Source: European Medicines Agency (EU) Revision Year: 2017 Publisher: Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark
In the following situations, treatment outcome is unlikely to be favourable, and therefore REKOVELLE should not be administered:
REKOVELLE contains a potent gonadotropic substance 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.
Gonadotropin therapy requires time commitment by physicians and supportive healthcare professionals, as well as the availability of appropriate monitoring facilities. Safe and effective use of REKOVELLE calls for monitoring of ovarian response with ultrasound alone, or in combination with measurement of serum estradiol levels, on a regular basis. The dose of REKOVELLE is individualised for each patient to obtain an ovarian response with favourable safety/efficacy profile. There may be a degree of interpatient variability in response to FSH administration, with poor response to FSH in some patients and exaggerated response in others.
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 and hyperprolactinemia, and the appropriate specific treatment should be given.
Use of results obtained with other assays than the ELECSYS AMH Plus immunoassay from Roche for REKOVELLE dose determination is not recommended, as there currently is no standardisation of available AMH assays.
Patients undergoing stimulation of follicular growth may experience ovarian enlargement and may be at risk of developing OHSS. Adherence to the REKOVELLE dose and regimen of administration and careful monitoring of therapy will minimise the incidence of such events.
A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in patients 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.
It is important to stress the value of careful and frequent monitoring of follicular development in order to reduce the risk of OHSS. The following symptoms may be observed in severe cases of OHSS: abdominal pain, discomfort 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, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction.
Excessive ovarian response to gonadotropin treatment seldom gives rise to OHSS unless hCG is administered to trigger final follicular maturation. Furthermore, the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, in cases of ovarian hyperstimulation it is prudent to withhold hCG and advise the patient to refrain from coitus or to use barrier contraceptive methods for at least 4 days. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event. It most often occurs after hormonal treatment has been discontinued. Also, as a consequence of the hormonal changes during pregnancy, late development of OHSS can occur. Because of the risk of developing OHSS patients should be followed for at least two weeks after triggering of final follicular maturation.
Women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, severe obesity (body mass index >30 kg/m²) or thrombophilia may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotropins. Treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however that pregnancy itself as well as OHSS also carry an increased risk of thromboembolic events.
Occurrence of ovarian torsion has been reported for ART cycles. It 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 ovaries. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.
Multiple pregnancy carries an increased risk of adverse maternal and perinatal outcomes. In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age, although twin pregnancy can in rare occasions develop from single embryo transfers. The patients should be advised of the potential risk of multiple births before starting treatment.
The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing controlled ovarian stimulation for ART than following natural conception.
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 has been reported to be higher than 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 treatment regimens for infertility treatment. It is not established whether or not treatment with gonadotropins increases the 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 pregnancy.
Medical conditions that contraindicate pregnancy should also be evaluated before starting treatment with REKOVELLE.
REKOVELLE has not been studied in patients with moderate/severe renal or hepatic impairment.
REKOVELLE contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.
No interaction studies have been performed with REKOVELLE. Clinically significant interactions with other medicinal products have neither been reported during REKOVELLE therapy, nor are expected.
REKOVELLE is not indicated during pregnancy. No teratogenic risk has been reported, following controlled ovarian stimulation, in clinical use with gonadotropins. There are no data from the inadvertent exposure to REKOVELLE in pregnant women. Studies in animals have shown reproductive toxicity with REKOVELLE doses above the recommended maximal dose in humans (section 5.3).
REKOVELLE is not indicated during breastfeeding.
REKOVELLE is indicated for use in infertility (see section 4.1).
REKOVELLE has no or negligible influence on the ability to drive and use machines.
The most frequently reported adverse reactions during treatment with REKOVELLE are headache, pelvic discomfort, OHSS, pelvic pain, nausea, adnexa uteri pain and fatigue. The frequency of these adverse reactions might decrease with repeated treatment cycles, as this has been observed in clinical trials.
The table below (Table 2) displays the adverse reactions in patients treated with REKOVELLE in the pivotal clinical trials according to MedDRA system organ class and frequency as follows: common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 2. Adverse reactions in pivotal clinical trials:
Uncommon: Mood swings
Common: Headache
Uncommon: Somnolence, Dizziness
Common: Nausea
Uncommon: Diarrhoea, Vomiting, Constipation, Abdominal discomfort
Common: OHSS, Pelvic pain, Adnexa uteri pain, Pelvic discomfort
Uncommon: Vaginal haemorrhage, Breast pain, Breast tenderness
Common: Fatigue
OHSS is an intrinsic risk of the ovarian stimulation. Known gastrointestinal symptoms associated with OHSS include abdominal pain, discomfort, and distension, nausea, vomiting and diarrhoea. Ovarian torsion and thromboembolic events are known to be rare complications of ovarian stimulation treatment (see section 4.4).
Immunogenicity in terms of development of anti-FSH antibodies is a potential risk of gonadotropin therapy (see section 5.1).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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