MENOPUR 150 IU POWDER AND SOLVENT FOR SOLUTION FOR INJECTION

Active substance: MENOTROPHIN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
MENOPUR 150 IU powder and solvent for solution for injection.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial with powder contains highly purified menotrophin (human
menopausal gonadotrophin, HMG) corresponding to 150 IU human follicle
stimulating hormone activity (FSH) and 150 IU human luteinizing hormone
activity (LH).
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Powder and solvent for solution for injection.
Appearance of powder: white to off-white lyophilied cake.
Appearance of solvent: clear colourless solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of female and male infertility in the following groups of patients:

-Anovulatory women: MENOPUR can be used to stimulate follicle
development in amenorrhoeic patients. Clomiphene (or a similar
ovulation inducing agent which influences steroid feed-back
mechanisms) is the preferred treatment for women with a variety of
menstrual cycle disturbances, including luteal phase insufficiency with
anovulatory cycles and with normal prolactin, and also amenorrhoeic
patients with evidence of endogenous oestrogen production but normal
prolactin and normal gonadotrophin levels. Non-responders may then be
selected for menotrophin therapy.
-Women undergoing superovulation within a medically assisted
fertilisation programme: MENOPUR can be used to induce multiple
follicular development in patients undergoing an assisted conception
technique such as in-vitro fertilisation (IVF).
-Hypogonadotrophic hypogonadism in men: MENOPUR may be given in
combination with human chorionic gonadotrophin (e.g. Choragon) for
the stimulation of spermatogenesis. Patients with primary testicular
failure are usually unresponsive.

4.2

Posology and method of administration
Anovulatory infertility:
Menotrophin is administered to induce follicular maturation and is followed
by treatment with chorionic gonadotrophin to stimulate ovulation and
corpus luteum formation.
The dosage and schedule of treatment must be determined according to the
needs of each patient. Response is monitored by studying the patient’s urinary
oestrogen excretion or by ultrasound visualisation of follicles. Menotrophin
may be given daily by either intramuscular or subcutaneous injection to
provide a dose of 75 to 150 units of FSH and 75 to 150 units of LH, and
gradually adjusted if necessary until an adequate response is achieved,
followed after 1 or 2 days by chorionic gonadotrophin. In menstruating
patients, treatment should be started within the first 7 days of the menstrual
cycle. The treatment course should be abandoned if no response is seen in 3
weeks. This treatment cycle may be repeated at least twice more if necessary.
Alternatively, three equal doses of menotrophin, each providing 225 to 375
units of FSH with 225 to 375 units of LH, may be given on alternate days
followed by chorionic gonadotrophin one week after the first dose.
In the daily therapy schedule, the dose is gradually increased until oestrogen
levels start to rise. The effective dose is then maintained until adequate

preovulatory oestrogen levels are reached. If oestrogen levels rise too rapidly,
the dose should be decreased.
As a measure of follicle maturity the following values can be taken:
-total urinary oestrogen: 75 -150 micrograms (270 – 540 nmol)/24 hours
-plasma 17 beta-oestradiol: 400 -800 picograms/ml (1500 – 3000 pmol/L).
When adequate pre-ovulatory oestrogen levels have been reached,
administration of MENOPUR is stopped, and ovulation may then be induced
by administering human chorionic gonadotrophin at a dose of 5000 -10000
IU.
Women undergoing superovulation in IVF or other assisted conception
techniques:
In in-vitro fertilisation procedures or other assisted conception techniques
menotrophin is used in conjunction with chorionic gonadotrophin and
sometimes also clomiphene citrate or a gonadorelin agonist. Stimulation of
follicular growth is produced by menotrophin in a dose providing 75 to 300
units of FSH with 75 to 300 units of LH daily. Treatment with menotrophin,
either alone or in conjunction with clomiphene or a gonadorelin agonist, is
continued until an adequate response is obtained and the final injection of
menotrophin is followed 1 or 2 days later with up to 10000 units of chorionic
gonadotrophin.
Maturation of follicles is monitored by measurement of oestrogen levels,
ultrasound and/or clinical evaluation of oestrogen activity. It is recommended
there should be at least 3 follicles greater than 17mm in diameter with 17 betaoestradiol levels of at least 3500 pmol/L (920 picograms/ml). Egg maturation
occurs by administration of human chorionic gonadotrophin in a dose of 500010000 IU, 30 -40 hours after the last MENOPUR injection. Human chorionic
gonadotrophin should not be administered if these criteria have not been met.
Egg retrieval is carried out 32 -36 hours after the human chorionic
gonadotrophin injection.
Male infertility:
Spermatogenesis is stimulated with chorionic gonadotrophin (1000 – 2000 IU
two to three times a week) and then menotrophin is given in a dose of 75 or
150 units of FSH with 75 or 150 units of LH two or three times weekly.
Treatment should be continued for at least 3 or 4 months.
Children:
Not recommended for use in children.

Elderly:
Not recommended for use in the elderly.
Method of Administration:
By intramuscular or subcutaneous use.
The dry substance must be reconstituted with the diluent prior to use, see
section 6.6 for reconstitution method.

4.3

Contraindications

Men and Women MENOPUR is contraindicated in men and women with: Tumours of the pituitary or hypothalamic glands -Hypersensitivity to the
active substance or any of the excipients used in
the formulation (see section 6.1)
Men
-Tumours in the testes
-Prostate carcinoma

Women -Ovarian, uterine or mammary carcinoma -Pregnancy and lactation Gynaecological haemorrhage of unknown aetiology -Ovarian cysts or enlarged
ovaries not due to polycystic ovarian disease.
In the following situations treatment outcome is unlikely to be favourable, and
therefore MENOPUR should not be administered:
-Primary ovarian failure
-Malformation of sexual organs incompatible with pregnancy
-Fibroid tumours of the uterus incompatible with pregnancy
-Structural abnormalities in which a satisfactory outcome cannot be
expected, for example, tubal occlusion (unless superovulation is to be
induced for IVF), ovarian dysgenesis, absent uterus or premature
menopause.

4.4

Special warnings and precautions for use
MENOPUR 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.
In the treatment of female infertility, ovarian activity should be checked (by
ultrasound and plasma 17 beta-oestradiol measurement) prior to MENOPUR
administration. During treatment, these tests and urinary oestrogen
measurement should be carried out at regular intervals, until stimulation
occurs. Close supervision is imperative during treatment. See “posology and
administration” for optimum response levels of urinary oestrogen and
plasma 17 beta-oestradiol. Values below these ranges may indicate
inadequate follicular development.
There is considerable inter-patient variability in response to menotrophin
administration, with a poor response to menotrophin in some patients. The
lowest effective dose in relation to the treatment objective should be used.
The first injection of MENOPUR 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
MENOPUR 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.
Ovarian Hyperstimulation Syndrome (OHSS)
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 severe form OHSS may be life-threatening and is characterised by large
ovarian cysts (prone to rupture), acute abdominal pain, ascites, very often
hydrothorax and occasionally thromboembolic phenomena. Other symptoms
that may be observed include: 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,
haemoperitoneum, pleural effusions and acute pulmonary distress.
If urinary oestrogen levels exceed 540 nmol (150 micrograms)/24 hours, or if
plasma 17 beta-oestradiol levels exceed 3000 pmol/L (800 picograms/ml), or
if there is any steep rise in values, there is an increased risk of
hyperstimulation and MENOPUR treatment should be immediately
discontinued and human chorionic gonadotrophin withheld. Ultrasound will
reveal any excessive follicular development and unintentional
hyperstimulation. In the event of hyperstimulation, the patient should refrain
from sexual intercourse or to use barrier contraception 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.
If during ultrasound, several mature follicles are visualised, human chorionic
gonadotrophin should not be given as there is a risk of multiple ovulation and
the occurrence of hyperstimulation syndrome.
Adherence to recommended MENOPUR 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). Patients
undergoing superovulation may be at an increased risk of developing
hyperstimulation in view of the excessive oestrogen response and multiple
follicular development. 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, 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 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.
Pregnancy wastage
The incidence of pregnancy wastage by miscarriage or abortion is higher in
patients undergoing stimulation of follicular growth for ART procedures 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
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.
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
gonadotrophins 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
In women with generally recognised risk factors for thromboembolic events,
such as personal or family history, treatment with gonadotrophins may further
increase the risk. In these women, the benefits of gonadotrophin
administration need to be weighed against the risks. It should be noted

however, that pregnancy itself also carries an increased risk of
thromboembolic events.

4.5

Interaction with other medicinal products and other forms of interaction
No drug/drug interaction studies have been conducted with MENOPUR in
humans.
Although there is no controlled clinical experience, it is expected that the
concomitant use of MENOPUR and clomiphene citrate may enhance the
follicular response. When using GnRH agonist for pituitary desensitization, a
higher dose of MENOPUR may be necessary to achieve adequate follicular
response.

4.6

Pregnancy and lactation
MENOPUR should not be given during pregnancy or to lactating mothers.

4.7

Effects on ability to drive and use machines
None known.

4.8

Undesirable effects
The most frequently reported adverse drug reactions during treatment with
MENOPUR in clinical trials are ovarian hyperstimulation, abdominal pain,
headache, enlarged abdomen, inflammation at the injection site, pain at the

injection site and nausea, with an incidence rate between 2% and 7%. The
table below displays the main adverse drug reactions in women treated with
MENOPUR in clinical trials according to body system and frequency.
Body System
Frequency
Adverse Drug Reaction

Central/peripheral
nervous system disorders

Common ( >1/100
<1/10)

Headache

Gastro-intestinal
disorders

Common ( >1/100
<1/10)

Abdominal pain, enlarged
abdomen, nausea and
vomiting

Female reproductive
disorders

Common ( >1/100
<1/10)

Ovarian hyperstimulation

Application site disorders

Common ( >1/100
<1/10)

Inflammation at injection
site, pain at injection site

Vascular (extracardiac)
disorders

Uncommon (
>1/1,000 <1/100)

Deep vein thrombosis

In very rare cases, long term use of menotrophin can lead to the formation of
antibodies making treatment ineffectual.
Very rare cases of allergic reactions, localised or generalised, and delayedtype hypersensitivity have been reported after treatment with gonadotrophin
containing products.

4.9

Overdose
The acute toxicity of menotrophin has been shown to be very low. However,
too high a dosage for more than one day may lead to hyperstimulation, which
is categorised as mild, moderate or severe. Symptoms of overdosage usually
appear 3 -6 days after treatment with human chorionic gonadotrophin.
Mild hyperstimulation -Symptoms include some abdominal swelling and
pain, ovaries enlarged to about 5cm diameter. Therapy -rest; careful
observation and symptomatic relief. Ovarian enlargement declines rapidly.
Moderate hyperstimulation -Symptoms include more pronounced abdominal
distension and pain, nausea, vomiting, occasional diarrhoea, ovaries enlarged

up to 12cm diameter. Therapy -bed rest; close observation especially in the
case of conception occurring, to detect any progression to severe
hyperstimulation.
Pelvic examination of enlarged ovaries should be gentle in order to avoid
rupture of the cysts. Symptoms subside spontaneously over 2 -3 weeks.
Severe hyperstimulation -This is a rare but serious complication -symptoms
include pronounced abdominal distension and pain, ascites, pleural effusion,
decreased blood volume, reduced urine output, electrolyte imbalance and
sometimes shock, ovaries enlarge to in excess of 12cm diameter. Therapy
hospitalisation; treatment should be conservative and concentrate on restoring
blood volume and preventing shock. Acute symptoms subside over several
days and ovaries return to normal over 20 -40 days if conception does not
occur -symptoms may be prolonged if conception occurs.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Gonadotrophins
ATC code: G03G A02
Menotrophin is a gonadotrophin extracted from the urine of postmenopausal
women and having both luteinising hormone and follicle stimulating hormone
activity. It is given by intramuscular or subcutaneous injection in the treatment
of male and female infertility.
Menotrophin (HMG) directly affects the ovaries and the testes. HMG has a
gametropic and steroidogenic effect.
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.
In the testes, FSH induces the transformation of premature to mature Sertoli
cells. It mainly causes the maturation of the seminal canals and the
development of the spermatozoa. However, a high concentration of androgens
within the testes is necessary and can be attained by a prior treatment using

hCG.

5.2

Pharmacokinetic properties
HMG is not effective when taken orally and is injected either intramuscularly
or subcutaneously. The biological effectiveness of HMG is mainly due to its
FSH content. The pharmacokinetics of HMG following intramuscular or
subcutaneous administration show great individual variation. The maximum
serum level of FSH is reached approximately 18 hours after intramuscular
injection and 12 hours after subcutaneous injection. After that, the serum level
decreases by a half-life of approximately 55 hours following intramuscular
administration and 50 hours following subcutaneous administration.
Excretion of HMG, following administration, is predominantly renal.

5.3

Preclinical safety data
Toxic effects caused by HMG are unknown in humans.
There is no evidence of teratogenic, mutagenic or carcinogenic activity of
HMG. Antibodies against HMG can be built up in single cases following
repeated cyclical administration of HMG, causing the treatment to be
ineffectual.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Powder:
Lactose monohydrate
Polysorbate 20

Sodium hydroxide
Hydrochloric acid (for pH adjustment)
Solvent:
Sodium chloride
Hydrochloric acid (for pH adjustment)
Water for injections.

6.2

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

6.3

Shelf life
Powder: 3 years
Solvent: 3 years
For immediate and single use following reconstitution.

6.4

Special precautions for storage
Do not store above 25°C. Do not freeze. Store in the original container to
protect from light.

6.5

Nature and contents of container

MENOPUR is available in the following containers and pack sizes:
Powder: 2 ml glass (Type I) vial with rubber (halobutyl type I) stopper closed
with a flip off seal.
Solvent: 1 ml glass (Type I) ampoule.
The product is supplied in packs of 5 or 10 vials with the corresponding
number of solvent ampoules.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
The reconstituted needle, syringe or hypodermic needle, are not included in
the packs, the following are recommended to be used;
For drawing up and mixing: 18 gauge 40 mm long needle and disposable
sterile 1ml syringe
For injecting: 30 gauge 16 mm needle (hypodermic needle), for
subcutaneous injection.
The powder should only be reconstituted with the solvent provided in the
package.
Attach the reconstitution needle to the syringe. Withdraw the entire content
from the ampoule with solvent and inject the total contents into the vial
containing the powder. The powder should dissolve quickly to a clear solution.
If not, roll the vial gently between the hands until the solution is clear.
Vigorous shaking should be avoided.
If needed, the solution can be drawn up into the syringe again to transfer it to
the next vial with powder until the prescribed dose has been reached. Up to
three powder vials can be dissolved with one ampoule of solvent.
When the prescribed dose has been reached, draw up the mixed solution
from the vial into the syringe, change to the hypodermic needle and
administer immediately.
The reconstituted solution should not be administered if it contains particles or
is not clear.

Any unused product or waste material should be disposed in accordance with
local requirements.

7

MARKETING AUTHORISATION HOLDER
Ferring Pharmaceuticals Limited
The Courtyard
Waterside Drive
Langley, Berkshire
SL3 6EZ

8

MARKETING AUTHORISATION NUMBER(S)
PL 03194/0109

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
21/09/2011

10

DATE OF REVISION OF THE TEXT
21/09/2011

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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