Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Ferring Pharmaceuticals Ltd., Drayton Hall, Church Road, West Drayton, UB7 7PS, United Kingdom
BRAVELLE is contraindicated in women who have:
In the following situations treatment outcome is unlikely to be favourable, and therefore BRAVELLE should not be administered:
BRAVELLE is a potent gonadotropic substance capable of causing mild to severe adverse reactions, and should only be used under the supervision of physicians who are thoroughly familiar with infertility problems and their management.
Gonadotropin 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 BRAVELLE 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 administration, with a poor response to FSH in some patients. The lowest effective dose in relation to the treatment objective should be used.
Repeated exposure to BRAVELLE has not been investigated in clinical trials.
The first injection of BRAVELLE should be performed under direct medical supervision.
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 pituitary or hypothalamic tumours, and appropriate specific treatment given.
Patients undergoing stimulation of follicular growth, whether in the frame of a treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended BRAVELLE dosage and regimen of administration and careful monitoring of therapy will minimise the incidence of such events. Acute interpretation of the indices of follicle development and maturation requires a physician who is experienced in the interpretation of the relevant tests.
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, 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, acute pulmonary distress, and thromboembolic events.
Excessive ovarian response to gonadotropin treatment seldom gives rise to OHSS unless hCG is administered to trigger ovulation. Therefore in cases of ovarian hyperstimulation it is prudent to withhold hCG and advise the patient to refrain from coitus or to use barrier methods for at least 4 days. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event, therefore patients should be followed for at least two weeks after the hCG administration.
Adherence to recommended BRAVELLE dosage, regimen of administration and careful monitoring of therapy will minimise the incidence of ovarian hyperstimulation and multiple pregnancy (see sections 4.2 and 4.8). In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.
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 seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses.
If severe OHSS occurs, gonadotropin treatment should be stopped if still ongoing, the patient hospitalised and specific therapy for OHSS started.
This syndrome occurs with higher incidence in patients with polycystic ovarian disease.
Multiple pregnancy, especially high order, carries an increased risk of adverse maternal and perinatal outcomes.
In patients undergoing ovulation induction with gonadotropins, the incidence of multiple pregnancy 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.
In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the age of the patient. The patient 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 or ART than in the normal population.
Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy is obtained by spontaneous conception or with fertility treatment. The prevalence of ectopic pregnancy after IVF has been reported to be 2 to 5%, as compared to 1 to 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 if treatment with gonadotropins increases the baseline risk of these tumors 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 pregnancies.
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. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however, that pregnancy itself also carries an increased risk of thromboembolic events.
No interaction studies have been performed.
Although there is no clinical experience, it is expected that the concomitant use of BRAVELLE and clomiphene citrate may enhance the follicular response. When using a GnRH agonist for pituitary desensitisation, a higher dose of BRAVELLE may be necessary to achieve adequate follicular response.
BRAVELLE is contraindicated in women who are pregnant or lactating (see section 4.3).
To date no teratogenic risk has been reported when gonadotropins are used clinically for controlled ovarian hyperstimulation. Data on exposed pregnancies are insufficient. Animal experiments did not reveal teratogenic effects (see section 5.3).
No studies on the effects on the ability to drive and use machines have been performed. However, BRAVELLE is unlikely to have influence on the patient’s performance to drive and use machines.
The most commonly reported adverse events during treatment with BRAVELLE in clinical trials are headache and abdominal pain, both occurring in 10% of patients followed by nausea, vaginal haemorrhage, OHSS and abdominal distension, each occurring in 5 to 9% of patients. The table below displays the adverse events occurring in more than 1% of the patients treated with BRAVELLE in clinical trials according to organ class and frequency.
Very common (>1/10)
Common (>1/100, <1/10)
Common: Urinary tract infection, nasopharyngitis
Very common: Headache
Common: Hot flushes
Very common: Abdominal pain
Common: Nausea, vomiting, abdominal distension, abdominal discomfort, diarrhoea, constipation
Common: Rash
Common: Muscle spasms
Common: Vaginal haemorrhage, OHSS, pelvic pain, breast tenderness, vaginal discharge
Common: Pain, injection site pain and reactions (redness, bruising, swelling and/or itching)
As complications of OHSS, venous thromboembolic events and ovarian torsion might occur.
Allergic, local or generalized skin reactions and delayed-type hypersensitivity have been reported with the use of gonadotropin preparations. Repeated exposure to BRAVELLE has not been investigated in clinical trials.
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 Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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