose. This should be taken into account in patients with diabetes mellitus.

Effects on Driving

4.7       Effects on ability to drive and use machines

Pergoveris has no or negligible influence on the ability to drive and use machines.