Ovitrelle 250 micrograms solution for injection in pre-filled pen

Each pre-filled pen contains 250 micrograms choriogonadotropin alfa* (equivalent to approximately 6,500 IU).

* recombinant human chorionic gonadotropin, r-hCG produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.

For a full list of excipients, see section 6.1.

Solution for injection in prefilled pen.

Clear, colourless to slightly yellow solution.

The pH of the solution is 7.0 ± 0.3, its osmolality 250-400 mOsm/kg.

Ovitrelle is indicated in the treatment of:

• Adult women undergoing superovulation prior to assisted reproductive techniques such as in vitro fertilisation (IVF): Ovitrelle is administered to trigger final follicular maturation and luteinisation after stimulation of follicular growth,

• Anovulatory or oligoovulatory adult women: Ovitrelle is administered to trigger ovulation and luteinisation in anovulatory or oligoovulatory women after stimulation of follicular growth.

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

Posology

The maximum dose is 250 micrograms. The following dose regimen should be used:

• Women undergoing superovulation prior to assisted reproductive techniques such as in vitro fertilisation (IVF):

One prefilled pen of Ovitrelle (250 micrograms) is administered 24 to 48 hours after the last administration of a follicle stimulating hormone (FSH) or human menopausal gonadotropin (hMG) preparation, i.e. when optimal stimulation of follicular growth is achieved.

• Anovulatory or oligoovulatory women:

One prefilled pen of Ovitrelle (250 micrograms) is administered 24 to 48 hours after optimal stimulation of follicular growth is achieved. The patient is recommended to have coitus on the day of, and the day after, Ovitrelle injection.

Special populations

Renal or hepatic impairment

Safety, efficacy and pharmacokinetics of Ovitrelle in patients with renal or hepatic impairment have not been established.

Paediatric population

There is no relevant use of Ovitrelle in the paediatric population.

Method of administration

For subcutaneous use. Selfadministration of Ovitrelle should only be performed by patients who are adequately trained and have access to expert advice.

Ovitrelle is for single use only.

For instructions on the administration with the prefilled pen, see section 6.6 and the “Instructions for use” provided in the carton.

• Hypersensitivity to choriogonadotropin alfa or to any of the excipients of Ovitrelle

• Tumours of the hypothalamus or pituitary gland

• Ovarian enlargement or cyst 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 thromboembolic disorders

• Primary ovarian failure

• Malformations of sexual organs incompatible with pregnancy

• Fibroid tumours of the uterus incompatible with pregnancy

• Postmenopausal women

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.

There is no clinical experience with Ovitrelle in the treatment of other conditions (such as corpus luteum insufficiency or male conditions) therefore Ovitrelle is not indicated in these conditions.

Ovarian Hyperstimulation Syndrome (OHSS)

Patients undergoing ovarian stimulation are at an increased risk of developing OHSS due to multiple follicular development.

OHSS may become a serious medical event characterised by large ovarian cysts which are prone to rupture, weight gain, dyspnoea, oliguria or the presence of ascites within a clinical picture of circulatory dysfunction. Severe OHSS could be complicated in rare cases by haemoperitoneum, acute pulmonary distress, ovarian torsion, and thromboembolism.

To minimise the risk of OHSS, ultrasonographic assessments of follicular development and/or determination of serum estradiol levels should be performed prior to treatment and at regular intervals during treatment. In anovulation, the risk of OHSS is increased by a serum estradiol level > 1,500 pg/ml (5,400 pmol/l) and more than 3 follicles of 14 mm or more in diameter. In assisted reproductive techniques, there is an increased risk of OHSS with a serum estradiol > 3,000 pg/ml (11,000 pmol/l) and 18 or more follicles of 11 mm or more in diameter.

OHSS due to excessive ovarian response can be avoided by withholding hCG administration. Therefore, if signs of ovarian hyperstimulation occur such as serum estradiol level > 5,500 pg/ml (20,000 pmol/l) and/or when there are 30 or more follicles in total, it is recommended to withhold hCG administration and the patient be advised to refrain from coitus or to use barrier contraceptive methods for at least 4 days.

Multiple pregnancy

In patients undergoing induction of ovulation, the incidence of multiple pregnancy and births (mostly twins) is increased compared with natural conception. The risk of multiple pregnancy following assisted reproductive techniques is related to the number of embryos replaced.

Adherence to recommended Ovitrelle dose, regimen of administration and careful monitoring of therapy will minimise the risk of OHSS and multiple pregnancy.

Miscarriage

The rate of miscarriage, in both anovulatory patients and women undergoing assisted reproductive techniques, is higher than that found in the normal population but comparable with the rates observed in women with other fertility problems.

Ectopic pregnancy

Since infertile women undergoing ART, and particularly IVF, often have tubal abnormalities, the incidence of ectopic pregnancies might be increased. It is important to have early ultrasound confirmation that a pregnancy is intrauterine, and to exclude the possibility of extrauterine pregnancy.

Congenital malformations

The incidence 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 the higher incidence of multiple pregnancies.

Thromboembolic events

In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted, however, that pregnancy itself as well as OHSS also carry an increased risk of thromboembolic events, such as pulmonary embolism, ischaemic stroke or myocardial infarction.

Interference with serum or urinary testing

Following administration, Ovitrelle may interfere for up to ten days with the immunological determination of serum or urinary hCG, potentially leading to a false positive pregnancy test.

Patients should be made aware of this.

Other information

During Ovitrelle therapy, a minor thyroid stimulation is possible, of which the clinical relevance is unknown.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially “sodiumfree”

No specific interaction studies with Ovitrelle and other medicinal products have been performed, however no clinically significant medicinal product interactions have been reported during hCG therapy.

Pregnancy

There is no indication for the use of Ovitrelle during pregnancy. No clinical data on exposed pregnancies are available. No reproduction studies with choriogonadotropin alfa in animals were performed (see section 5.3). The potential risk for humans is unknown.

Breast feeding

Ovitrelle is not indicated during breastfeeding. There are no data on the excretion of choriogonadotropin alfa in milk.

Fertility

Ovitrelle is indicated for use in infertility (see section 4.1).

Ovitrelle is expected to have no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

In comparative trials with different doses of Ovitrelle, the following adverse reactions were found to be associated with Ovitrelle in a doserelated fashion: OHSS, vomiting and nausea. OHSS was observed in approximately 4% of patients treated with Ovitrelle. Severe OHSS was reported in less than 0.5% of patients (see section 4.4).

Tabulated list of adverse reactions

The following definitions apply to the frequency terminology used hereafter:

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 from the available data)

Immune system disorders

Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock

Psychiatric disorders

Uncommon: Depression, irritability, restlessness

Nervous system disorders

Common: Headache

Vascular disorders

Very rare: Thromboembolism, usually associated with severe OHSS

Gastrointestinal disorders

Common: Vomiting, nausea, abdominal pain

Uncommon: Diarrhoea

Skin and subcutaneous tissue disorders

Very rare: Mild reversible skin reactions manifesting as rash

Reproductive system and breast disorders

Common: Mild or moderate OHSS

Uncommon: Severe OHSS, breast pain

General disorders and administration site conditions

Common: Tiredness, injection site reactions.

Ectopic pregnancy, ovarian torsion and other complications have been reported in patients after hCG administration. These are considered concomitant effects related to assisted reproductive techniques.

The effects of an overdose of Ovitrelle are unknown. Nevertheless, there is a possibility that OHSS may result from an overdose of Ovitrelle (see section 4.4).

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, gonadotropins, ATC code: G03GA08

Mechanism of action

Ovitrelle is a medicinal product of choriogonadotropin alfa produced by recombinant DNA techniques. It shares the amino acid sequence with urinary hCG. Chorionic gonadotropin binds on the ovarian theca (and granulosa) cells to a transmembrane receptor shared with the luteinising hormone, the LH/CG receptor.

Pharmacodynamic effects

The principal pharmacodynamic activity in women is oocyte meiosis resumption, follicular rupture (ovulation), corpus luteum formation and production of progesterone and estradiol by the corpus luteum.

In women, chorionic gonadotropin acts as a surrogate luteinising hormone surge that triggers ovulation.

Ovitrelle is used to trigger final follicular maturation and early luteinisation after use of medicinal products for stimulation of follicular growth.

Clinical efficacy and safety

In comparative clinical trials, administration of a dose of 250 micrograms of Ovitrelle was as effective as 5,000 IU and 10,000 IU of urinary hCG in inducing final follicular maturation and early luteinisation in assisted reproductive techniques, and as effective as 5,000 IU of urinary hCG in ovulation induction.

So far, there are no signs of antibody development in humans to Ovitrelle. Repeated exposure to Ovitrelle was investigated in male patients only. Clinical investigation in women for the indication of ART and anovulation was limited to one treatment cycle.

Following intravenous administration, choriogonadotropin alfa is distributed to the extracellular fluid space with a distribution halflife of around 4.5 hours. The steadystate volume of distribution and the total clearance are 6 l and 0.2 l/h, respectively. There are no indications that choriogonadotropin alfa is metabolised and excreted differently than endogenous hCG.

Following subcutaneous administration, choriogonadotropin alfa is eliminated from the body with a terminal halflife of about 30 hours, and the absolute bioavailability is about 40%.

A comparative study between the freezedried and the liquid formulation showed bioequivalence between the two formulations.

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Studies on carcinogenic potential were not performed. This is justified, given the proteinous nature of the active substance and the negative outcome of the genotoxicity testing.

Studies on reproduction were not performed in animals.

Mannitol

Methionine

Disodium phosphate dihydrate

Sodium dihydrogen phosphate monohydrate

Poloxamer 188

Diluted phosphoric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

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

2 years.

After opening, the medicinal product should be used immediately.

Store in a refrigerator (2°C-8°C). Do not freeze.

3 ml cartridge (type I glass, with a bromobutyl rubber plunger stopper and an aluminium crimp cap with bromobutyl rubber) preassembled in a prefilled pen. Each prefilled pen contains 0.5 ml of solution for injection.

Pack of 1 prefilled pen and 1 injection needle.

See the “Instructions for use” provided in the carton.

Only clear solution without particles should be used. Use each needle and pen only once.

Selfadministration of Ovitrelle should only be performed by patients who are adequately trained and have access to expert advice.

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

Merck Serono Europe Limited

56, Marsh Wall

London E14 9TP

United Kingdom

EU/1/00/165/008

Date of first authorisation: 2 February 2001

Date of last renewal: 2 February 2006

06/2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu