Ovulation induction: for the induction of ovulation in amenorrhoeic or anovulatory women
who have not responded to treatment with clomiphene citrate.
Controlled ovarian hyperstimulation (COH) within a medically assisted reproduction
technology (ART): induction of multiple follicular development in women undergoing
assisted reproduction techniques such as in vitro fertilization (IVF).

Posology
Treatment with Merional should be initiated under the supervision of a physician experienced
in the treatment of infertility problems.
There are great inter- and intra-individual variations in the response of the ovaries to
exogenous gonadotrophins. This makes it impossible to set a uniform dosage scheme. The
dosage should, therefore, be adjusted individually depending on the ovarian response. This
requires ultrasonography and may also include monitoring of oestradiol levels.
Females with anovulation:
The objective of a treatment with Merional is to develop a single mature de Graaf follicle
from which the ovum will be released after the administration of human chorionic
gonadotrophin (hCG).
Merional can be administered by daily injection. In menstruating patients the treatment
should begin within the first 7 days of the menstrual cycle.
A commonly used regimen starts at 75 to 150 IU of FSH per day and is increased if
necessary by 37.5 IU (up to 75 IU), with intervals of 7 or 14 days preferably, in order to
achieve an adequate but not excessive response.
Maximum daily dosages of HMG Merional should generally not exceed 225 IU.
The treatment should be adjusted to the individual patient's response, assessed by measuring
the follicle size by ultrasonography and/or oestrogen levels.
The daily dose is then maintained until pre-ovulatory conditions are reached. Usually, 7 to 14
days of treatment is sufficient to reach this state.
The administration of Merional is then discontinued and ovulation can be induced by
administering human chorionic gonadotrophin (hCG).
If the number of responding follicles is too high or oestradiol levels increase too rapidly, i.e.
more than a daily doubling for oestradiol for two or three consecutive days, the daily dose
should be decreased. Since follicles of over 14 mm may lead to pregnancies, multiple preovulatory
follicles exceeding 14 mm carry the risk of multiple gestations. In that case hCG
should be withheld and pregnancy should be avoided in order to prevent multiple gestations.
The patient should use a barrier method of contraception or refrain from having coitus until
the next menstrual bleeding has started (see section 4.4). The treatment should recommence
in the next treatment cycle at a lower dose than in the previous cycle.
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.
Once the ideal response is obtained, a single injection of 5 000 IU to 10 000 IU of hCG
should be administered 24 to 48 hours after the last Merional injection.
The patient is recommended to have coitus on the day of hCG injection and the following
day.

Alternatively, intrauterine insemination may be performed.
Females undergoing ovary stimulation for induction of multiple follicular development
– as part of assisted reproductive technology:
Pituitary down-regulation in order to suppress the endogenous LH peak and to control basal
levels of LH is now commonly achieved by administration of a gonadotrophin releasing
hormone agonist (GnRH agonist) or gonadotrophin releasing hormone antagonist (GnRHAntagonist).
In a commonly used protocol, the administration of Merional begins approximately two
weeks after the start of the agonist treatment, both treatments are then continued until
adequate follicular development has been achieved. For example, following two weeks of
pituitary down-regulation with agonist, 150 to 225 IU of Merional are administered for the
first five-seven days. The dose is then adjusted according to the patient's ovarian response.
An alternative protocol for controlled ovarian hyperstimulation involves the administration of
150 to 225 IU of Merional daily starting on the 2nd or 3rd day of the cycle. The treatment is
continued until sufficient follicular development has been achieved (assessed by monitoring
of serum oestrogen concentrations and/or ultrasound) with the dose adjusted according to the
patient's response (usually not higher than 450 IU daily). Adequate follicular development is
usually achieved on average around the tenth day of treatment (5 to 20 days).
When an optimal response is obtained a single injection of 5 000 IU to 10 000 IU of hCG
administered 24 to 48 hours after the last Merional injection, to induce final follicular
maturation.
Oocyte retrieval is performed 34-35 hours later.
Paediatric population
The product is not intended for paediatric use
Method of administration
Merional is intended for subcutaneous and intramuscular administration.
The powder should be reconstituted immediately prior to use with the solvent provided.
To prevent painful injections and minimize leakage from the injection site Merional should
be slowly administered subcutaneously. The subcutaneous injection site should be alternated
to prevent lipo-atrophy. Any unused solution should be discarded.
Subcutaneous injections can be self-administered by the patient, provided the physician's
instructions and recommendations are strictly followed.

Anaphylactic reactions may occur, particularly in patients with known hypersensitivity to
gonadotropins. The first injection of Merional should be always performed under direct
medical supervision and in settings with facilities for cardio-pulmonary resuscitation.
The first injection of Merional should be performed under direct medical supervision.
Self-injections of Merional should be performed only by motivated, trained and well
informed patients. Prior to self-injections, the patient must be shown how to perform a
subcutaneous injection, showing her where the injection can be given and how to prepare the
solution to be injected.
Before starting the 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, for which appropriate specific treatments are given.
Ovarian hyperstimulation syndrome (OHSS)
Ultrasonographic assessment of follicular development, and determination of oestradiol
levels should be performed prior to treatment and monitored at regular intervals during
treatment. This is particularly important at the beginning of the stimulation (see below).
Apart from the development of a high number of follicles, oestradiol levels may rise very
rapidly, e.g. more than a daily doubling for two or three consecutive days, and possibly
reaching excessively high values. The diagnosis of ovarian hyperstimulation may be
confirmed by ultrasound examination. If this unwanted ovarian hyperstimulation occurs (i.e.
not as part of controlled ovarian hyperstimulation in medically assisted reproduction
programs), the administration of Merional should be discontinued. In that case pregnancy
should be avoided and hCG must be withheld, because it may induce, in addition to multiple
ovulation, the ovarian hyperstimulation syndrome (OHSS). Clinical symptoms and signs of mild
ovarian hyperstimulation syndrome are abdominal pain, nausea, diarrhoea, and mild to
moderate enlargement of ovaries and ovarian cysts. In rare cases severe ovarian
hyperstimulation syndrome occurs, which may be life-threatening. This is characterised by
large ovarian cysts (prone to rupture), ascites, often hydrothorax and weight gain. In rare

instances, venous or arterial thromboembolism may occur in association with OHSS (see
section 4.8).
Multiple Pregnancies
In patients undergoing ART procedures the risk of multiple pregnancies is related mainly to
the number of replaced embryos. In patients undergoing a treatment for ovulation induction
the incidence of multiple pregnancies and births is increased as compared to natural
conception. The majority of multiple conceptions are twins. To minimise the risk of multiple
pregnancy, careful monitoring of ovarian response is recommended.
Pregnancy wastage
The incidence of spontaneous miscarriage is higher in patients treated with FSH than in the
general population, but it is comparable to the incidence found in women with other fertility
disorders.
Ectopic pregnancy
Since infertile women undergoing assisted reproduction, and particularly IVF, often have
tubal abnormalities the incidence of ectopic pregnancies might be increased. Early ultrasound
confirmation that a pregnancy is intrauterine is therefore important.
Reproductive system neoplasms
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 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
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 gonadotrophins. In these women, the benefits of gonadotrophin administration need to
be weighed against the risks (see section 4.8).

No drug/drug interaction studies have been conducted for Merional in humans. Although
there is no clinical experience, it is expected that the concomitant use of Merional 75-150 IU
and clomiphene citrate may enhance the follicular response. When using GnRH agonist for
pituitary desensitisation, a higher dose of Merional 75-150 IU may be necessary to achieve
adequate follicular response

Merional should not be used during pregnancy.
No teratogenic risk has been reported following controlled ovarian stimulation in clinical use
with urinary gonadotrophins. To date, no other relevant epidemiological data are available.
Animal studies do not indicate teratogenic effect.
Lactation
Merional should not be used during lactation.
During lactation the secretion of prolactin can entail a poor response to ovarian stimulation.

No studies on the effects on the ability to drive and use machines have been performed.
However, Merional is unlikely to have influence on the patient’s performance to drive and
use machines.

The most relevant occurring adverse drug reaction in clinical trials with Merional is (doserelated)
ovarian hyperstimulation (OHSS), generally mild with small ovarian enlargement,
abdominal discomfort or pain. Only one case of OHSS was serious.
The most frequent adverse reactions with Merional were headache and abdominal distension
as well as nausea, fatigue, dizziness and pain at the injection site
The table below displays the main adverse drug reactions (>1%) in women treated with
Merional in clinical trials according to body system and frequency. Within each frequency
grouping, adverse reactions are presented in order of decreasing seriousness.
Within each system organ class, the ADRs are ranked under headings of frequency, most
frequent reactions first, 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), not known (cannot be estimated form the
available data).
Body System* Frequency Adverse Drug Reaction
Nervous system disorders Very common
Common
Headache
Dizziness
Gastro-intestinal disorders Very common Abdominal distension
Abdominal discomfort, Abdominal

Common
pain, Nausea
Musculoskeletal and
connective tissue disorders
Common Back pain, Sensation of heaviness
Reproductive system and
breast disorders
Common
Ovarian hyperstimulation syndrome,
Pelvic pain, Breast tenderness
General disorders and
Application site disorders
Common
Pain at injection site, Injection site
reaction, Fatigue, Malaise, Thirst
Vascular disorders Common Hot flushing
*The most appropriate MedDRA term is listed to describe a certain reaction; synonyms or related conditions are
not listed, but should be taken into consideration as well.
From published studies, the following adverse reactions have been seen in patients treated
with human menopausal gonadotrophins.
*Severe ovarian hyperstimulation (OHSS) with marked ovarian enlargement and cyst
formation, acute abdominal pain, ascites, pleural effusion, hypovolaemia, shock and
thromboembolic disorders. (see also section 4.4)
* Ovarian torsion, usually in association with severe cases of OHSS
* Rupture of ovarian cysts with intraperitoneal haemorrhage, fatal outcomes of cyst rupture
have been reported.
*Allergic reactions also with generalised symptoms have been reported after treatment with
gonadotrophin containing products. (see also section 4.4)
Local reactions at the site of injection such as pain, redness, bruising, swelling and/or
irritation are expected AE following administration of gonadotrophins.
The frequency of such events are expected to be higher with the intramuscular than with the
subcutaneous administration.
To report any side effects:
 Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
o SFDA Call Center: 19999.
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

 Other GCC States:
Please contact the relevant competent authority.

No data on acute toxicity of Menotrophin in humans is available, but the acute toxicity of
urinary gonadotrophin preparations in animal studies has been shown to be very low. Too
high a dosage of Menotrophin may lead to hyperstimulation of the ovaries (see section 4.4).

Pharmacotherapeutic group: Gonadotrophins.
ATC CODE: G03GA02
The active substance in Merional is highly purified human menopausal gonadotrophin.
The FSH activity in Merional is obtained from urine of post-menopausal women; the LH
activity is obtained both from urine of post-menopausal women and urine of pregnant
women. The preparation is standardised to have a FSH/LH activity ratio of approximately 1.
In the ovaries, the FSH-component in HMG induces an increase in the number of growing
follicles and stimulates their development. FSH increases the production of oestradiol in the
granulosa cells by aromatising androgens that originate in the Theca cells under the influence
of the LH-component.

The biological effectiveness of Menotrophin is mainly due to its FSH content. The
pharmacokinetics of Menotrophin following intramuscular or subcutaneous administration
shows great inter-individual variability. According to data collected from the studies
performed with Menotrophin, after a single injection of 300 IU, the maximum serum level of
FSH is reached approximately 19 hours after intramuscular injection and 22 hours after
subcutaneous injection. FSH peak concentrations reached 6.5 ±2.1 IU/L with an AUC0-t of
438.0 ± 124.0 IUxh/L after i.m. administration. After sc administration, Cmax reached 7.5
±2.8 IU/L with an AUC0-t of 485.0 ± 93.5 IUxh/L.
AUC and Cmax levels for LH resulted to be significantly lower in the s.c. group compared to
the i.m group. This result may be due to very low levels detected (close to or below the
detection limits) in both groups and to a great intra- and inter-individual variability.
After that, the serum level decreases by a half-life of approximately 45 hours following
intramuscular administration and 40 hours following subcutaneous administration.
Excretion of Menotrophin, following administration, is predominantly renal.
No pharmacokinetic studies were performed in patients with impaired hepatic or renal
function.

No non-clinical studies have been performed with Merional.

Powder: lactose monohydrate
Solvent: 0.9 per cent sodium chloride solution

In the absence of compatibility studies, this product must not be mixed with other medicinal
products.

Do not store above 25°C. Keep the vial and the ampoule of solvent in the outer carton, in
order to protect from light.

1 set contains: Powder in a vial (type I glass), sealed with a rubber closure and held in place
with a flip-off cap (aluminium and coloured plastic: 75 IU light green, 150 IU dark green) +
1 ml of solvent in an ampoule (type I glass). Pack size of 1 and 10 sets.
Not all pack sizes may be marketed.
The product is packaged in secondary packaging along with instructions for use.

The solution must be prepared just before injection.
Each vial is for single use only. The medicinal product must be reconstituted under aseptic
conditions.
Merional must only be reconstituted with the solvent provided in the package.
A clean preparation area should be prepared and hands should first be washed before the
solution is reconstituted.

Set out all the following items on the clean surface:
- two cotton-wool alcohol swabs (not provided)
- one vial containing Merional powder
- one solvent in ampoule
- one syringe (not provided)
- one needle for preparing the injection (not provided)
- a fine bore needle for subcutaneous injection (not provided)
Reconstitution of the solution for injection
Open the solvent ampoule containing the clear liquid.
A coloured mark is indicated on the tip of the solvent ampoule:
At this mark the ampoule neck is specifically designed to break more easily. Gently tap the
top of the ampoule to dislodge any liquid which may remain in the tip. Firmly press the
ampoule above the neck and break it while levering up at the coloured mark. Carefully place
the opened ampoule onto the preparation area.
Withdraw the solvent:
Attach the reconstitution needle (long needle) to the syringe. With the syringe in one hand,
hold the previously opened solvent ampoule, place the needle into it and withdraw all the
solvent.
Place the syringe very carefully on the preparation area and avoid touching the needle.
Prepare the solution for injection:
1. Remove the aluminium capsule cover from the vial containing Merional powder and
disinfect the rubber area of the cap with a cotton-wool swab moistened with alcohol
2. Take the syringe and slowly inject the solvent into the powder vial through the rubber
cap.
3. Gently roll the vial between the hands until the powder is completely dissolved,
taking care to avoid creating foam.
4. Once the powder is dissolved (which, in general, occurs immediately), slowly draw
the solution into the syringe.
When reconstituting more than 1 vial of Merional, draw back the reconstituted contents of
the first vial into the syringe and slowly inject into a second vial after repeating the step 1 to
4.
If multiple vials of powder are used, the amount of menotrophin contained in 1 ml of
reconstituted solution will be as follows: