CHORAPUR 1500 IU POWDER AND SOLVENT FOR SOLUTION FOR INJECTION - summary of medicine characteristics

CHORAPUR 1500 IU powder and solvent for solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of CHORAPUR 1500 contains 1500 IU highly purified human chorionic gonadotrophin (hCG).

The active ingredient in CHORAPUR is extracted and purified from the urine of pregnant women.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Appearance of the powder: white lyophilised cake.

Appearance of the solvent: clear colourless solution.

4.1 Therapeutic indications

Andrology

Establishment of fertility in cases of hypogonadotrophic hypogonadism (also in combination with hMG or FSH).

Paediatric population

Treatment of undescended testes.

4.2 Posology and method of administration

Posology

Andrology

Treatment with CHORAPUR should be performed under the supervision of a physician experienced in the treatment of fertility problems.

In case of hypogonadotrophic hypogonadism, 1 vial of CHORAPUR 1500 IU twice a week (corresponding to 3000 IU chorionic gonadotrophin per week) in combination with hMG or FSH over a period of several months.

The treatment should be continued for at least 3 months before any improvement in spermatogenesis can be expected. During this treatment testosterone replacement therapy should be suspended, and the testosterone levels should be monitored at intervals. It may be necessary to increase the hCG dose to achieve normal testosterone levels. If the response to general hCG therapy is not sufficient, additional administration of hMG or FSH may be necessary. Once an improvement has been achieved under combination therapy, it may in some cases be maintained by hCG alone.

Paediatric population

Therapy of undescended testes should be completed by the end of the first year of life.

The following dosage is recommended in young infants: 250 IU/dose (0.17 ml of the 1500 IU vial) twice a week for five weeks.

Special populations

Renal/hepatic impairment

Patients with renal or hepatic impairment have not been included in clinical trials.

Method of administration

CHORAPUR is intended for intramuscular administration. The powder should be reconstituted immediately prior to use with the solvent provided.

4.3 Contraindications

General

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Gynaecology

– Tumours of the pituitary gland or hypothalamus

– Ovarian cysts or enlarged ovaries due to reasons other than polycystic ovarian disease

– Gynaecological haemorrhages of unknown aetiology

– Ovarian, uterine or mammary carcinoma

– Extrauterine pregnancy in the previous 3 months

– Active thrombo-embolic disorders

– Ovarian hyperstimulation syndrome (OHSS)

In the following situations treatment outcome is unlikely to be favourable, and therefore CHORAPUR should not be administered:

– Primary ovarian failure

– Malformations of sexual organs incompatible with pregnancy

– Uterine myomas of the uterus incompatible with pregnancy

– Post-menopausal women

Paediatric population and andrology

CHORAPUR must not be used in case of sex hormone dependent tumours.

CHORAPUR must not be used for the treatment of undescended testes known to be of organic origin (inguinal hernia, surgery in the inguinal region, ectopic testicle).

4.4 Special warnings and precautions for use

General

hCG-therapy leads to increased androgen production and fluid retention. Patients with suspected or known heart or kidney disease, increased blood pressure, epilepsy or migraine (also in the anamnesis) should be monitored closely, since aggravation and recurrence may occasionally be caused by the use of CHORAPUR (see section 4.8).

Thromboembolism

Patients with generally recognised risk factors for thromboembolic events, such as personal or family history, 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 patients, 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.

Gynaecology

Before starting treatment, the reason for infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinaemia and pituitary or hypothalamic tumours, and appropriate specific treatment given.

Ovarian Hyperstimulation Syndrome (OHSS):

Patients undergoing stimulation of follicular growth may have a higher risk of ovarian hyperstimulation syndrome (OHSS) due to multifollicle development.

OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS is a syndrome that can manifest itself with increasing degrees of severity. Excessive ovarian response to gonadotrophin treatment seldom gives rise to OHSS unless hCG is administered to trigger ovulation. Therefore, in cases of ovarian hyperstimulation it is prudent to withhold hCG and advise the patient to use a barrier method of contraception or refrain from having coitus until the next menstrual bleeding has started.

OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event. Early onset OHSS usually occur within the first 9 days following triggering of final oocyte maturation with hCG, whereas late onset OHSS may occur when pregnancy is established. Usually, OHSS resolves spontaneously with the onset of menses. OHSS may be more severe and more protracted if pregnancy occurs. Therefore, patients should be followed for at least two weeks after hCG administration.

Clinical signs and symptoms of mild and moderate OHSS, which usually resolve spontaneously, comprise gastrointestinal problems (abdominal discomfort, abdominal pain, abdominal distension, nausea, vomiting and/ or diarrhoea), mild to moderate ovarian enlargement, weight gain, ovarian cysts. In severe cases additional symtomatology include severe ovarian enlargement, dyspnoea and oliguria Clinical evaluation may reveal high serum sex steroids, hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax and/or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events.

To minimise the risk of OHSS, close monitoring of the ovarian response by means of ultrasonography, alone or in combination with measurement of the estradiol levels, before and during the stimulation therapy is recommended for all patients. Adherence to recommended CHORAPUR dosage, regimen of administration and careful monitoring of therapy will minimise the incidence of OHSS. In assisted reproductive technology (ART), aspiration of all follicles prior to ovulation may reduce the occurrence of OHSS.

If severe OHSS occurs, gonadotrophin treatment should be stopped if still ongoing, the patient hospitalised and specific therapy for OHSS started.

OHSS occurs with higher incidence in patients with polycystic ovarian disease (PCOD).

Multiple pregnancy:

Multiple pregnancy, especially high order, carries an increased risk of adverse maternal and perinatal outcomes.

In patients undergoing ovulation induction with gonadotrophins, the incidence of multiple pregnancies 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.

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 of increased 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.

Interference with laboratory tests

Following administration, CHORAPUR may interfere for up to 10 days with the immunological determination of serum/urinary hCG, leading to a false positive pregnancy test.

CHORAPUR contains sodium, but less than 1 mmol (23 mg) sodium per ml solvent.

The use of CHORAPUR may lead to positive results in doping controls.

The use of CHORAPUR for doping purposes can result in health hazards.

Paediatric population

hCG should be used cautiously in prepubertal boys to avoid premature epiphyseal closure or precocious sexual development, and skeletal maturation should be monitored regularly.

hCG has been associated with signs of inflammation and increased apoptosis of germ cells in boys treated for undescended testes after the end of their first year of life.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed in humans.

4.6 Fertility, pregnancy and lactation

Fertility

CHORAPUR is indicated for the treatment of infertility (see section 4.1).

Pregnancy

Considering the indication, CHORAPUR should not be used during pregnancy.

Mice which were given hCG for ovulation induction showed an increased dosedependent embryonic lethality, in particular preimplantation loss (see section 5.3).

Breastfeeding

Considering the indication, CHORAPUR should not be used during lactation.

4.7 Effects on ability to drive and use machines

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

It is expected that CHORAPUR has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Most commonly observed adverse drug reactions are related to overstimulation of the ovaries e.g. OHSS. They are mainly dose-dependent and dependent on the individual patient's response to treatment.

The assessment of undesirable effects is based on the following grades of frequency:

Very common (>1/10)

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

Uncommon (>1/1000 to <1/100)

Rare (>1/10000 to <1/1000)

Very rare (<1/10000)

Not known (cannot be estimated from the available data)

a Literature data reported in adolescent males

b Hot flush has only been reported in males.

c Clinical signs and symptoms of mild and moderate OHSS, comprise gastrointestinal problems (abdominal discomfort, abdominal pain, abdominal distension, nausea, vomiting and/ or diarrhoea), mild to moderate ovarian enlargement, weight gain, ovarian cysts. In cases of severe OHSS, ascites, pelvic fluid collection, pleural effusion, dyspnoea, oliguria, thromboembolic events (arterial and venous) and ovarian torsion have been reported as rare complications.

d Single cases of localised or generalised allergic reactions, including anaphylactic reaction and anaphylactic shock, along with associated symptomatology have been reported.

Increase in size of penis and erections due to increased testosterone secretion caused by induction, and/or proliferative change in the prostate can be seen.

Paediatric population

Occasionally, minor emotional changes in boys similar to those at the beginning of puberty may occur, which are limited to the course of treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

The effects of an overdose is unknown, nevertheless one could expect ovarian hyperstimulation to occur.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Gonadotrophins, ATC code: G03GA01

Mechanism of action

Human chorionic gonadotrophin (hCG) is a glycoprotein comprising an alpha subunit that is common to luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and a beta subunit that is unique to hCG. hCG is purified from the urine of pregnant women and is not homogeneous. Even highly purified products contain several fractions differing in sialic acid content and activity. The amount of hCG is indicated in units of biological activity.

The hormonal effect of chorionic gonadotrophin is based on its ability to stimulate the biosynthesis of sexual steroids in the gonads (ovaries and testes). The action of hCG is qualitatively the same as that of the pituitary gonadotrophin LH. However, hCG has a significantly longer half-life and thus has a greater effect compared to LH in case of cumulative administration.

Pharmacodynamic effects

In the ovaries, hCG stimulates the granulosa, theca, and stroma or luteal cells to support the production of progesterone and estradiol. In the granulosa cells of the small follicles, high doses of hCG stimulate preferably the biosynthesis of estradiol, while in the granulosa cells of the mature, dominant follicles and/or in the luteinising granulosa cells, high doses of hCG stimulate the biosynthesis of progesterone. Furthermore, hCG stimulates the production of biologically active peptides in the ovary that are important for the regulation of reproduction (e.g. inhibin, relaxin, prorenin, plasminogen-activator-inhibitor).

The administration of 5000 IU up to 10000 IU hCG to women with mature follicles (e.g. after stimulation with gonadotrophin or Clomiphene) induces ovulation approximately 36 hours after the intramuscular injection.

Clinical efficacy and safety

In the Leydig cells in men, hCG stimulates the production of testosterone and other steroids such as 17 OH-progesterone and estradiol. The single administration of 5000 IU hCG to boys and men increases the testosterone secretion in a bi-phasic manner, resulting in a first maximum plasma concentration after 2 to 4 hours and a second maximum after 3 to 4 days. The maximum amount of estradiol in serum is reached approximately 24 hours after the administration of hCG. This principle is used for the differential diagnosis of cryptorchidism in order to differentiate between cryptorchidism and anorchism as well as for the assessment of the function of the testes with hypogonadotrophic hypogonadism.

5.2 Pharmacokinetic properties

hCG is administered by intramuscular injection. The maximum serum level of hCG is reached after approx. 10 hours (dose-dependent) and decreases afterwards with a halflife of approx. 30 hours. Due to the slow elimination, hCG may cumulate in serum after several (e.g. daily) intramuscular injections.

hCG is excreted via the kidneys, and 10 – 20 % is found unchanged in the urine, whilst the remainder is probably excreted as the beta-core fragment.

5.3 Preclinical safety data

Animal experiments in mice showed dose-dependent increased pre-implantation embryonic deaths, and postimplantation fetal deaths, smaller fetuses, less fetuses per litter, as well as a significant increase of congenital malformations (open eyelids, cleft palates) after administration of hCG for ovulation induction in the therapeutic range.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder:

Lactose monohydrate

Sodium hydroxide

Solvent:

Sodium chloride

Hydrochloric acid 10%

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

3 years.

For immediate and single use following opening and reconstitution.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions. Do not freeze.

Store in the original container in order to protect from light.

6.5 Nature and contents of container

CHORAPUR is available in the following containers:

Powder:

Colourless glass (Type I) vials with rubber stopper closed with a cap.

Solvent:

1 ml colourless glass (Type I) ampoules.

CHORAPUR is supplied in the following pack sizes:

The product is supplied in packs of 1, 3 or 5 powder vials with the corresponding number of solvent ampoules.

6.6 Special precautions for disposal

The powder should only be reconstituted with the solvent provided in the package.

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.

Method of administration

– BREVACTID must be administered intramuscularly immediately after reconstitution.

– Attach a reconstitution needle to the syringe.

– Withdraw the entire content of 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 fingers (hands) until the solution is clear. Shaking should be avoided.

– The reconstituted solution contains 1500 IU or 5000 IU per ml.

– Depending on the required dose, withdraw the appropriate amount of reconstituted solution from the vial into the syringe, change to an injection (hypodermic) needle and administer immediately.