SODIUM CHLORIDE SOLUTION FOR INJECTIONS 0.9%W/V

Active substance: SODIUM CHLORIDE

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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 a 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 the development of multiple
follicles for 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.

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
Dosage
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 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.

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

In the following situations treatment outcome is unlikely to be favourable, and
therefore BRAVELLE should not be 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,
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/m2) 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 drug/drug interaction studies have been conducted for BRAVELLE in
humans.
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

Pregnancy and lactation
BRAVELLE is contraindicated in women who are pregnant or lactating (see
section 4.3).
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.
Organ Class
Very common (>1/10) Common (>1/100, <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 Rash
disorders
Muscoloskeletal and
Muscle spasms
connective tissue disorders
Reproductive system and
Vaginal haemorrhage,
breast disorders
OHSS, pelvic pain, breast
tenderness, vaginal
discharge
General disorders and
Pain, injection site pain
administration site disorders
and reactions (redness,
bruising, swelling and/or
itching)
As complications of OHSS, venous thromboembolic events and ovarian
torsion might occur.
Allergic, local or 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.

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 Cmax 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 of 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.

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.

6.6

Special precautions for disposal
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 the 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 product or waste material should be disposed of in accordance with
local requirements.

7.

MARKETING AUTHORISATION HOLDER
Ferring Pharmaceuticals Limited,
The Courtyard,
Waterside Drive,
Langley,
Berkshire
SL3 6EZ

8

MARKETING AUTHORISATION NUMBER(S)
PL 03194/0060

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/03/2009

10

DATE OF REVISION OF THE TEXT
27/03/2009

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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