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MENOPUR 1200 IU POWDER AND SOLVENT FOR SOLUTION FOR INJECTION

Active substance(s): MENOTROPHIN / MENOTROPHIN / MENOTROPHIN

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
MENOPUR® 1200IU Powder and solvent for solution for injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Active ingredient
Each vial of lyophilised product contains highly purified menotrophin (human
menopausal gonadotrophin, HMG) corresponding to 1200IU human follicle
stimulating hormone (FSH) and 1200IU human luteinising hormone (LH)
activity.
Human Chorionic Gonadotrophin (hCG), a naturally occurring hormone in
postmenopausal urine, is present in MENOPUR and contributes to the overall
luteinizing hormone activity.
For excipients see section 6.1.

3

PHARMACEUTICAL FORM
Powder and solvent for solution for injection
Appearance of powder: white to off-white lyophilised 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:
- Anovulation, including polycystic ovarian disease (PCOD) in 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. Nonresponders may then be selected for menotrophin therapy.
- Women undergoing controlled ovarian hyperstimulation: MENOPUR can
induce the development of multiple follicles for assisted reproductive
technologies (ART) (e.g. in vitro fertilisation/embryo transfer (IVF/ET),
gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection
(ICSI)).

- 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 (including PCOD):
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 in 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 70 to 150 units of FSH and 70 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 – 540nmol)/24 hours
- plasma 17 beta-oestradiol: 400 - 800 micrograms (1500 – 3000pmol/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 controlled ovarian hyperstimulation for multiple follicular
development for assisted reproductive technologies (ART):
In in-vitro fertilisation (IVF) procedures or other assisted reproductive
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 3500pmol/L (920picograms/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 to 150 units of LH two of 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:
For intramuscular or subcutaneous use
The powder must be reconstituted immediately with the solvent provided prior
to use (see section 6.6). The reconstituted solution is for multiple injections
and can be used for up to 28 days. Vigorous shaking should be avoided. The
solution should not be used if it contains particles or if it is not clear.

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
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 administrated:
- 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 540nmol (150 micrograms)/24 hours, or if
plasma 17 beta-oestradiol levels exceed 3000pmol/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, severe obesity (Body Mass Index
>30kg/m2) or thrombophilia may have an increased risk of venous or arterial
thromboembolic events, during or following treatment with gonadotrophin
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
Central/Peripheral
nervous system
disorders
Gastro-intestinal
disorders

Frequency
Common
(>1/100<1/10)

Adverse Drug Reaction
Headache

Common
(>1/100<1/10)

Female reproductive
disorders

Common
(>1/100<1/10)
Common
(>1/100<1/10)
Uncommon
(>1/1,000<1/100)

Abdominal pain, enlarged
abdomen, nausea and
vomiting
Ovarian hyperstimulation,
Pelvic pain

Application site
disorders
Vascular (extracardiac)
disorders

Inflammation at injection
site, pain at injection site
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, 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.
The pharmacokinetics of MENOPUR in patients with renal or hepatic
impairment has not been investigated.

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 phosphate dibasic heptahydrate
Phosphoric acid (concentrated) for pH adjustment
Solvent:
Metacresol
Water for injection

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
After reconstitution, the solution may be stored for a maximum of 28 days at
room temperature.

6.4

Special precautions for storage
Prior to reconstitution, store in a refrigerator at 2ºC - 8ºC. Do not freeze. Keep
in the original container in order to protect from light.
After reconstitution, the solution may be stored for a maximum of 28 days at
room temperature, not more than 25°C. Do not freeze.

6.5

Nature and contents of container
MENOPUR is available in the following containers and pack sizes:
Powder: 2ml glass (type I) vial with rubber (halobutyl type I) stopper closed
with a flip off seal.
Solvent: 1ml pre-filled syringe (type I glass) with rubber (type I) tip cap and
plunger stopper (halobutyl rubber type I), without needle.
Each pack contains 1 vial of powder, 2 pre-filled syringes with solvent for
reconstitution, 1 needle for reconstitution, 18 alcohol pads and 18 disposable
syringes for administration graduated in FSH/LH units with pre-fixed needles.

6.6

Special precautions for disposal
The powder must be reconstituted with the diluent prior to use.
Attach the reconstitution needle to the pre-filled syringe. Inject the total
contents of the solvent 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.
The reconstituted solution should not be administered if it contains particles or
is not clear.
The administration syringes are graduated in FSH/LH units from 37.5 – 600
IU and supplied with needles in the Menopur multidose carton. Draw up the
exact prescribed dose of reconstituted solution from the vial using one of the
disposable syringes provided for injection and administer the dose
immediately. Discard the syringe after use.
Each reconstituted vial should be for individual patient use only.
Any unused product or waste material should be disposed in accordance with
local requirements.

7

MARKETING AUTHORISATION HOLDER
Ferring Pharmaceuticals Ltd
Drayton Hall
Church Road
West Drayton
UB7 7PS
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 03194/0107

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
25/10/2010

10

DATE OF REVISION OF THE TEXT
11/05/2015

Expand Transcript

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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