Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Theramex Ireland Limited 3<sup>rd</sup> Floor, Kilmore House, Park Lane, Spencer Dock, Dublin 1, D01 YE64, Ireland
Ovaleap must not be used when an effective response cannot be obtained, such as:
In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered medicinal product should be clearly recorded in the patient file.
Follitropin alfa is 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 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 follitropin alfa 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 and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women.
Patients with porphyria or a family history of porphyria should be closely monitored during treatment with follitropin alfa. Deterioration or a first appearance of this condition may require cessation of treatment.
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 given.
Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended follitropin alfa dose and regimen of administration and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests.
In clinical trials, an increase of the ovarian sensitivity to follitropin alfa was shown when administered with lutropin alfa. 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.
No direct comparison of follitropin alfa/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with follitropin alfa/LH is similar to that obtained with hMG.
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. 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 polycystic ovarian syndrome high absolute or rapidly rising serum oestradiol levels (e.g. >900 pg/mL or >3,300 pmol/L in anovulation; >3,000 pg/mL or >11,000 pmol/L in ART) and large number of developing ovarian follicles (e.g. >3 follicles of ≥14 mm in diameter in anovulation; ≥20 follicles of ≥12 mm in diameter in ART).
Adherence to recommended follitropin alfa dose and regimen of administration can minimise the risk of ovarian hyperstimulation (see sections 4.2 and 4.8). 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 ovarian hyperstimulation 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 7 to 10 days following treatment. Therefore, patients should be followed for at least 2 weeks after hCG administration.
In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.
Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing and that the patient be hospitalised and appropriate therapy be started.
In patients undergoing ovulation induction, the incidence of multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes.
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 patient age.
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 stimulation of follicular growth for ovulation induction or 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, was 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 yet 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 pregnancies.
In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, 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.
Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to follitropin alfa/hCG therapy. Follitropin alfa should not be used when an effective response cannot be obtained.
Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response.
Ovaleap contains 0.02 mg/mL of benzalkonium chloride
Benzyl alcohol content
Ovaleap contains 10.0 mg per mL benzyl alcohol
Benzyl alcohol may cause allergic reactions.
High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment as well as in pregnant women or while breast-feeding, because of the risk of accumulation and toxicity (metabolic acidosis).
Ovaleap contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodiumfree”.
Concomitant use of follitropin alfa with other medicinal products used to stimulate ovulation (e.g. hCG, clomifene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dose of follitropin alfa needed to elicit an adequate ovarian response. No other clinically significant medicinal product interaction has been reported during follitropin alfa therapy.
There is no indication for use of Ovaleap during pregnancy. Data on a limited number of exposed pregnancies (less than 300 pregnancy outcomes) indicate no malformative or foeto/neonatal toxicity of follitropin alfa.
No teratogenic effect has been observed in animal studies (see section 5.3). In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of follitropin alfa.
Ovaleap is not indicated during breast-feeding.
Ovaleap is indicated for use in infertility (see section 4.1).
Ovaleap has no or negligible influence on the ability to drive and use machines.
The most commonly reported adverse reactions are headache, ovarian cysts and local injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection).
Mild or moderate OHSS has been commonly reported and should be considered as an intrinsic risk of the stimulation procedure. Severe OHSS is uncommon (see section 4.4).
Thromboembolism may occur very rarely (see section 4.4).
The adverse reactions are ranked under heading of frequency using the following convention: 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. Adverse reactions in women:
Very rare: Mild to severe hypersensitivity reactions, including anaphylactic reactions and shock
Very common: Headache
Very rare: Thromboembolism (both in association with and separate from OHSS)
Very rare: Exacerbation or aggravation of asthma
Common: Abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea
Very common: Ovarian cysts
Common: Mild or moderate OHSS (including associated symptomatology)
Uncommon: Severe OHSS (including associated symptomatology) (see section 4.4)
Rare: Complication of severe OHSS
Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection)
Table 2. Adverse reactions in men:
Very rare: Mild to severe hypersensitivity reactions, including anaphylactic reactions and shock
Very rare: Exacerbation or aggravation of asthma
Common: Acne
Common: Gynaecomastia, varicocele
Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection)
Common: Weight gain
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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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