ORGALUTRAN 0.25 MG/0.5 ML

Israel - English - Ministry of Health

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Active ingredient:
GANIRELIX 0.25 MG / 0.5 ML
Available from:
MERCK SHARP & DOHME ISRAEL LTD
ATC code:
H01CC
Pharmaceutical form:
SOLUTION FOR INJECTION
Administration route:
S.C
Manufactured by:
ORGANON (IRELAND) LTD, IRELAND
Therapeutic indications:
The prevention of premature luteinsing hormone (LT) surges in women undergoing controlled ovarian hyperstimulation (COH) for assisted reproduction techniques (ART).
Authorization number:
124953044821
Authorization date:
2012-05-01

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

25-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

25-01-2021

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS

REGULATIONS (PREPARATIONS) 1986

This medicine can be sold under doctor's prescription only

ORGALUTRAN

®

0.25 mg/0.5 ml

Solution for Injection, for Subcutaneous Use

Each pre-filled syringe contains:

0.25 mg ganirelix in 0.5 ml aqueous solution.

For a list of inactive ingredients see section 6. "FURTHER INFORMATION". See also section

“Important information about some of the ingredients of ORGALUTRAN”.

Read the entire leaflet carefully before you start using this medicine.

This leaflet contains concise information about the medicine. If you have any further

questions, ask your doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them,

even if their ailment seems similar to yours.

If any of the side effects gets serious, or if you notice any side effects not listed in this

leaflet, please tell your doctor or pharmacist.

1. WHAT THE MEDICINE IS INTENDED FOR?

ORGALUTRAN is intended for the prevention of premature luteinising hormone (LH) surges in

women undergoing controlled ovarian hyperstimulation (COH) for assisted reproduction

techniques (ART).

Therapeutic group: anti-gonadotrophin-releasing hormones.

ORGALUTRAN belongs to a group of medicines called “anti-gonadotrophin-releasing

hormones” which act against the actions of the natural gonadotrophin releasing hormone

(GnRH). GnRH regulates the release of gonadotrophins (luteinising hormone (LH) and follicle

stimulating hormone (FSH)).

Gonadotrophins play an important role in human fertility and reproduction. In women, FSH is

needed for the growth and development of follicles in the ovaries. Follicles are small round

sacs that contain the egg cells. LH is needed to release the mature egg cells from the

follicles and ovaries (i.e. ovulation). ORGALUTRAN inhibits the action of GnRH, resulting in

suppression of the release of especially LH.

ORGALUTRAN is used for

In women undergoing assisted reproduction techniques, including in vitro fertilisation (IVF)

and other methods, occasionally ovulation may occur too early causing a significant

reduction in the chance of getting pregnant. ORGALUTRAN is used to prevent the

premature LH surge that might cause such a premature release of egg cells.

In clinical studies ORGALUTRAN was used with recombinant follicle stimulating hormone

(FSH) or corifollitropin alfa, a follicle stimulant with a long duration of action.

2. BEFORE USING THE MEDICINE

2.1 Do not use ORGALUTRAN if:

you are allergic (hypersensitive) to ganirelix or to any of the other ingredients of

ORGALUTRAN (for a list of all ingredients, see section 6.1);

you suffer from hypersensitivity to gonadotrophin releasing hormone (GnRH) or a GnRH

analogue;

you have a moderate or severe kidney or liver disease;

you are pregnant or breast-feeding.

2.2 Special warnings concerning use of ORGALUTRAN

Before starting treatment with ORGALUTRAN, tell your doctor if:

Allergic reactions: if you have an active allergic condition, please tell your doctor. Your

doctor will decide, depending on the severity, if additional monitoring is required during

treatment.

Cases of allergic reactions have been reported, as early as with the first dose.

Allergic reactions, both generalised and local, including hives (urticaria), swelling of the

face, lips tongue, and/or throat that may cause difficulty in breathing and/or swallowing

(angioedema and/or anaphylaxis) have been reported. (See also section 4.) If you have

an allergic reaction, stop taking Orgalutran and seek immediate medical assistance.

Latex allergy: The needle cover contains dry natural rubber/latex which comes into

contact with the needle and may cause allergic reactions.

Ovarian hyperstimulation syndrome (OHSS): During or following hormonal stimulation of

the ovaries, ovarian hyperstimulation syndrome may develop. This syndrome is related to

the stimulation procedure with gonadotrophins. Please refer to the Package Leaflet of the

gonadotrophin-containing medicine prescribed for you.

Multiple births or birth defects: The incidence of congenital malformations after assisted

reproduction techniques may be slightly higher than after spontaneous conceptions. This

slightly higher incidence is thought to be related to characteristics of the patients

undergoing fertility treatment (e.g. age of the woman, sperm characteristics) and to the

higher incidence of multiple gestations after assisted reproduction techniques. The

incidence of congenital malformations after assisted reproduction techniques using

ORGALUTRAN is not different from that after using other GnRH analogues in the course

of assisted reproduction techniques.

Pregnancy complications: There is a slightly increased risk of pregnancy outside of the

uterus (an ectopic pregnancy) in women with damaged fallopian tubes.

Women weighing less than 50 kg or more than 90 kg: The efficacy and safety of

ORGALUTRAN has not been established in women weighing less than 50 kg or more

than 90 kg. Ask your doctor for further information.

Children and adolescents

There is no relevant use of ORGALUTRAN in children or adolescents.

Taking other medicines

If you are taking, or have recently taken, other medicines including non-prescription

medicines and nutritional supplements, you should tell the doctor or pharmacist.

Pregnancy, breast-feeding and fertility

ORGALUTRAN should be used during controlled ovarian stimulation for assisted

reproduction techniques (ART). Do not use ORGALUTRAN during pregnancy and breast-

feeding.

If you are pregnant or breast-feeding, consult the doctor or pharmacist before using any

medicine.

Driving and using machines

The effects of ORGALUTRAN on ability to drive and use machines have not been studied.

Important information about some of the ingredients of ORGALUTRAN

This medicine contains less than 1 mmol sodium (23 mg) per injection, that is to say

essentially ‘sodium-free’.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use ORGALUTRAN as instructed by the doctor. You should check with the doctor or

the pharmacist if you are not sure.

ORGALUTRAN is used as part of the treatment for assisted reproduction techniques (ART)

including in vitro fertilisation (IVF).

The dosage and method of treatment will be determined by the doctor only.

The usual recommended dosage is:

Ovarian stimulation with follicle stimulating hormone (FSH) or corifollitropin may start at day 2

or 3 of your period. ORGALUTRAN (0.25 mg) should be injected just under the skin once

daily, starting on day 5 or day 6 of stimulation. Based on your ovarian response, your doctor

may decide to start on another day.

ORGALUTRAN and FSH should be administered approximately at the same time. However,

the preparations should not be mixed and different injection sites are to be used.

Daily treatment with ORGALUTRAN should be continued up to the day that sufficient follicles

of adequate size are present. Final maturation of the egg cells in the follicles can be induced

by administering human chorionic gonadotrophin (hCG). The time between two

ORGALUTRAN injections as well as the time between the last ORGALUTRAN injection and

hCG injection should not exceed 30 hours, as otherwise a premature ovulation (i.e. release

of egg cells) may occur. Therefore, when injecting ORGALUTRAN in the morning treatment

with ORGALUTRAN should be continued throughout the gonadotrophin treatment period

including the day of triggering ovulation. When injecting ORGALUTRAN in the afternoon the

last ORGALUTRAN injection should be given in the afternoon prior to the day of triggering

ovulation.

Do not exceed the recommended dose.

Instructions for use

Injection site

ORGALUTRAN is supplied in pre-filled syringes and should be injected slowly, just under the

skin, preferably in the upper leg.

Inspect the solution before use. Do not use if the solution contains particles or is not clear. If

you administer the injections yourself or have it done by your partner, follow the instructions

below carefully. Do not mix ORGALUTRAN with any other medicines.

Preparing the injection site

Wash your hands thoroughly with soap and water. Swab the injection site with a disinfectant

(for example alcohol) to remove any surface bacteria. Clean about 5 cm (two inches) around

the point where the needle will go in and let the disinfectant dry for at least one minute before

proceeding.

Inserting the needle

Remove needle cover. Pinch up a large area of skin between finger and thumb. Insert the

needle at the base of the pinched-up skin at an angle of 45° to the skin surface. Vary the

injection site with each injection.

Checking the correct needle position

Gently draw back the plunger to check if the needle is positioned correctly. Any blood drawn

into the syringe means the needle tip has penetrated a blood vessel. If this happens, do not

inject ORGALUTRAN but remove the syringe, cover the injection site with a swab containing

disinfectant and apply pressure; bleeding should stop in a minute or two. Do not use this

syringe and dispose of it properly. Start again with a new syringe.

Injecting the solution

Once the needle has been correctly placed, depress the plunger slowly and steadily, so the

solution is correctly injected and the skin tissues are not damaged.

Removing the syringe

Pull the syringe out quickly and apply pressure to the site with a swab containing disinfectant.

Use the pre-filled syringe only once.

If you have accidentally taken a higher dose than you should

Contact your doctor.

If you have forgotten to use ORGALUTRAN

If you realize that you forgot a dose, administer it as soon as possible.

Do not inject a double dose to make up for a forgotten dose.

If you are more than 6 hours late (so the time between two injections is longer than 30 hours)

administer the dose as soon as possible and contact your doctor for further advice.

If you stop using ORGALUTRAN

Do not stop using ORGALUTRAN unless advised to by your doctor, as this may affect the

outcome of your treatment.

Do not take medicines in the dark! Check the label and the dose each time you take your

medicine. Wear glasses if you need them.

If you have any further questions on the use of the medicine, consult with a doctor or a

pharmacist.

4. SIDE EFFECTS

As with any medicine, ORGALUTRAN may cause side effects in some users.

Do not be alarmed by reading the list of side effects, you may not suffer from any of them.

The chance of having a side effect is described by the following categories:

Very Common side effects: may affect more than 1 in 10 women

-

Local skin reactions at the site of injection (predominantly redness, with or without

swelling). The local reaction normally disappears within 4 hours of administration.

Uncommon side effects: may affect up to 1 in 100 women

-

Headache

-

Nausea

-

Malaise

Very rare side effects: may affect up to 1 in 10,000 women

-

Allergic reactions have been observed, as early as with the first dose.

-

Rash

-

Facial swelling

-

Difficulty breathing (dyspnoea)

-

Swelling of face, lips, tongue, and/or throat that may cause difficulty in breathing and/or

swallowing (angioedema and/or anaphylaxis)

-

Hives (urticaria)

-

Worsening of a pre-existing rash (eczema) has been reported in one subject after the

first ORGALUTRAN dose.

In addition, side effects are reported which are known to occur with controlled ovarian

hyperstimulation treatment (e.g. abdominal pain, ovarian hyperstimulation syndrome

(OHSS), ectopic pregnancy (when the embryo develops outside the womb) and miscarriage

(see the patient information leaflet of the FSH-containing preparation you are treated with).

If a side effect appears, if any of the side effects worsens or if you suffer from a side effect

not mentioned in this leaflet, consult with the doctor.

Side effects can be reported to the Ministry of Health by using the link "Reporting side effects

due to medicinal treatment" at the home page of the Ministry of Health's web site

(www.health.gov.il

) which refers to the online side effects reporting form, or by using the link:

https://sideeffects.health.gov.il

5. HOW TO STORE THE MEDICINE?

Avoid Poisoning! This medicine, as all other medicines, must be stored in a safe place out

of the reach of children and/or infants, in order to avoid poisoning. Do not induce vomiting

unless explicitly instructed to do so by a doctor.

Do not use the medicine after the expiry date (exp. date) that appears on the packaging.

The expiry date refers to the last day of the indicated month.

Storage conditions: 2-30ºC. Do not freeze. Store in the original package, in order to

protect from light.

Inspect the syringe before use. Use only syringes with clear, particle-free solutions and

from undamaged containers.

Medicines should not be disposed of via wastewater or household waste. Ask your

pharmacist how to dispose of medicines no longer required. These measures will help to

protect the environment.

6. FURTHER INFORMATION

In addition to the active ingredient the medicine also contains: mannitol, acetic acid

(glacial), water for injections. The pH (a measurement of the acidity) may have been

adjusted with sodium hydroxide and/or acetic acid.

What ORGALUTRAN looks like and content of the package

ORGALUTRAN is a clear and colourless aqueous solution for injection. The solution is

ready for use and intended for subcutaneous administration. The needle cover contains

dry natural rubber/latex which comes into contact with the needle.

ORGALUTRAN is available in packs of 1 pre-filled syringe.

Manufacturer

N.V. Organon, Oss, The Netherlands.

Marketing Authorization Holder

Merck Sharp & Dohme (Israel-1996) Company Ltd., P.O.Box 7121 Petah-Tikva, 49170.

Drug registration no. listed in the official registry of the Ministry of Health

124-95-30448

Revised in May 2020.

1.

NAME OF THE MEDICINAL PRODUCT

Orgalutran

0.25 mg/0.5 mL

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe contains 0.25 mg of ganirelix in 0.5 mL aqueous

solution. The active substance ganirelix (INN) is a synthetic decapeptide with

high antagonistic activity to the naturally occurring gonadotrophin releasing

hormone (GnRH). The amino acids at positions 1, 2, 3, 6, 8 and 10 of the

natural GnRH decapeptide have been substituted resulting in N-Ac-D-Nal(2)

D-pClPhe

, D-Pal(3)

, D-hArg(Et2)

, L-hArg(Et2)

, D-Ala

]-GnRH with a

molecular weight of 1570.4.

Excipient with known effect:

This medicinal product contains less than 1 mmol sodium (23 mg) per

injectionthat is to say

essentially ‘sodium-free’.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection.

Clear and colourless aqueous solution.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

The prevention of premature luteinising hormone (LH) surges in women

undergoing controlled ovarian hyperstimulation (COH) for assisted

reproduction techniques (ART).

In clinical studies Orgalutran was used with recombinant follicle stimulating

hormone (FSH) or corifollitropin alfa, the sustained follicle stimulant.

4.2

Posology and method of administration

Orgalutran should only be prescribed by a specialist experienced in the treatment of

infertility.

Posology

Orgalutran is used to prevent premature LH surges in women undergoing COH.

Controlled ovarian hyperstimulation with FSH or corifollitropin alfa may start at day 2

or 3 of menses. Orgalutran (0.25 mg) should be injected subcutaneously once daily,

starting on day 5 or day 6 of FSH administration or on day 5 or day 6 following the

administration of corifollitropin alfa. The starting day of Orgalutran is depending on

the ovarian response, i.e. the number and size of growing follicles and/or the amount

of circulating oestradiol.The start of Orgalutran may be delayed in absence of

follicular growth, although clinical experience is based on starting Orgalutran on day

5 or day 6 of stimulation.

Orgalutran and FSH should be administered approximately at the same time.

However, the preparations should not be mixed and different injection sites are to be

used.

FSH dose adjustments should be based on the number and size of growing follicles,

rather than on the amount of circulating oestradiol (see section 5.1). Daily treatment

with Orgalutran should be continued up to the day that sufficient follicles of adequate

size are present. Final maturation of follicles can be induced by administering human

chorionic gonadotrophin (hCG).

Timing of last injection

Because of the half-life of ganirelix, the time between two Orgalutran injections as

well as the time between the last Orgalutran injection and the hCG injection should

not exceed 30 hours

, as otherwise a premature LH surge may occur. Therefore,

when injecting Orgalutran in the morning, treatment with Orgalutran should be

continued throughout the gonadotrophin treatment period including the day of

triggering ovulation. When injecting Orgalutran in the afternoon the last Orgalutran

injection should be given in the afternoon prior to the day of triggering ovulation.

Orgalutran has shown to be safe and effective in women undergoing multiple

treatment cycles.

The need for luteal phase support in cycles using Orgalutran has not been studied. In

clinical studies, luteal phase support was given according to study centres’ practice

or according to the clinical protocol.

Special populations

Renal impairment

There is no experience on the use of Orgalutran in subjects with renal impairment, as

they were excluded from clinical studies. Therefore, the use of Orgalutran is

contraindicated in patients with moderate or severe renal impairment (see section

4.3).

Hepatic impairment

There is no experience on the use of Orgalutran in subjects with hepatic impairment,

as they were excluded from clinical studies. Therefore, the use of Orgalutran is

contraindicated in patients with moderate or severe hepatic impairment (see section

4.3).

Paediatric population

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

Method of administration

Orgalutran should be administered subcutaneously, preferably in the upper leg. The

injection site should be varied to prevent lipoatrophy. The patient or her partner may

perform the injections of Orgalutran themselves, provided that they are adequately

instructed and have access to expert advice.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in

section 6.1.

Hypersensitivity to gonadotrophin-releasing hormone (GnRH) or any other

GnRH analogue.

Moderate or severe impairment of renal or hepatic function.

Pregnancy or breast-feeding.

4.4

Special warnings and precautions for use

Hypersensitivity reaction

Special care should be taken in women with signs and symptoms of active allergic

conditions. Cases of hypersensitivity reactions, (both generalised and local), have

been reported with Orgalutran, as early as with the first dose, during post-marketing

surveillance. These events have included anaphylaxis (including anaphylactic shock),

angioedema and urticaria. (see section 4.8). If a hypersensitivity reaction is

suspected, Orgalutran should be discontinued and appropriate treatment

administered. In the absence of clinical experience, Orgalutran treatment is not

advised in women with severe allergic conditions.

Latex allergy

The needle cover contains dry natural/ rubber latex which comes into contact with the

needle and may cause allergic reactions (see section 6.5).

Ovarian hyperstimulation syndrome (OHSS)

Ovarian hyperstimulation syndrome (OHSS) may occur during or following ovarian

stimulation. OHSS must be considered an intrinsic risk of gonadotrophin stimulation.

OHSS should be treated symptomatically, e.g. with rest, intravenous infusion of

electrolyte solutions or colloids and heparin.

Ectopic pregnancy

Since infertile women undergoing assisted reproduction, and particularly in vitro

fertilisation (IVF), often have tubal abnormalities the incidence of ectopic pregnancies

might be increased. Early ultrasound confirmation that a pregnancy is intrauterine is

therefore important.

Congenital malformations

The incidence of congenital malformations after Assisted Reproductive Technologies

(ART) may be higher than after spontaneous conceptions. This is thought to be due

to differences in parental characteristics (e.g., maternal age, sperm characteristics)

and an increased incidence of multiple gestations. In clinical studies investigating

more than 1,000 newborns it has been demonstrated that the incidence of congenital

malformations in children born after COH treatment using Orgalutran is comparable

with that reported after COH treatment using a GnRH agonist.

Women weighing less than 50 kg or more than 90 kg

The safety and efficacy of Orgalutran have not been established in women weighing

less than 50 kg or more than 90 kg (see sections 5.1 and 5.2).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, that

is to say essentially ‘sodium-free’.

4.5

Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

The possibility of interactions with commonly used medicinal products, including

histamine liberating medicinal products, cannot be excluded.

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of ganirelix in pregnant women.

In animals, exposure to ganirelix at the time of implantation resulted in litter

resorption (see section 5.3). The relevance of these data for humans is unknown.

Breast-feeding

It is not known whether ganirelix is excreted in breast milk.

The use of Orgalutran is contraindicated during pregnancy and breast-feeding (see

section 4.3).

Fertility

Ganirelix is used in the treatment of women undergoing controlled ovarian

hyperstimulation in assisted reproduction programmes. Ganirelix is used to prevent

premature LH surges that might otherwise occur in these women during the ovarian

stimulation.

For posology and method of administration, see section 4.2.

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.

4.8

Undesirable effects

Summary of the safety profile

The table below shows all adverse reactions in women treated with Orgalutran in

clinical studies using recFSH for ovarian stimulation. The adverse reactions with

Orgalutran using corifollitropin alfa for ovarian stimulation are expected to be similar

Tabulated list of adverse reactions

The adverse reactions are classified according to MedDRA system organ class and

frequency; very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to

<1/100). The frequency of hypersensitivity reactions (very rare, <1/10,000) has been

deduced from post-marketing surveillance.

System organ class

Frequency

Adverse reaction

Immune system disorders

Very rare

Hypersensitivity reactions (including

rash, facial swelling, dyspnoea

anaphylaxis (including anaphylactic

shock), angioedema and urticaria)

Worsening of a pre-existing eczema

Nervous system disorders

Uncommon

Headache

Gastrointestinal disorders

Uncommon

Nausea

General disorders and

administration site

conditions

Very common

Local skin reaction at the site of

injection (predominantly redness, with

or without swelling)

Uncommon

Malaise

Cases have been reported, as early as with the first dose, among patients administered

Orgalutran.

Reported in one subject after the first Orgalutran dose.

In clinical studies, one hour after injection, the incidence of at least once a moderate or

severe local skin reaction per treatment cycle, as reported by patients, was 12 % in

Orgalutran treated patients and 25 % in patients treated subcutaneously with a GnRH

agonist. The local reactions generally disappear within 4 hours after administration.

Description of selected adverse reactions

Other reported adverse reactions are related to the controlled ovarian

hyperstimulation treatment for ART, notably pelvic pain, abdominal distension,

OHSS, (see section 4.4), ectopic pregnancy and spontaneous abortion.

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.

Any suspected adverse events should be reported to the Ministry of Health according

to the National Regulation by using an online form

https://sideeffects.health.gov.il

4.9 Overdose

Overdose in humans may result in a prolonged duration of action.

No data on acute toxicity of Orgalutran in humans are available. Clinical studies with

subcutaneous administration of Orgalutran at single doses up to 12 mg did not show

systemic adverse reactions. In acute toxicity studies in rats and monkeys

non-specific toxic symptoms such as hypotension and bradycardia were only

observed after intravenous administration of ganirelix over 1 and 3 mg/kg,

respectively.

In case of overdose, Orgalutran treatment should be (temporarily) discontinued.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues,

anti-gonadotrophinreleasing hormones, ATC code: H01CC01.

Mechanism of action

Orgalutran is a GnRH antagonist, which modulates the hypothalamic-pituitary-

gonadal axis by competitive binding to the GnRH receptors in the pituitary gland. As

a result a rapid, profound, reversible suppression of endogenous gonadotrophins

occurs, without initial stimulation as induced by GnRH agonists. Following

administration of multiple doses of 0.25 mg Orgalutran to female volunteers serum

LH, FSH and E

concentrations were maximally decreased by 74%, 32% and 25% at

4, 16 and 16 hours after injection, respectively. Serum hormone levels returned to

pre-treatment values within two days after the last injection.

Pharmacodynamic effects

In patients undergoing controlled ovarian stimulation the median duration of

Orgalutran treatment was 5 days. During Orgalutran treatment the average incidence

of LH rises (>10 IU/l) with concomitant progesterone rise (>1 ng/mL) was 0.3 -1.2%

compared to 0.8% during GnRH agonist treatment. There was a tendency towards

an increased incidence of LH and progesterone rises, in women with a higher body

weight (>80 kg), but, no effect on clinical outcome was observed. However, based on

the small number of patients treated so far, an effect cannot be excluded.

In case of a high ovarian response, either as a result of a high exposure to

gonadotrophins in the early follicular phase or as a result of high ovarian

responsiveness, premature LH rises may occur earlier than day 6 of stimulation.

Initiation of Orgalutran treatment on day 5 can prevent these premature LH rises

without compromising the clinical outcome.

Clinical efficacy and safety

In controlled studies of Orgalutran with FSH, using a long protocol of GnRH agonist

as a reference, treatment with the Orgalutran regimen resulted in a faster follicular

growth during the first days of stimulation but the final cohort of growing follicles was

slightly smaller and produced on average less oestradiol. This different pattern of

follicular growth requires that FSH dose adjustments are based on the number and

size of growing follicles, rather than on the amount of circulating oestradiol. Similar

comparative studies with corifollitropin alfa using either a GnRH antagonist or long

agonist protocol have not been performed.

5.2

Pharmacokinetic properties

Pharmacokinetic parameters after multiple subcutaneous dosing of Orgalutran (once

daily injection) were similar to those after a single subcutaneous dose. After repeated

dosing 0.25 mg/day steady-state levels of approximately 0.6 ng/mL were reached

within 2 to 3 days.

Pharmacokinetic analysis indicates an inverse relationship between body weight and

serum concentrations of Orgalutran.

Absorption

After a single subcutaneous administration of 0.25 mg, serum levels of ganirelix rise

rapidly and reach peak levels (C

) of approximately 15 ng/mL within 1 to 2 hours

). The bioavailability of Orgalutran following subcutaneous administration is

approximately 91 %.

Biotransformation

The major circulating component in plasma is ganirelix. Ganirelix is also the main

compound found in urine. Faeces only contain metabolites. The metabolites are

small peptide fragments formed by enzymatic hydrolysis of ganirelix at restricted

sites. The metabolite profile of Orgalutran in humans was similar to that found in

animals.

Elimination

The elimination half-life (t

) is approximately 13 hours and clearance is

approximately 2.4 L/h. Excretion occurs via faeces (approximately 75 %) and urine

(approximately 22 %).

5.3

Preclinical safety data

Preclinical data reveal no special hazard for humans based on safety pharmacology,

repeated dose toxicity and genotoxicity.

Reproduction studies carried out with ganirelix at doses of 0.1 to 10

g/kg/day

subcutaneously in the rat and 0.1 to 50

g/kg/day subcutaneously in the rabbit

showed increased litter resorption in the highest dose groups. No teratogenic effects

were observed.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Mannitol,

Acetic acid, glacial,

Water for injections.

The pH may have been adjusted with sodium hydroxide and/or acetic acid.

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.

6.4

Special precautions for storage

Do not freeze.

Store between 2°C and 30°C.

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

6.5

Nature and contents of container

Disposable pre-filled syringes (siliconised type I glass), containing 0.5 mL of sterile,

ready for use, aqueous solution closed with a rubber piston that does not contain

latex. Each pre-filled syringe is affixed with a needle closed by a needle cover of

dry natural rubber/latex which comes into contact with the needle. (See section

4.4).

Supplied in cartons containing 1 pre-filled syringe.

6.6

Special precautions for disposal and other handling

Inspect the syringe before use. Use only syringes with clear, particle-free solutions

and from undamaged containers.

Any unused medicinal product or waste material should be disposed of in

accordance with local requirements.

6.7

Manufacturer

N.V. Organon, Oss, the Netherlands

6.8

License Holder

Merck Sharp & Dohme (Israel-1996) Company Ltd., P.O.Box 7121 Petah-Tikva,

49170

6.9

Registration no.

124-95-30448

Revised in May 2020.

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