Genric Menopur
MERIONAL 75 IU Powder and solvent for solution for injection.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Active ingredient:
Each one ml vial of Merional 150 IU contains:
150 IU Menotrophin BP (Human menopausal gonadotrophin, HMG) providing 150 IU
follicle stimulating hormone (FSH) and 150 IU luteinizing hormone (LH) activity*.
Menotrophin is purified from human urine.
*The LH activity may be augmented by the addition of Human chorionic
gonadotrophin (hCG) to provide a 1:1 ratio of FSH to LH activities.
Pharmaceutical Form
Powder and solvent for solution for injection
Appearance of the powder: white lyophilised pellet
Appearance of the solvent: clear colourless solution
CLINICAL PARTICULARS
Therapeutic indications
Anovulation (including polycystic ovarian disease, PCOD) in women who have
been unresponsive to treatment with clomiphene citrate.
Stimulation of multifollicular development in patients undergoing assisted
reproductive technologies (ART) such as in-vitro fertilization (IVF), gamete
intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT).
Merional 75 IU may be given in combination with human Chorionic
Gonadotrophin (hCG) for the stimulation of spermatogenesis in men who have
congenital or acquired hypogonadotrophic hypogonadism.
Merional is indicated for use in adults only.
Posology and method of administration
Treatment with Merional should be initiated under the supervision of a physician
experienced in the treatment of fertility issues.
Males
Male infertility: Spermatogenesis is stimulated with hCG (1,000 to 2,000 IU hCG 2-3
times per week) then Merional (75 IU or 150 IU) is administered 2-3 times per week.
This treatment should be continued for at least 3 months before any improvement in
spermatogenesis can be expected. Current clinical experience indicates that treatment
for at least 18 months may be necessary to achieve spermatogenesis.
Females with anovulation (including PCOD)
The objective of treatment with Merional is to develop a single mature Graafian
follicle from which the ovum will be released after the administration of hCG
Merional may be given as a course of daily injections. In menstruating patients
treatment should be started within the first seven days of the menstrual cycle.
The treatment should be adjusted to the individual patient’s response as assessed by
measuring follicle size by ultrasound and/or oestrogen secretion. A commonly used
regimen commences at 75-150 IU of Merional and is increased according to the
patient’s response. The maximum daily dose is usually not higher than 225 IU. If a
patient fails to adequately respond after 4 weeks of treatment, the cycle should be
abandoned and the patient should recommence at a higher initial dose than in the
previous cycle.
When an ideal response is obtained a single injection of 5,000-10,000 IU of hCG
should be administered 24-48 hrs after the last Merional injection. The patient should
be recommended to have coitus on the hCG injection day and the following day.
Alternatively intrauterine insemination (IUI) may be performed.
In the event of an excessive response treatment should be suspended and hCG
withheld (see section 4.4). Treatment should recommence in the next cycle at a lower
dose than in the previous cycle.
Females undergoing controlled ovarian stimulation for multiple follicular
development prior to in-vitro fertilization or other assisted reproductive technologies.
A commonly used protocol for superovulation involves the administration of 150-225
IU of Merional daily commencing on days 2 or 3 of the cycle and continued until
sufficient follicular development has been achieved as assessed by monitoring serum
oestrogen concentrations and/or ultrasound examination with the dose adjusted
according to the patient’s response but usually not higher than 450 IU daily.
Adequate follicular development is usually achieved by the tenth day of treatment
(range 5-20 days).
A single injection of 5,000 IU-10,000 IU of hCG should be administered 24-48 hours
after the last injection to induce follicular maturation.
Pituitary down-regulation in order to suppress the endogenous LH surge and to
control tonic levels of LH is now commonly achieved by administration of a
gonadotrophin releasing hormone (GnRH) agonist. In a commonly used protocol the
administration of Merional is started approximately two weeks after the start of
agonist treatment, both being continued until adequate follicular development has
been achieved. For example, following two weeks of pituitary down-regulation with
an agonist, 150-225 IU Merional are administered for seven days; the dose is then
adjusted according to the patient’s ovarian response.
Experience with ART indicates that in general the treatment success rate remains
stable during the first four attempts and gradually declines thereafter.
Females with anovulation resulting from severe LH and FSH deficiency
In these women (hypogonadotrophic hypogonadism) the objective of Merional
treatment is to develop a single mature Graafian follicle from which the oocyte will
be released following the administration of hCG. As these women are amenorrhoeic
and have low endogenous oestrogen secretion treatment may commence at any time.
The treatment should be adjusted to the individual patient’s response as assessed by
measuring follicle size by ultrasound and/or oestrogen secretion. A commonly used
regimen commences at 75-150 IU of Merional and is increased according to the
patient’s response. Should an increased dose of Merional be deemed appropriate,
dose adaptation should preferably be made after 7-14 day intervals and preferably by
150 IU increments. It may be acceptable to extend the duration of stimulation in any
one cycle up to 5 weeks.
When an ideal response is obtained a single injection of 5,000 IU-10,000 IU of hCG
should be administered 24-48 hrs after the last Merional injection. The patient should
be recommended to have coitus on the hCG injection day and the following day.
Alternatively intrauterine insemination (IUI) may be performed.
Luteal support may be considered since lack of substances with luteotrophic activity
(LH/hCG) after ovulation may lead to a premature loss of the corpus luteum.
In the event of an excessive response treatment should be suspended and hCG
withheld (see section 4.4). Treatment should recommence in the next cycle at a lower
dose than in the previous cycle.
Paediatric population
There is no relevant use of Merional in the paediatric population in the indications
(anovulatory Infertility, females undergoing controlled ovarian stimulation for
multiple follicular development prior to assisted reproductive technologies and males
with hypogonadotrophic hypogonadism).
Method of administration.
Merional is intended for intramuscular and subcutaneous administration. The powder
should be reconstituted immediately prior to use with the solvent provided. In order
to avoid injection of large volumes up to 5 vials of Merional 75 IU may be dissolved
in one ml of solvent. (see section 6.6 for full details).
Appearance of reconstituted product: The solution must be clear and colourless.
Merional should be reconstituted prior to administration according to the instructions
provided in section 6.6.
Patients must be suitably trained in how to handle the product by their physician or
other healthcare professional prior to self-administration.
Contraindications
Merional should not be administered to children or to patients who have:
Hypersensitivity to the active substance menotrophin or to any of the excipients
Tumours of the hypothalamus or pituitary gland and to females who have:
Ovarian enlargement or a cyst not due to polycystic ovarian disease
Gynaecological haemorrhages of unknown cause
Ovarian, uterine or mammary carcinoma
Merional should not be used when an effective response cannot be achieved, such as:
In females:
• Primary ovarian failure
• Malformation of sexual organs incompatible with pregnancy
• Fibroid tumours of the uterus incompatible with pregnancy
In males:
• Primary testicular insufficiency.
Special warnings and precautions for use
Merional is a potent gonadotrophin capable of causing mild to severe adverse
reactions and should only be used by physicians who are thoroughly experienced with
infertility problems and their management. To minimize the risks of Ovarian
Hyperstimulation Syndrome (OHSS) or of multiple pregnancies, ultrasound scans as
well as oestradiol measurements are recommended.
Gonadotrophin therapy requires a certain time commitment by physicians and
supportive health professionals as well as the availability of appropriate monitoring
facilities. In females, safe and effective use of Merional 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 menotrophin administration with a poor
response in some cases. The lowest effective dose in relation to the treatment
objective should be used in both men and women.
Treatment in females
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 Merional
dosage and regimen of administration and careful monitoring of therapy will
minimise the incidence of such events. Accurate interpretation of the indices of
follicular development and maturation require a physician who is experienced in the
interpretation of such data.
Ovarian Hyperstimulation
OHSS is a medical event distinct from uncomplicated ovarian enlargement. It 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, pleural and rarely in pericardial cavities.
The following symptoms may be observed in severe cases of OHSS: abdominal pain,
abdominal distensions, severe ovarian enlargement, weight gain, dyspnoea, oliguria
and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical
examination may reveal hypovolaemia, haemoconcentation, electrolyte imbalances,
ascites, haemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress
and thromboembolic events.
Excessive ovarian response to gonadotrophin treatment seldom gives rise to OHSS
unless hCG is administered to trigger ovulation. Therefore in cases of OHSS it is
prudent to withhold hCG and to advise the patient to refrain from coitus or to use
barrier methods for at least four 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 hCG administration.
To minimize the risk of OHSS or of multiple pregnancy, ultrasound scans as well as
oestradiol measurements are recommended. In anovulation the risk of OHSS and
multiple pregnancy is increased by a serum oestradiol >900 pg/ml (3300pmol/L) and
more than 3 follicles of 14 mm or more in diameter. In ART there is an increased risk
of OHSS with a serum oestradiol > 3000 pg/ml (11000 pmol/L) and 20 or more
follicles of 12 mm or more in diameter. When the oestradiol level is > 5500 pg/ml
(20200 pmol/L) and where there are 40 or more follicles in total, it may be necessary
to withhold hCG administration.
Adherence to recommended Merional dosage, regimen of administration and careful
monitoring of therapy will minimise the incidence of ovarian hyperstimulation and
multiple pregnancy.
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 7-10 days following treatment. Usually, OHSS resolves
spontaneously with the onset of menses.
If severe OHSS occurs, gonadotrophin 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
Multiple pregnancy, especially high order, carries an increased risk of adverse
maternal and perinatal outcomes.
In patients undergoing ovulation induction with Merional the incidence of multiple
pregnancies is increased as compared with natural conception. The majority of multiple conceptions are twins. To minimize 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’s age.
The patient should be advised of the potential risk of multiple births before starting
treatment.
Pregnancy Wastage
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.
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 IVF is reported to 2-5% as compared to 1-1.5%
in the general population.
Neoplasms of the Reproductive System
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 whether or not treatment with
gonadotrophins increases the baseline risk of these tumours in infertile women.
Congenital Malformations
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 females with generally recognised risk factors for thromboembolic events, such as
personal or family history or significant obesity treatment with gonadotrophins may
further increase the risk. In these women, the benefits of gonadotrophin
administration should be weighed against the risks. It should be noted however, that
pregnancy itself also carries an increased risk of thromboembolic events.
Treatment in males
Elevated endogenous FSH levels are indicative of primary testicular failure. Such
patients are unresponsive to Merional/hCG therapy.
Semen analysis is recommended 4-6 months after the beginning of treatment in
assessing the response.
Interaction
Interactions with other medicinal products and other forms of
Concomitant use of Merional with other agents used to stimulate ovulation
(e.g. hCG, clomiphene citrate) may potentiate the follicular response, whereas
concurrent use GnRH agonists to induce pituitary suppression may increase
the dosage of Merional needed to elicit an adequate ovarian response. No other
clinically significant drug interactions have been reported.
Merional should not be administered as mixture with other medicinal products
in the same injection.
Pregnancy and lactation
Pregnancy
Merional 150 IU should not be administered during pregnancy. No teratogenic
risk has been reported following controlled ovarian hyperstimulation, in
clinical use with gonadotrophins. In case of exposure during pregnancy
clinical data are insufficient to exclude a teratogenic effect.
Breastfeeding
Merional should not be used during breast-feeding. During lactation the
secretion of prolactin can entail a poor response to ovarian stimulation.
Fertility
Merional is used in the treatment of some forms of infertility .
