Pergoveris is indicated for the stimulation of follicular development in women with severe LH and
FSH deficiency.
In clinical trials, these patients were defined by an endogenous serum LH level < 1.2 IU/l.

Treatment with Pergoveris should be initiated under the supervision of a physician experienced in the
treatment of fertility problems.
Pergoveris is intended for subcutaneous administration. The powder should be reconstituted
immediately prior to use with the solvent provided.
In LH and FSH deficient women (hypogonadotrophic hypogonadism), the objective of Pergoveris
therapy is to develop a single mature Graafian follicle from which the oocyte will be liberated after the
administration of human chorionic gonadotrophin (hCG). Pergoveris should be given as a course of
daily injections. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion,
treatment can commence at any time.

 

Pergoveris is contraindicated in patients with: • hypersensitivity to the active substances follitropin alfa and lutropin alfa or to any of the excipients • case of tumours of the hypothalamus and pituitary gland • ovarian enlargement or cyst not due to polycystic ovarian disease • gynaecological haemorrhages of unknown aetiology • ovarian, uterine or mammary carcinoma Pergoveris must not be used when an effective response cannot be obtained, such as: • primary ovarian failure • malformations of sexual organs incompatible with pregnancy • fibroid tumours of the uterus incompatible with pregnancy

Pergoveris contains potent gonadotrophic substances 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.
Gonadotrophin 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 Pergoveris 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/LH administration, with a poor response to
FSH/LH in some patients. The lowest effective dose in relation to the treatment objective should be
used in women.

Self-administration of Pergoveris should only be performed by patients who are well motivated,
adequately trained and with access to expert advice.
The first injection of Pergoveris should be performed under direct medical supervision.
Patients with porphyria or a family history of porphyria should be closely monitored during treatment
with Pergoveris. Deterioration or a first appearance of this condition may require cessation of
treatment.
Pergoveris contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.
Pergoveris contains 30 mg of sucrose per dose. This should be taken into account in patients with
diabetes mellitus.
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 the
following:
• hypothyroidism
• adrenocortical deficiency
• hyperprolactinemia and pituitary or hypothalamic tumours
Appropriate specific treatment should be given.
Patients undergoing stimulation of follicular growth are at an increased risk of developing
hyperstimulation in view of possible excessive oestrogen response and multiple follicular
development.
In clinical trials, lutropin alfa in combination with follitropin alfa has been shown to increase the
ovarian sensitivity to gonadotropins. 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 using a licensed
follitropin alfa preparation.
Ovarian Hyperstimulation Syndrome (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 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
• acute pulmonary distress, and thromboembolic events.
Very rarely, severe OHSS may be complicated by pulmonary embolism, ischemic stroke and
myocardial infarction.
Excessive ovarian response seldom gives rise to significant hyperstimulation unless hCG is
administered to induce ovulation. Therefore in cases of ovarian hyperstimulation it is prudent to
withhold hCG in such cases and advise the patient to refrain from coitus or use barrier 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 hCG administration.
To minimise the risk of OHSS or of multiple pregnancy (see below), ultrasound scans as well as
oestradiol measurements are recommended. In anovulation the risk of OHSS is increased by a serum
oestradiol level > 900 pg/ml (3,300 pmol/l) and by the presence of more than 3 follicles of 14 mm or
more in diameter.
Adherence to recommended Pergoveris and FSH dosage and regimen of administration and careful
monitoring of therapy will minimise the incidence of ovarian hyperstimulation and multiple pregnancy
(see below).
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 should
be hospitalised and specific therapy for OHSS started.
This syndrome occurs with higher incidence in patients with polycystic ovarian disease.
In patients undergoing induction of ovulation, the incidence of multiple pregnancies and births is
increased compared with natural conception. The majority of multiple conceptions are twins. To
minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.
The patients should be advised of the potential risk of multiple births before starting treatment.
The incidence of pregnancy wastage by miscarriage or abortion is higher in patients undergoing
stimulation of follicular growth for ovulation induction than in the normal population.
When risk of OHSS or multiple pregnancies is assumed, treatment discontinuation should be
considered.
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 was reported to be 2 to 5%, as compared to 1 to 1.5% 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 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.
6
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 generally recognised risk factors for thrombo-embolic 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 thrombo-embolic events.

Pergoveris should not be administered as a mixture with other medicinal products, in the same
injection, except follitropin alfa.

Pergoveris should not be used during pregnancy or lactation.

No studies on the effects on the ability to drive and use machines have been performed.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Nervous system disorders Very Common (≥1/10)
Common (≥1/100 to <1/10)
Headache
Somnolence
Respiratory, thoracic and
mediastinal disorders
Very rare (<1/10,000) Exacerbation or worsening of
asthma
Gastrointestinal disorders Common (≥1/100 to <1/10) Abdominal pain and
gastrointestinal symptoms such
as nausea, vomiting, diarrhoea,
abdominal cramps and bloating
Vascular disorders Very rare (<1/10,000) Thromboembolism, usually
associated with severe ovarian
hyperstimulation syndrome
(OHSS)
General disorders and
administration site conditions
Very Common (≥1/10) Mild to severe injection site
reaction (pain, redness, bruising,
swelling and/or irritation at the
site of injection)
Immune system disorders Very rare (<1/10,000) Mild systemic allergic reactions
(e.g. mild forms of erythema,
rash, facial swelling, urticaria,
oedema, difficulty breathing).
Serious cases of allergic
reactions, including
anaphylactic reactions, have
also been reported.

Reproductive system and breast
disorders
Very Common (≥1/10) Ovarian cysts
Common (≥1/100 to <1/10) Breast pain, pelvic pain, mild to
moderate OHSS
Uncommon (≥1/1,000 to
<1/100)
Severe OHSS
Rare (≥1/10,000 to <1/1,000) Ovarian torsion, a complication
of OHSS

The effects of an overdose of Pergoveris are unknown. Nevertheless one could expect ovarian
hyperstimulation syndrome to occur, which is further described in section 4.4.

Pharmacotherapeutic group: Gonadotrophins, ATC code: G03GA05 / G03GA07.
Pergoveris is a preparation of follicle stimulating hormone and luteinising hormone produced by
genetically engineered Chinese Hamster Ovary (CHO) cells.
In clinical trials the efficacy of the combination of follitropin alfa and lutropin alfa has been
demonstrated in women with hypogonadotropic hypogonadism.
In the stimulation of follicular development in anovulatory women deficient in LH and FSH, the
primary effect resulting from administration of lutropin alfa is an increase in oestradiol secretion by
the follicles, the growth of which is stimulated by FSH.
In one clinical study of women with hypogonadotrophic hypogonadism and an endogenous serum LH
concentration below 1.2 IU/L the appropriate dose of r-hLH (lutropin alfa) was investigated. A dose of
75 IU r-hLH daily (in combination with 150 IU follitropin alfa (r-hFSH)) resulted in adequate
follicular development and oestrogen production. A dose of 25 IU r-hLH daily (in combination with
150 IU follitropin alfa) resulted in insufficient follicular development. Therefore, administration of
less than one vial of Pergoveris daily may provide too little LH-activity to ensure adequate follicular
development.

Follitropin alfa and lutropin alfa have shown the same pharmacokinetic profile as follitropin alfa and
lutropin alfa separately.
Follitropin alfa
Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with
an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about
one day. The steady state volume of distribution and total clearance are 10 l and 0.6 l/h, respectively.
One-eighth of the follitropin alfa dose is excreted in the urine.
Following subcutaneous administration, the absolute bioavailability is about 70%. Following repeated
administration, follitropin alfa accumulates 3-fold achieving a steady-state within 3-4 days. In women whose endogenous gonadotrophin secretion is suppressed, follitropin alfa has nevertheless been shown
to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.
Lutropin alfa
Following intravenous administration, lutropin alfa is rapidly distributed with an initial half-life of
approximately one hour and eliminated from the body with a terminal half-life of about 10-12 hours.
The steady state volume of distribution is around 10-14 l. Lutropin alfa shows linear
pharmacokinetics, as assessed by AUC which is directly proportional to the dose administered. Total
clearance is around 2 l/h, and less than 5% of the dose is excreted in the urine. The mean residence
time is approximately 5 hours.
Following subcutaneous administration, the absolute bioavailability is approximately 60%; the
terminal half-life is slightly prolonged. The lutropin alfa pharmacokinetics following single and
repeated administration of lutropin alfa are comparable and the accumulation ratio of lutropin alfa is
minimal. There is no pharmacokinetic interaction with follitropin alfa when administered
simultaneously.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity and genotoxicity.

Powder:
Sucrose
Polysorbate 20
Methionine
Disodium phosphate dihydrate
Sodium dihydrogen phosphate monohydrate
Phosphoric acid, concentrated for pH adjustment
Sodium hydroxide for pH adjustment
Solvent:
Water for Injections

This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.

3 years. For immediate and single use following first opening and reconstitution.

Do not store above 25°C.
Store in the original package in order to protect from light.

Powder: 3 ml vials (Type I glass) with a stopper (bromobutyl rubber) and aluminium flip-off cap.
1 vial contains 11 micrograms r-hFSH and 3 micrograms r-hLH.
Solvent: 3 ml vials (Type I glass) with a Teflon coated rubber stopper and aluminium flip-off cap.
1 vial of solvent contains 1 ml of water for injections.
The medicinal product is supplied in pack sizes of 1, 3 and 10 vials with the corresponding number of
1, 3 and 10 vials of solvent.
Not all pack sizes may be marketed

For single use only.
Pergoveris must be reconstituted with the solvent before use.
The reconstituted solution should not be administered if it contains particles or is not clear.
Pergoveris may be mixed with follitropin alfa and co-administered as a single injection.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.