BRAVELLE

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
UROFOLLITROPIN
Available from:
Ferring Ireland Ltd
ATC code:
G03GA04
INN (International Name):
UROFOLLITROPIN
Dosage:
75 International Unit
Pharmaceutical form:
Pdr+Solv for Soln for Inj
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
urofollitropin
Authorization status:
Not Marketed
Authorization number:
PA1009/019/001
Authorization date:
2006-01-09

Package leaflet: InformatIon for the user

BRAVELLE

75 IU powder and solvent for solution for injection.

(urofollitropin)

Read all of this leaflet carefully before you start using this

medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or nurse.

This medicine has been prescribed for you only. Do not pass it on

to others. It may harm them, even if their symptoms are the same

as yours.

If you get any side effects, talk to your doctur or nurse. This includes

any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

What BRAVELLE is and what it is used for

What you need to know before you use BRAVELLE

How to use BRAVELLE

Possible side effects

How to store BRAVELLE

Contents of the pack and other information

1. What BRAVELLE is and what it is used for

BRAVELLE is provided as a powder which must be mixed with liquid

(solvent) before it is used. It is given as an injection under the skin.

BRAVELLE contains a hormone called follicle stimulating hormone (FSH).

FSH is a natural hormone produced in both males and females. It helps

the reproductive organs to work normally. The FSH in this medicine is

obtained from the urine of postmenopausal women. It is highly purified,

and is then known as urofollitropin.

BRAVELLE is used to treat female infertility in the following two

situations:

i. Women who cannot become pregnant because their ovaries do not

produce eggs (including polycystic ovarian disease). BRAVELLE is used

in women who have already been given a medicine called clomiphene

citrate to treat their infertility, but this medicine has not helped.

ii. Women in assisted reproduction programmes (including

in vitro

fertilisation/embryo transfer [IVF/ET], gamete intra-fallopian transfer

[GIFT] and intracytoplasmic sperm injection [ICSI]). BRAVELLE helps the

ovaries develop many egg sacs (follicles) where an egg might develop

(multiple follicular development).

2. What you need to know before you use BRAVELLE

Before starting treatment with this medicine, you and your partner

should be assessed by a doctor for causes of your fertility problems. In

particular you should be checked for the following conditions so that any

other appropriate treatment can be given:

Underactive thyroid or adrenal glands

High levels of a hormone called prolactin (hyperprolactinemia)

Tumours of the pituitary gland (a gland located on the base of the

brain)

Tumours of the hypothalamus (an area located under the part of the

brain called the thalamus)

If you know you have any of the conditions listed above, please tell

your doctor before starting treatment with this medicine.

Do not use BRAVELLE:

If you are allergic (hypersensitive) to urofollitropin or any

of the other

ingredients of this medicine (listed in section 6)

If you have tumours of the uterus (womb), ovaries, breasts, pituitary

gland or hypothalamus

If you have cysts on your ovaries or enlarged ovaries (unless caused

by polycystic ovarian disease)

If you have malformations of the sexual organs which make a normal

pregnancy impossible

If you suffer from bleeding from the vagina where the cause is not

known

If you have fibroids of the uterus (womb) which make a normal

pregnancy impossible

If you are pregnant or breastfeeding

If you have experienced an early menopause

Warnings and precautions

Talk to your doctor or nurse before using BRAVELLE.

If you get:

Pain in the abdomen

Swelling in the abdomen

Nausea

Vomiting

Diarrhoea

Weight gain

Difficulty breathing

Decreased urination.

Tell your doctor straight away, even if the symptoms develop some days

after the last injection has been given. These can be signs of high levels

of activity in the ovaries which might become severe.

If these symptoms become severe, the infertility treatment should be

stopped and you should receive treatment in hospital.

Keeping to your recommended BRAVELLE dose and careful monitoring

of your treatment will reduce your chances of getting these symptoms.

If you stop using this medicine you might still experience these

symptoms. Please contact your doctor immediately if any of these

symptoms occur.

While you are being treated with this medicine, your doctor will normally

arrange for you to have ultrasound scans and sometimes blood tests

to monitor your response to treatment.

Being treated with hormones like this medicine can increase the risk of:

Ectopic pregnancy (pregnancy outside of the womb) if you have a

history of fallopian tube disease

Miscarriage

Multiple pregnancy (twins, triplets, etc.)

Congenital malformations (physical defects present in baby at birth).

Some women who have been given infertility treatment have developed

tumours in the ovaries and other reproductive organs. It is not yet known

if treatment with hormones like this medicine causes these problems.

Blood clots in the veins or arteries are more likely to occur in women

who are pregnant. Infertility treatment can increase the chances of this

happening, especially if you are overweight or if you or someone in your

family (blood relative) has had blood clots. Tell your doctor if you think

this applies to you.

Other medicines and BRAVELLE

Tell your doctor if you are taking, have recently taken or might take any

other medicines.

Clomiphene citrate is another medicine used in the treatment of

infertility. If BRAVELLE is used at the same time as clomiphene citrate

the effect on the ovaries may be increased.

BRAVELLE can be used at the same time as MENOPUR. Please refer to

section 3 ‘How to take BRAVELLE’.

Pregnancy and breast-feeding

This medicine should not be used during pregnancy or breast-feeding.

Driving and using machines

This medicine is unlikely to affect your ability to drive and use machines.

Important information about some of the ingredients of BRAVELLE

BRAVELLE contains less than 1 mmol sodium (23 mg) per dose, i.e.

essentially ‘sodium-free’.

3. How to use BRAVELLE

Always use this medicine exactly as your doctor has told you. Check

with your doctor if you are not sure.

i. Women who are not ovulating (not producing eggs):

Treatment should start within the first 7 days of the menstrual cycle (day

1 is the first day of your period). Treatment should be given every day for

at least 7 days.

The starting dose is normally 75 IU daily (one vial of powder) but this

may be adjusted depending on your response (up to a maximum of 225

IU – 3 vials of powders per day). A particular dose should be given for

at least 7 days before the dose is changed. It is recommended that the

dose should be increased by 37.5 IU (half a vial of powder) each time

(and not more than 75 IU). The cycle of treatment should be abandoned

if there is no response after 4 weeks.

When a good response is obtained a single injection of another hormone

called human chorionic gonadotrophin (hCG), at a dose of 5,000 to

10,000 IU, should be given 1 day following the last BRAVELLE injection.

It is recommended to have sexual intercourse on the day of the hCG

injection and the day after. Alternatively, artificial insemination (injection

of sperm directly into the womb) may be performed. Your doctor will

closely monitor your progress for at least 2 weeks after you have

received the hCG injection.

Your doctor will monitor the effect of BRAVELLE treatment. Depending on

your progress, your doctor may decide to stop treatment with BRAVELLE

and not give you the hCG injection. In this case, you will be instructed to

use a barrier method of contraception (e.g. condom) or not have sexual

intercourse until your next period has started.

ii. Women in assisted reproduction programs:

If you are also receiving treatment with a GnRH agonist (a medicine

which helps a hormone called Gonadotropin Releasing Hormone (GnRH)

to work), BRAVELLE should be started approximately 2 weeks after the

start of the GnRH agonist therapy.

In patients not receiving a GnRH agonist, BRAVELLE treatment should

be started on day 2 or 3 of the menstrual cycle (day 1 is the first day of

your period).

Treatment should be given every day for at least 5 days. The initial dose

of this medicine is normally 150 - 225 IU (2 or 3 vials of powder). This

dose may be increased according to your response to the treatment

up to a maximum of 450 IU (6 vials of powder) per day. The dose

should not be increased by more than 150 IU per adjustment. Normally

treatment should not continue for more than 12 days.

If enough egg sacs are present, you will be given a single injection of a

medicine called human chorionic gonadotrophin (hCG) at a dose of up to

10,000 IU to induce ovulation (release of an egg).

Your doctor will closely monitor your progress for at least 2 weeks after

you have received the hCG injection.

Your doctor will monitor the effect of BRAVELLE treatment. Depending on

your progress, your doctor may decide to stop treatment with BRAVELLE

and not give you the hCG injection. In this case, you will be instructed to

use a barrier method of contraception (e.g. condom) or not have sexual

intercourse until your next period has started.

InstRUctIOns fOR UsE

If your clinic has asked you to inject this medicine yourself, you

should follow any instructions they provide.

The first injection of this medicine should be given under the supervision

of a doctor.

DILUTING BRAVELLE:

This medicine is provided as a powder, and must be diluted before

it is injected. The liquid which you should use to dilute this medicine

is provided with the powder. This medicine should only be diluted

immediately before use.

To do this:

Firmly attach the long, thick needle

(drawing up /reconstitution needle) to the

syringe.

Break the top off the ampoule with the liquid.

Draw up all of the liquid from the ampoule into

the syringe.

Insert the needle through the rubber top of

the BRAVELLE powder vial and slowly inject all

of the liquid. Aim at the side of the vial, to avoid

creating bubbles.

The powder should quickly dissolve (within 2

minutes) to form a clear solution. This normally

happens when only few drops of solvent have

been added.

To help the powder dissolve, swirl the solution.

Do not shake as this will cause air bubbles to

form.

If the solution is not clear or if it contains

particles, it should not be used.

Draw up the solution back into the syringe.

If you have been prescribed more than one vial of BRAVELLE powder

per injection, you can draw up the solution (the first BRAVELLE dilution)

back into the syringe and inject it into a second vial of powder. You can

do this with up to six vials of powder in total – but only do as your doctor

has told you.

If you have been prescribed MENOPUR at the same time as BRAVELLE,

you may mix the two medicines by diluting BRAVELLE and injecting the

solution into the MENOPUR powder. Allow this to dissolve, and draw up

this combined solution: you can then inject them together instead of

injecting each one separately.

INJECTING BRAVELLE:

Once you have your prescribed dose

drawn up into the syringe, change the

needle to the short, thin needle (the

injection needle).

Your doctor or nurse will tell you where to inject (e.g. front of the thigh,

abdomen etc.)

To inject, pinch the skin to produce a fold, and insert the needle in one

swift motion at 90 degrees to the body. Press down on the plunger to

inject the solution, and then remove the needle.

After removing the syringe, apply pressure

to the injection site to stop any bleeding.

Gently massaging the injection site will help

to disperse the solution under the skin.

Do not put used items into normal

domestic waste; these should be disposed

of appropriately.

If you use more BRAVELLE than you should

Please tell a nurse or doctor

If you forget to use BRAVELLE

Do not take a double dose to make up for a forgotten dose. Please tell a

nurse or doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not

everybody gets them.

Treatment with this medicine may cause high levels of activity in

the ovaries, especially in women with polycystic ovaries. Symptoms

include: pain in the abdomen, swelling in the abdomen, nausea,

vomiting, diarrhoea, weight gain, difficulty breathing and decreased

urination.

As complications to high levels of activity in the ovaries, blood clots

and twisting of an ovary might occur. If you experience any of these

symptoms contact your doctor immediately, even if they develop some

days after the last injection has been given.

Allergic (hypersensitivity) reactions may occur when using this

medicine. Symptoms of these reactions might include: rash, itching,

swelling of the throat and difficulty breathing. If you experience any

of these symptoms, contact your doctor immediately.

the following very common side effects may affect more than 10 of

every 100 patients treated:

Pain in the abdomen

Headache

the following common side effects may affect between 1 and 10 of

every 100 patients treated:

Urinary tract infection

Inflammation of the throat and nasal passage

Hot flushes

Nausea

Vomiting

Discomfort in the abdomen

Swelling in the abdomen

Diarrhoea

Constipation

Rash

Muscle spasms

Pelvic pain

Overstimulation of the ovaries (high levels of activity)

Breast tenderness

Vaginal bleeding

Vaginal discharge

Pain

Injection site pain and reactions (redness, bruising, swelling and/or

itching)

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any

possible side effects not listed in this leaflet.

You can also report side effects via;

UK: The Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard

Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2;

Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie;

E-mail: medsafety@hpra.ie.

By reporting side effects you can help provide more information on the

safety of this medicine.

5. How to store BRAVELLE

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the

carton. The expiry date refers to the last day of that month.

Do not store above 25°C. Do not freeze.

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

Do not throw away any medicines via wastewater or household waste.

Ask your pharmacist how to dispose of medicines you no longer

required. These measures will help to protect the environment.

6. contents of the pack and other information

What BRAVELLE contains

The active substance is urofollitropin.

Each vial of powder contains 82.5 IU highly purified follicle stimulating

hormone (FSH), urofollitropin. When reconstituted with the solvent

provided, each vial delivers 75 IU of FSH.

The other ingredients in the powder are:

Lactose monohydrate

Sodium phosphate dibasic heptahydrate

Polysorbate 20

Phosphoric acid

Water

The ingredients in the solvent are:

Sodium chloride

Water

Hydrochloric acid

What BRAVELLE looks like and contents of the pack

This medicine is a powder and solvent for solution for injection.

The carton contains five or ten clear glass vials which contain a light

powder. The carton also contains an equal number of clear glass

ampoules containing a colourless solvent.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder of UK:

Ferring Pharmaceuticals Ltd, Drayton Hall, Church Road,

West Drayton UB7 7PS.

PL 03194/0087 - Bravelle

PL 03194/0060 - Sodium Chloride Solution 0.9% w/v

Marketing Authorisation Holder of Ireland:

Ferring Ireland Ltd, United Drug House, Magna Drive, Magna

Business Park, Citywest Road, Dublin 24

PA 1009/19/1

Manufacturers

Ferring GmbH

Wittland 11, D-24109 Kiel, Germany

this leaflet was last revised in 04/2016

2009052201

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

BRAVELLE 75 IU powder and solvent for solution for injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of powder contains 82.5 IU of highly purified urinary follicle stimulating hormone (FSH), urofollitropin.

When reconstituted with the solvent provided, each vial delivers 75 IU of FSH.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Appearance of powder: Lyophilised, white to off-white caked mass.

Appearance of solvent: Clear colourless solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

BRAVELLE is indicated for the treatment of female infertility in the following clinical situations:

Anovulation (including polycystic ovarian disease (PCOD)) in women who have been unresponsive to treatment with

clomiphene citrate.

Controlled ovarian hyperstimulation to induce

development

multiple

follicles

assisted reproductive

technologies (ART) (e.g.

in vitro fertilisation/embryo transfer (IVF/ET),

gamete intra-fallopian transfer (GIFT) and

intracytoplasmic sperm injection (ICSI)).

4.2 Posology and method of administration

Treatment with BRAVELLE should be initiated under the supervision of a physician experienced in the treatment of

fertility problems.

Posology

There are great inter- and intra-individual variations in the response of the ovaries to exogenous gonadotropins. This

makes it impossible to set a uniform dosage scheme. The dosage should, therefore, be adjusted individually depending

on the ovarian response. This requires monitoring of ovarian response by ultrasonography alone or preferably in

combination with measurement of oestradiol levels. BRAVELLE can be given alone or in combination with a

gonadotropin-releasing hormone (GnRH) agonist or antagonist for controlled ovarian hyperstimulation. There is no

clinical trial experience with the use of BRAVELLE in combination with GnRH antagonists in this indication.

Recommendations about dosage and duration of treatment may change depending on the actual treatment protocol.

Clinical trial experience with BRAVELLE is based upon one treatment cycle in both indications.

Women with anovulation (including PCOD):

The object of BRAVELLE therapy is to develop a single Graafian follicle from which the oocyte will be liberated after

the administration of human chorionic gonadotropin (hCG).

BRAVELLE therapy should start within the initial 7 days of the menstrual cycle. The recommended initial dose of

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

6

/

0

7

/

2

0

1

6

C

R

N

2

1

7

8

5

8

2

p

a

g

e

n

u

m

b

e

r

:

1

BRAVELLE is 75 IU daily, which should be maintained for at least 7 days. Based on clinical monitoring (including

ovarian ultrasound alone or in combination with measurement of oestradiol levels) subsequent dosing should be

adjusted according to individual patient response. Adjustments in dose should not be made more frequently than every

7 days. The recommended dose increment is 37.5 IU per adjustment and should not exceed 75 IU. The maximum daily

dose should not be higher than 225 IU. If a patient fails to respond adequately after 4 weeks of treatment, that cycle

should be abandoned.

When an optimal response is obtained a single injection of 5,000 to 10,000 IU hCG should be given 1 day following

the last BRAVELLE injection. The patient is recommended to have coitus on the day of and the day following hCG

administration. Alternatively intrauterine insemination may be performed. Patients should be followed closely for at

least 2 weeks after hCG administration. If an excessive response to BRAVELLE is obtained treatment should be

stopped and hCG withheld (see section 4.4), and the patient should use a barrier method of contraception or refrain

from having coitus until the next menstrual bleeding has started.

Women undergoing controlled ovarian hyperstimulation for multiple follicular development for assisted

reproductive technologies (ART):

In line with clinical trials with BRAVELLE that involved downregulation with GnRH agonists, BRAVELLE therapy

should start approximately 2 weeks after the start of agonist treatment. The recommended initial dose of BRAVELLE

is 150-225 IU daily for at least the first 5 days of treatment. Based on clinical monitoring (including ovarian ultrasound

alone or in combination with measurement of oestradiol levels) subsequent dosing should be adjusted according to

individual patient response, and should not exceed 150 IU per adjustment. The maximum daily dose given should not

be higher than 450 IU daily and in most cases dosing beyond 12 days is not recommended.

In protocols not involving downregulation, BRAVELLE therapy should start on day 2 or 3 of the menstrual cycle. It is

recommended to use the dose ranges and regimen of administration suggested above for protocols with downregulation

with GnRH agonists.

When an optimal response is obtained a single injection of up to 10,000 IU hCG should be administered to induce final

follicular maturation in preparation for oocyte retrieval. Patients should be followed closely for at least 2 weeks after

hCG administration. If an excessive response to BRAVELLE is obtained treatment should be stopped and hCG

withheld (see section 4.4), and the patient should use a barrier method of contraception or refrain from having coitus

until the next menstrual bleeding has started.

Paediatric population

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

Method of administration

BRAVELLE is intended for subcutaneous (SC) injection after reconstitution with the solvent provided. The powder

should be reconstituted immediately prior to use. In order to avoid the injection of large volumes up to 6 vials of the

powder may be dissolved in the solvent provided.

The solution should not be used if it contains particles or if it is not

clear.

Appearance of reconstituted solution: clear solution.

For instructions of reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

BRAVELLE is contraindicated in women who have:

Tumours of the pituitary or hypothalamic glands

Ovarian, uterine or mammary carcinoma

Pregnancy and lactation

Gynaecological haemorrhage of unknown aetiology

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

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

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

6

/

0

7

/

2

0

1

6

C

R

N

2

1

7

8

5

8

2

p

a

g

e

n

u

m

b

e

r

:

2

administered:

Primary ovarian failure

Ovarian cysts or enlarged ovaries not due to polycystic ovarian disease.

Malformation of sexual organs incompatible with pregnancy

Fibroid tumours of the uterus incompatible with pregnancy

4.4 Special warnings and precautions for use

BRAVELLE is a potent gonadotropic substance capable of causing mild to severe adverse reactions, and should only

be used under the supervision of physicians who are thoroughly familiar with infertility problems and their

management.

Gonadotropin 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 BRAVELLE 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

administration, with a poor response to FSH in some patients. The lowest effective dose in relation to the treatment

objective should be used.

Repeated exposure to BRAVELLE has not been investigated in clinical trials.

The first injection of BRAVELLE 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

BRAVELLE 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 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.

Excessive ovarian response to gonadotropin 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 refrain

from coitus or to 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 the hCG

administration.

Adherence to recommended BRAVELLE 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). 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,

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

6

/

0

7

/

2

0

1

6

C

R

N

2

1

7

8

5

8

2

p

a

g

e

n

u

m

b

e

r

:

3

OHSS resolves spontaneously with the onset of menses.

If severe OHSS occurs, gonadotropin 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 ovulation induction with gonadotropins, 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 ovulation induction or ART 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

gonadotropins increases the baseline risk of these tumors 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

Women with generally recognised risk factors for thromboembolic events, such as personal or family history, severe

obesity (Body Mass Index > 30 kg/m

) or thrombophilia, may have an increased risk of venous or arterial

thromboembolic events, during or following treatment with gonadotropins. In these women, the benefits of

gonadotropin 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 interaction studies have been performed.

Although there is no clinical experience, it is expected that the concomitant use of BRAVELLE and clomiphene citrate

may enhance the follicular response. When using a GnRH agonist for pituitary desensitisation, a higher dose of

BRAVELLE may be necessary to achieve adequate follicular response.

4.6 Fertility, pregnancy and lactation

BRAVELLE is contraindicated in women who are pregnant or lactating (see section 4.3).

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

6

/

0

7

/

2

0

1

6

C

R

N

2

1

7

8

5

8

2

p

a

g

e

n

u

m

b

e

r

:

4

To date no teratogenic risk has been reported when gonadotropins are used clinically for controlled ovarian

hyperstimulation. Data on exposed pregnancies are insufficient. Animal experiments did not reveal teratogenic effects

(see section 5.3).

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. However, BRAVELLE is

unlikely to have influence on the patient’s performance to drive and use machines.

4.8 Undesirable effects

The most

commonly reported adverse events during treatment

with BRAVELLE in clinical

trials are headache and

abdominal

pain,

both occurring in 10% of patients followed by nausea,

vaginal

haemorrhage,

OHSS and abdominal

distension, each occurring in 5 to 9% of patients. The table below displays the adverse events occurring in more than

1% of the patients treated with BRAVELLE in clinical trials according to organ class and frequency.

As complications of OHSS, venous thromboembolic events and ovarian torsion might occur.

Allergic,

local

generalized skin reactions and delayed-type hypersensitivity have been reported with the use of

gonadotropin preparations.

Repeated exposure to BRAVELLE has not been investigated in clinical trials.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517; Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Organ Class

Very common (>1/10)

Common (

1/100 to

<1/10)

Infections and infestations

Urinary tract infection,

nasopharyngitis

Nervous system disorders

Headache

Vascular disorders

Hot flushes

Gastrointestinal disorders

Abdominal pain

Nausea, vomiting,

abdominal distension,

abdominal discomfort,

diarrhoea, constipation

Skin and subcutaneous tissue

disorders

Rash

Muscoloskeletal and

connective tissue disorders

Muscle spasms

Reproductive system and

breast disorders

Vaginal haemorrhage,

OHSS, pelvic pain, breast

tenderness, vaginal

discharge

General disorders and

administration site disorders

Pain, injection site pain

and reactions (redness,

bruising, swelling and/or

itching)

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

6

/

0

7

/

2

0

1

6

C

R

N

2

1

7

8

5

8

2

p

a

g

e

n

u

m

b

e

r

:

5

4.9 Overdose

The effects of an overdose is unknown, nevertheless ovarian hyperstimulation syndrome could be expected to occur

(see section 4.4).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Gonadotropins

ATC code: G03G A04

BRAVELLE contains a highly purified preparation of urinary FSH extracted from the urine of postmenopausal women.

FSH stimulates ovarian follicular growth and development as well as gonadal steroid production in women who do not

have primary ovarian failure.

The isoform composition of

the highly purified FSH in BRAVELLE displays

more basic isoforms

than other

urofollitropin preparations,

and is similar to that observed for recombinant FSH preparations. According to data from

clinical

trials,

the pharmacodynamic responses

associated with BRAVELLE treatment

do not

differ

from those

associated with recombinant

FSH when administered by the same route.

After

SC administration,

similar

follicle

response,

peak oestradiol

levels,

number of oocytes retrieved and number of mature oocytes have been found with

BRAVELLE and recombinant FSH, without differences in total FSH dose or duration of treatment.

Treatment

with BRAVELLE is usually followed by administration of hCG to induce final

follicle maturation and

ovulation.

5.2 Pharmacokinetic properties

Following single doses of SC administration of BRAVELLE maximum FSH concentrations were reached within 21

hours.

Steady-state was observed after

4 to 5 days.

After

7 days of

repeated administration,

the maximum FSH

concentrations were attained at 10 hours after injection.

Following single doses of SC administration of BRAVELLE, mean elimination half-life of FSH was 41 hours. After 7

days of repeated administration, the mean elimination half-life of FSH was 30 hours for the SC route.

After 7 days of dosing with BRAVELLE SC, FSH C

was 11.1 IU/L and steady state FSH AUC was 235 IU/L*h.

The pharmacokinetics of BRAVELLE in patients with renal or hepatic impairment has not been investigated.

5.3 Preclinical safety data

Preclinical

data

reveal

no special

hazard for

humans

based on conventional

studies

cardiovascular

safety

pharmacology, single and repeat dose toxicity, and local tolerance.

Impaired fertility was observed in rats which were treated with high doses of recombinant

follitropin for prolonged

time. Repeat dose toxicity studies in rats and dogs have demonstrated that high doses of BRAVELLE have the potential

to impair fertility due to follicular atresia and cysts in the ovaries.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

6

/

0

7

/

2

0

1

6

C

R

N

2

1

7

8

5

8

2

p

a

g

e

n

u

m

b

e

r

:

6

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder:

Lactose monohydrate

Polysorbate 20

Sodium phosphate dibasic heptahydrate (for pH adjustment)

Phosphoric acid (for pH adjustment)

Water for injections

Solvent:

Sodium chloride

Hydrochloric acid (for pH adjustment)

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

2 years.

After reconstitution: use immediately.

6.4 Special precautions for storage

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

6.5 Nature and contents of container

Powder:

The powder for solution for injection is supplied in a 2 mL single dose colourless type I glass vial with a bromobutyl

rubber stopper closed with an aluminium/polypropen cap.

Solvent:

The solvent for solution for injection is provided in a 1 mL single dose colourless type I glass ampoule.

BRAVELLE is supplied in the following pack sizes:

5 vials of powder + 5 ampoules of solvent

10 vials of powder + 10 ampoules of solvent

5 vials of powder + 5 ampoules of solvent,

5 syringes with needles for dissolution of the powder, 5 injection needles,

5 disposable alcohol swabs

10 vials of powder + 10 ampoules of solvent,

10 syringes with needles for dissolution of the powder, 10 injection needles,

10 disposable alcohol swabs

30 vials of powder + 30 ampoules of solvent,

15 syringes with needles for dissolution of the powder, 15 injection needles,

15 disposable alcohol swabs

Not all pack sizes may be marketed.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

6

/

0

7

/

2

0

1

6

C

R

N

2

1

7

8

5

8

2

p

a

g

e

n

u

m

b

e

r

:

7

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from

such medicinal product and other handling of the product

BRAVELLE should only be reconstituted with the solvent provided prior to use.

Attach the reconstitution needle to the syringe. Withdraw the entire content from the ampoule with solvent and inject

the total contents into the vial containing the powder. The powder should dissolve within 2 minutes to a clear solution.

If not, roll the vial gently between the hands until the solution is clear. Vigorous shaking should be avoided.

After reconstitution, the solution can be mixed with Ferring’s menotrophin (hMG) MENOPUR powder for solution for

injection before administration.

Studies have shown that co-administration of BRAVELLE and MENOPUR does not

significantly alter the expected bioactivity.

If needed,

the solution can be drawn up into the syringe again to transfer it

to the next

vial

with powder until

prescribed dose has been reached. Up to six powder vials (450 IU) can be dissolved in one ampoule of solvent.

When the prescribed dose has been reached, draw up the mixed solution from the vial into the syringe, change to the

hypodermic needle and administer immediately.

The solution should not be used if it contains particles or if it is not clear.

BRAVELLE should be administered immediately after reconstitution. Any unused medicinal product or waste material

should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Ferring Ireland Limited

United Drug House

Magna Drive

Magna Business Park

Citywest Road

Dublin 24

8 MARKETING AUTHORISATION NUMBER

PA 1009/019/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

09 January 2006

Date of last renewal:

24 March 2009

10 DATE OF REVISION OF THE TEXT

July 2016

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

6

/

0

7

/

2

0

1

6

C

R

N

2

1

7

8

5

8

2

p

a

g

e

n

u

m

b

e

r

:

8

Similar products

Search alerts related to this product

View documents history

Share this information