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PROSTAP 3 DCS 11.25MG POWDER FOR PROLONGED-RELEASE SUSPENSION FOR INJECTION IN PRE-FILLED SYRINGE

Active substance(s): LEUPRORELIN ACETATE

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DCS

6145382.03

HEALTH PROFESSIONALS’ USER LEAFLET

DCS
Leuprorelin Acetate Depot Injection 11.25 mg
1 NAME OF THE MEDICINAL PRODUCT
PROSTAP® 3 DCS 11.25 mg Powder and Solvent for Suspension for Injection
2







QUALITATIVE AND QUANTITATIVE COMPOSITION
PROSTAP 3 Powder: contains 11.25 mg leuprorelin acetate (equivalent to 10.72 mg base).
Sterile Solvent: Each ml contains carmellose sodium 5 mg, mannitol (E421) 50 mg, polysorbate 80 1 mg, acetic acid, glacial up to 0.05 mg
and water for injections.
When reconstituted with Sterile Solvent, the suspension contains 11.25 mg/ml leuprorelin acetate.
For the full list of excipients, see section 6.1






3 PHARMACEUTICAL FORM

Powder and solvent for suspension for injection in pre-filled syringe

Powder: A sterile, lyophilised, white, odourless powder.
Solvent: A clear, odourless, slightly viscous, sterile solvent.



4 CLINICAL PARTICULARS
4.1 Therapeutic indications

(i) Metastatic prostate cancer.

(ii) Locally advanced prostate cancer, as an alternative to surgical castration.

(iii) As an adjuvant treatment to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.

(iv) As an adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression.
(v) As neo-adjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.

(vi) Management of endometriosis, including pain relief and reduction of endometriotic lesions.

In children:

Treatment of central precocious puberty (girls under 9 years of age, boys under 10 years of age).

(See Section 5.1)





4.2 Posology and method of administration

Posology

Prostate Cancer: The usual recommended dose is 11.25  mg presented as a three month depot injection and administered as a single
subcutaneous injection at intervals of three months. The majority of patients will respond to this dosage. PROSTAP 3 therapy should not be
discontinued when remission or improvement occurs. As with other drugs administered regularly by injection, the injection site should be
varied periodically.

Response to PROSTAP 3 therapy should be monitored by clinical parameters and by measuring prostate-specific antigen (PSA) serum
levels. Clinical studies with leuprorelin acetate have shown that testosterone levels increased during the first 4 days of treatment in the
majority of non-orchidectomised patients. They then decreased and reached castrate levels by 2-4 weeks. Once attained, castrate levels
were maintained as long as drug therapy continued. If a patient’s response appears to be sub-optimal, then it would be advisable to confirm
that serum testosterone levels have reached or are remaining at castrate levels. Transient increases in acid phosphatase levels sometimes
occur early in the treatment period but usually return to normal or near normal values by the 4th week of treatment.

In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of castrate-resistant prostate
cancer. Reference should be made to relevant guidelines.

Endometriosis: The recommended dose is 11.25 mg administered as a single intramuscular injection every 3 months for a period of 6 months
only. Treatment should be initiated during the first 5 days of the menstrual cycle.

In women receiving GnRH analogues for the treatment of endometriosis, the addition of hormone replacement therapy (HRT - an estrogen
and progestogen) has been shown to reduce bone mineral density loss and vasomotor symptoms. Therefore if appropriate, HRT should be
co-administered with PROSTAP 3 taking into account the risks and benefits of each treatment.

Elderly: As for adults.

Paediatric population

The treatment of children with leuprorelin acetate should be under the overall supervision of the paediatric endocrinologist.

The dosing scheme needs to be adapted individually.

The recommended starting dose is dependent on the body weight.

Children with a body weight ≥ 20 kg

1 ml (11.25 mg leuprorelin acetate) suspension of 130.0 mg sustained-release microcapsules in 1 ml vehicle solution are administered every
3 months as a single subcutaneous injection.

Children with a body weight < 20 kg

In these rare cases the following dosage should be administered according to the clinical activity of the central precocious puberty:

0.5 ml (5.625 mg leuprorelin acetate) suspension of 130.0 mg sustained-release microcapsules in 1 ml vehicle solution are administered every
3 months as a single subcutaneous injection.

The remainder of the suspension should be discarded. The child’s weight gain should be monitored.

Depending on the activity of the central precocious puberty, it may be necessary to increase the dosage in the presence of inadequate
suppression (clinical evidence e.g. spotting or inadequate gonadotropin suppression in the LHRH test). The minimal effective 3-monthly
dose to be administered should then be determined by means of the LHRH test.
Sterile abscesses at the injection site often occurred when leuprorelin acetate was administered intramuscularly at higher than the
recommended dosages. Therefore, in such cases, the medicinal product should be administered subcutaneously (see 4.4).

It is recommended to use the lowest volumes possible for injections in children in order to decrease the inconvenience which is associated
with the intramuscular/subcutaneous injection.
The duration of treatment depends on the clinical parameters at the start of treatment or during the course of treatment (final height
prognosis, growth velocity, bone age and/or bone age acceleration) and is decided by the treating paediatrician together with the legal
guardian and, if appropriate, the treated child. The bone age should be monitored during treatment at 6-12 month intervals.

In girls with bone maturation of older than 12 years and boys with bone maturation of older than 13 years discontinuation of treatment should
be considered taking into account the clinical parameters.

In girls, pregnancy should be excluded before the start of treatment. The occurrence of pregnancy during treatment cannot be generally
excluded. In such cases, medical advice should be sought.

Note:

The administration interval should be 90 ± 2 days in order to prevent the recurrence of precocious puberty symptoms.
Administration

INSTRUCTIONS ON HOW TO MIX AND ADMINISTER












There is an increased risk of incident depression (which may be severe) in patients undergoing treatment with GnRH agonists, such as
leuprorelin. Patients should be informed accordingly and treated as appropriate if symptoms occur.
Postmarketing reports of seizures have been observed in patients treated with leuprorelin acetate and these events have been reported in
both children and adults, and in those with or without a history of epilepsy, seizure disorders or risk disorders for seizures.
Men: In the initial stages of therapy, a transient rise in levels of testosterone, dihydrotestosterone and acid phosphatase may occur.
In some cases, this may be associated with a “flare” or exacerbation of the tumour growth resulting in temporary deterioration of the patient’s
condition. These symptoms usually subside on continuation of therapy. “Flare” may manifest itself as systemic or neurological symptoms in
some cases.
In order to reduce the risk of “flare”, an anti-androgen may be administered beginning 3 days prior to leuprorelin acetate therapy and
continuing for the first two to three weeks of treatment. This has been reported to prevent the sequelae of an initial rise in serum testosterone.
In the rare event of an abscess occurring at the injection site, testosterone level should be monitored as there may be inadequate absorption
of leuprorelin from the depot formulation.
Patients at risk of ureteric obstruction or spinal cord compression should be considered carefully and closely supervised in the first few
weeks of treatment. These patients should be considered for prophylactic treatment with anti-androgens. Should urological/neurological
complications occur, these should be treated by appropriate specific measures.
Long-term androgen deprivation either by bilateral orchiectomy or administration of GnRH analogues is associated with increased risk of
bone loss which, in patients with additional risk factors, may lead to osteoporosis and increased risk of bone fracture.
If an anti-androgen is used over a prolonged period, due attention should be paid to the contra-indications and precautions associated with
its extended use.
Whilst the development of pituitary adenomas has been noted in chronic toxicity studies at high doses in some animal species, this has not
been observed in long term clinical studies with leuprorelin acetate.
Androgen deprivation therapy may prolong the QT interval.
In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong
the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to
initiating PROSTAP 3.
Women: During the early phase of endometriosis therapy, sex steroids temporarily rise above baseline because of the physiological effect of
the drug. Therefore, a worsening of clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate
with continued therapy.
When receiving GnRH analogues for the treatment of endometriosis, the addition of HRT (an estrogen and progestogen) has been shown to
reduce bone mineral density loss and vasomotor symptoms (see ‘Posology and Method of Administration’ section 4.2 for further information).
The induced hypo-estrogenic state results in a small loss in bone density over the course of treatment, some of which may not be reversible.
The extent of bone demineralisation due to hypo-estrogenaemia is proportional to time and, consequently, is the adverse event responsible
for limiting the duration of therapy to 6 months. The generally accepted level of bone loss with LHRH analogues such as PROSTAP 3 is
5%. In clinical studies with PROSTAP 3 the levels varied between 2.3% and 15.7% depending on the method of measurement. During one
six-month treatment period, this bone loss should not be important. In patients with major risk factors for decreased bone mineral content
such as chronic alcohol and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such
as anticonvulsants or corticosteroids, PROSTAP 3 therapy may pose an additional risk. In these patients, the risks and benefits must be
weighed carefully before therapy with PROSTAP 3 is instituted.
In women with submucous fibroids there have been reports of severe bleeding following administration of PROSTAP 3 as a consequence
of the acute degeneration of the fibroids. Patients should be warned of the possibility of abnormal bleeding or pain in case earlier surgical
intervention is required.
PROSTAP 3 may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix for intrauterine surgical
procedures.

Precautions

Men: Patients with urinary obstruction and patients with metastatic vertebral lesions should begin PROSTAP 3 therapy under close
supervision for the first few weeks of treatment.

Women: Since menstruation should stop with effective doses of PROSTAP 3, the patient should notify her physician if regular menstruation
persists.

In girls with central precocious puberty: Before starting the therapy, a precise diagnosis of idiopathic and/or neurogenic central precocious
puberty is necessary.

The therapy is a long-term treatment, adjusted individually. PROSTAP 3 should be administered as precisely as possible in regular 3-monthly
periods. An exceptional delay of the injection date for a few days (90 ± 2 days) does not influence the results of the therapy.
In the event of a sterile abscess at the injection site (mostly reported after i.m. injection of higher than the recommended dosage) the
absorption of leuprorelin acetate from the depot can be decreased. In this case the hormonal parameters (testosterone, oestradiol) should
be monitored at 2-week intervals (see 4.2).

The treatment of children with progressive brain tumours should follow a careful individual appraisal of the risks and benefits.

The occurrence of vaginal bleeding, spotting and discharge after the first injection may occur as a sign of hormone withdrawal in girls.
Vaginal bleeding beyond the first/second month of treatment needs to be investigated.

Bone mineral density (BMD) may decrease during GnRH therapy for central precocious puberty. However, after cessation of treatment
subsequent bone mass accrual is preserved, and peak bone mass in late adolescence does not seem to be affected by treatment.

Slipped femoral epiphysis can be seen after withdrawal of GnRH treatment. The suggested theory is that the low concentrations of estrogen
during treatment with GnRH agonists weakens the epiphysial plate. The increase in growth velocity after stopping the treatment subsequently
results in a reduction of the shearing force needed for displacement of the epiphysis.
4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of PROSTAP 3 with medicinal products known to
prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III
(e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be
carefully evaluated (see section 4.4).
4.6 Fertility, Pregnancy and lactation

Safe use of leuprorelin acetate in pregnancy has not been established clinically.
Studies in animals have shown reproductive toxicity (see section 5.3). Before starting treatment with PROSTAP 3, pregnancy must be
excluded. There have been reports of foetal malformation when PROSTAP 3 has been given during pregnancy.

PROSTAP 3 should not be used in women who are breastfeeding.
When used 3-monthly at the recommended dose, PROSTAP 3 usually inhibits ovulation and stops menstruation. Contraception is not
ensured, however, by taking PROSTAP 3 and therefore patients should use non-hormonal methods of contraception during treatment.
Patients should be advised that if they miss successive doses of PROSTAP 3, breakthrough bleeding or ovulation may occur with the
potential for conception. Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes
pregnant during treatment, the drug must be discontinued. The patient must be apprised of this evidence and the potential for an unknown
risk to the foetus.

In girls with central precocious puberty: See section 4.3 Contraindications.
4.7 Effects on ability to drive and use machines

PROSTAP 3 can influence the ability to drive and use machines due to visual disturbances and dizziness.

1. To prepare for injection, screw the plunger
rod into the end stopper until the stopper
begins to turn.

2. Remember to check if the needle is tight by
twisting the needle cap clockwise.
Do not overtighten.

3. Holding the syringe upright, release the
diluents by SLOWLY PUSHING the plunger
until the middle stopper is at the blue line in
the middle of the barrel.

4.8 Undesirable effects

Adverse reactions seen with PROSTAP 3 are due mainly to the specific pharmacological action, namely increases and decreases in certain
hormone levels.

The following tables list adverse reactions with leuprorelin based on experience from clinical trials as well as from post-marketing experience.
Adverse reactions are grouped by MedDRA System Organ Classes and frequency classification. Frequencies are defined as: very common
(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot
be estimated from the available data).

Men: In cases where a “tumour flare” occurs after PROSTAP 3 therapy, an exacerbation may occur in any symptoms or signs due to disease,
for example, bone pain, urinary obstruction, weakness of the lower extremities and paraesthesia. These symptoms subside on continuation
of therapy.

Tabulated list of adverse reactions
SOC

NOTE: Pushing the plunger rod quickly or
over the blue line will cause leakage of the
suspension from the needle.

NOTE: Avoid hard tapping to prevent the generation of bubbles.

upside

skin
ARTWORK
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TAKEDA

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QUALITY SYSTEM - ISO 9001:2008

PRODUCT NAME:
I-Prostap 11,25 mg
DCS (GB)
PRODUCT CODE:

ISSUE DATE OPERATOR

25/03/16 RI007M

6145382.03

SEPARATIONS: ( BLACK )

03

FONT TYPE: HELVETICA Size: 9 PT
PREVIOUS CODE: 6145382.02
EURPACK Grafifarma Grafiflex
Aprilia (LT) tel. +39 06 92732420 produzione@grafifarma.it
Robecco s/N (MI) tel. +39 02 94974002 milano@grafifarma.it
Ricordiamo che il risultato cromatico delle stampe potrà essere diverso in funzione del supporto e della tecnica utilizzata. We remind
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GRAFIFARMA GRAFIFLEX Srl, termina con l’approvazione del seguente documento. EURPACK GRAFIFARMA GRAFIFLEX’s responsability ends with the approval of the present document. - Vietato l’utilizzo del presente tassello di informazioni se non espressamente
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from EURPACK GRAFIFARMA GRAFIFLEX Srl.
v.01-2013

DATE
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6. At the time of injection, check the direction of the safety device (with
round mark face up), as illustrated, and inject the entire contents of
the syringe subcutaneously or intramuscularly as you would for a
normal injection.

AFTER INJECTION

7. Withdraw the needle from the patient. Immediately activate the safety
device by pushing the arrow forward with the thumb or finger until the
device is fully extended and a CLICK is heard or felt.

Note: The suspension settles out very quickly following reconstitution and therefore the product should be mixed and used immediately.

4.3 Contraindications

Hypersensitivity to the active substance, any of the excipients listed in section 6.1 or to synthetic gonadotrophin releasing homone (Gn-RH)
or Gn-RH derivatives.

Women: PROSTAP 3 is contra-indicated in women who are or may become pregnant while receiving the drug. PROSTAP 3 should not be
used in women who are breastfeeding or have undiagnosed abnormal vaginal bleeding.

Men: There are no known contra-indications to the use of PROSTAP 3 in men.

In girls with central precocious puberty:

- Pregnancy and lactation

- Undiagnosed vaginal bleeding
4.4 Special warnings and precautions for use

As would be expected with this class of drug, development or aggravation of diabetes may occur; therefore diabetic patients may require
more frequent monitoring of blood glucose during treatment with PROSTAP 3.

Epidemiological data have shown that during androgen deprivation therapy changes in the metabolic condition (e.g. reduction in glucose
tolerance or aggravation of pre-existing diabetes) as well as an increased risk for cardiovascular diseases may occur. However, prospective
data did not confirm the link between treatment with GnRH analogues and an increase in cardiovascular mortality. Patients at high risk for
metabolic or cardiovascular diseases should be appropriately monitored.
Hepatic dysfunction and jaundice with elevated liver enzyme have been reported. Therefore, close observation should be made and
appropriate measures taken if necessary.

Spinal fracture, paralysis and hypotension have been reported.



Very rare

Not known

Immune system
disorders

weight fluctuation

Lipids abnormal, glucose
tolerance abnormal

decreased appetite
insomnia, depression
(see Section 4.4),
mood changes
(long-term use)**

headache
(occasionaly severe)

mood
changes
(short term
use)**

dizziness,
parasthesiae

pituitary
apoplexy has
been reported
paralysis (see Section 4.4),
following initial
seizure
administration
in patients with
pituitary adenoma

Eye disorders

visual impairment

Cardiac
disorders

palpitations,
electrocardiogram QT
prolonged (see Sections 4.4
and 4.5)

Vascular
disorders

DRAFT

MEASURE (mm): 420x680 (FOLD 105x50)

CLIENT APPROVAL

Round mark

Rare

hypersensitivity reactions
(including rash, pruritus,
urticaria and rarely, wheezing
or interstitial pneumonitis,
anaphylactic reactions)

Nervous system
disorders

5. Remove the needle cap and advance the plunger to expel the air
from the syringe.

Uncommon

anaemia (reported in
medicinal products of this
class), thrombocytopaenia,
leucopenia

Psychiatric
disorders

4. Gently tap the syringe on the palm keeping the syringe upright
to thoroughly mix the particles to form a uniform suspension. The
suspension will appear milky.

Common

Blood and
lymphatic
system disorders

Metabolism
and nutrition
disorders


Very common

pulmonary embolism,
hypertension, hypotension
(see Section 4.4)

hot flush

Gastrointestinal
disorders

nausea

Hepatobiliary
disorders

hepatic function
abnormal, liver
function test
abnormal (usually
transient)

Skin and
subcutaneous
tissue disorders

hyperhydrosis

Musculoskeletal,
connective
tissue and bone
disorders

muscle weakness,
bone pain

arthralgia

diarrhoea,
vomiting

jaundice

myalgia,
weakness
of lower
extremities

Renal and
urinary disorders

spinal fracture (see Section
4.4), reduction in bone mass
which may occur with the use
of GnRH agonists
urinary tract obstruction

Reproductive
system and
breast disorders

Libido decreased,
erectile dysfunction, gynaecomastia
testicular atrophy

General
disorders and
administration
site conditions

Fatigue, injection
site reaction,
e.g., induration,
erythema, pain,
abscesses,
swelling, nodules,
ulcers and necrosis

oedema peripheral

** mood changes (long term use: frequency of ‘common’ and short term use: frequency of ‘uncommon’)

pyrexia

FRONT



Women: Those adverse events occurring most frequently with PROSTAP 3 are associated with hypo-estrogenism; the most frequently
reported are hot flushes, mood swings including depression (occasionally severe), and vaginal dryness. Estrogen levels return to normal
after treatment is discontinued.
The induced hypo-estrogenic state results in a small loss in bone density over the course of treatment, some of which may not be reversible
(see Section 4.4).
Vaginal haemorrhage may occur during therapy due to acute degeneration of submucous fibroids (see Section 4.4).








In children:
Figure 1 presents the leuprorelin serum levels in children during the first 6 months of treatment following s.c. administration of leuprorelin
acetate 3-month depot (two injections).
From the first injection, the leuprorelin serum levels increase reaching maximal serum levels at month 4 (294.79 pg/ml ± 105.42) and slightly
decrease until month 6 (229.02 pg/ml ± 103.33).

Tabulated list of adverse reactions

295

Very common

Common

Uncommon

Rare

Very rare

Not known

275
255

Anaemia (reported in medicinal
products of this class),
thrombocytopaenia, leucopenia

Blood and lymphatic
system disorders

235
215

Leuprorelin (pgml)

SOC

hypersensitivity reactions (including
rash, pruritus, urticaria and rarely,
wheezing and interstitial pneumonitis,
anaphylactic reactions)

Immune system
disorders

195
175
155
135
115

Metabolism and
nutrition disorders

weight
fluctuation

Psychiatric disorders

mood altered
depression
(see Section
4.4)

decreased
appetite, lipids
abnormal

glucose tolerance abnormal, which may
affect diabetic control

95
75
55

Nervous system
disorders

insomnia

headache
(occasionally
severe)

35

pituitary
haemorrhage
has been
reported
following
paralysis (see Section 4.4), seizure
initial
administration
in patients with
pituitary
adenoma

parasthesiae,
dizziness

visual
impairment

Cardiac disorders

palpitations
pulmonary embolism, hypertension,
hypotension (see Section 4.4)

hot flush

Gastrointestinal
disorders

diarrhoea,
vomiting

nausea

Hepatobiliary
disorders

liver function
test abnormal
(usually
transient)

Skin and subcutaneous
tissue disorders

hair loss

Musculoskeletal,
connective tissue and
bone disorders

arthralgia,
muscle
weakness

hepatic function abnormal, jaundice

spinal fracture (see section 4.4),
reduction in bone mass which may
occur with the use of GnRH agonists

myalgia

breast
tenderness,
breast atrophy,
vulvovaginal
dryness

Reproductive system
and breast disorders

Oedema
peripheral,
injection site
reaction
e.g.injection
site induration,
erythema,
pain,
abscesses,
swelling,
nodules,
ulcers and
necrosis

General disorders and
administration site
conditions

2 Months

3 Months

4 Months

5 Months

6 Months

Leuprorelin

Eye disorders

Vascular disorders

1 Month



Figure 1: Leuprorelin serum levels during the first six months of treatment with the leuprorelin acetate 3-month depot formulation (two s.c.
injections) (n=42-43)

5.3 Preclinical safety data

Animal studies have shown that leuprorelin acetate has a high acute safety factor. No major overt toxicological problems have been seen
during repeated administration. Whilst the development of pituitary adenomas has been noted in chronic toxicity studies at high doses in
some animal species, this has not been observed in long-term clinical studies. No evidence of mutagenicity or teratogenicity has been
shown. Animal reproductive studies showed increased foetal mortality and decreased foetal weights reflecting the pharmacological effects
of this LHRH agonist.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients

PROSTAP 3 Powder

Poly (D-L lactic acid)

Mannitol (E421)

Sterile Solvent

Carmellose sodium

Mannitol (E421)

Polysorbate 80

Acetic acid, glacial

Water for Injections
6.2 Incompatibilities

Not applicable.
6.3 Shelf life

3 years unopened.

Once reconstituted with sterile solvent, the suspension should be administered immediately.
6.4 Special precautions for storage

Do not store above 25oC.

Do not refrigerate or freeze.

Store in the original container in order to protect from light.
6.5 Nature and contents of container

One dual chamber pre-filled syringe containing 11.25 mg leuprorelin acetate powder in the front chamber and 1 ml of Sterile Solvent in the
rear chamber.

1 x 23 gauge syringe needle fitted with safety device

1 x syringe plunger

vaginal haemorrhage

6.6 Special precautions for disposal and other handling

Always ensure that the safety device to prevent needle-stick injury is deployed after injection.

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

pyrexia,
fatigue

In Children: In the initial phase of therapy, a short-term increase as flare-up of the sex hormone level occurs, followed by a decrease to values
within the pre-pubertal range. Due to this pharmacological effect, adverse events may occur particularly at the beginning of treatment.

7




MARKETING AUTHORISATION HOLDER
Takeda UK Limited
Building 3, Glory Park, Glory Park Avenue,
Wooburn Green, BUCKS, HP10 0DF, UK

8

MARKETING AUTHORISATION NUMBER(S): PL 16189/0013

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION: 28/04/2011

10 DATE OF REVISION OF THE TEXT: 16/03/2016

Tabulated list of adverse reactions
SOC

Very common

Common

Rare

Very rare

Not known

Hypersensitivity (fever, rash,
e.g. itching, anaphylactic
reactions)

Immune system
disorders
Psychiatric
disorders

Uncommon

Further Information may be obtained from:
Takeda ( UK) Limited, Building 3, Glory Park, Glory Park Avenue,
Wooburn Green, BUCKS, HP10 0DF, UK
Telephone: +44 (0) 1628 537900


emotional
lability

Nervous system
disorders

headache

Gastrointestinal
disorders

abdominal pain /
abdominal cramps,
nausea/vomiting

Skin and subcutaneous
tissue disorders

acne

Reproductive system
and breast disorders

vaginal haemorrhage,
spotting**, vaginal
discharge

General disorders and
administration site
conditions

injection site
reactions

pituitary haemorrhage
following initial
administration in patients with
pituitary adenoma

seizure

** In general, the occurrence of vaginal spotting with continued treatment (subsequent to possible withdrawal bleeding in the first month of
treatment) should be assessed as a sign of potential underdosage. The pituitary suppression should then be determined by an LHRH test.



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

4.9 Overdose

No case of overdose has been reported.

In animal studies, doses of up to 500 times the recommended human dose resulted in dyspnoea, decreased activity and local irritation at
the injection site. In cases of overdose, the patients should be monitored closely and management should be symptomatic and supportive.

ARTWORK
THIS ARTWORK IS PROPERTY OF:

TAKEDA

PDF 1.5

Realized by:

QUALITY SYSTEM - ISO 9001:2008

PRODUCT NAME:
I-Prostap 11,25 mg
DCS (GB)
PRODUCT CODE:

ISSUE DATE OPERATOR

25/03/16 RI007M

6145382.03

SEPARATIONS: ( BLACK )

DRAFT

03

MEASURE (mm): 420x680 (FOLD 105x50)
FONT TYPE: HELVETICA Size: 9 PT
PREVIOUS CODE: 6145382.02
EURPACK Grafifarma Grafiflex
Aprilia (LT) tel. +39 06 92732420 produzione@grafifarma.it
Robecco s/N (MI) tel. +39 02 94974002 milano@grafifarma.it
Ricordiamo che il risultato cromatico delle stampe potrà essere diverso in funzione del supporto e della tecnica utilizzata. We remind
you that prints chromatic results could be different depending on support and used technique. - La responsabilità della EURPACK
GRAFIFARMA GRAFIFLEX Srl, termina con l’approvazione del seguente documento. EURPACK GRAFIFARMA GRAFIFLEX’s responsability ends with the approval of the present document. - Vietato l’utilizzo del presente tassello di informazioni se non espressamente
autorizzato dalla EURPACK GRAFIFARMA GRAFIFLEX Srl. It is forbidden the use of the present information if not officially allowed
from EURPACK GRAFIFARMA GRAFIFLEX Srl.
v.01-2013

CLIENT APPROVAL
DATE
SIGNATURE

5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Gonadotrophin-Releasing Hormone Analogues

ATC code: L02AE 02
PROSTAP 3 contains leuprorelin acetate, a synthetic nonapeptide analogue of naturally occurring gonadotrophin releasing hormone
(GnRH) which possesses greater potency than the natural hormone. Leuprorelin acetate is a peptide and therefore unrelated to the steroids.
Chronic administration results in an inhibition of gonadotrophin production and subsequent suppression of ovarian and testicular steroid
secretion. This effect is reversible on discontinuation of therapy.

Administration of leuprorelin acetate results in an initial increase in circulating levels of gonadotrophins which leads to a transient increase
in gonadal steroid levels in both men and women. Continued administration of leuprorelin acetate results in a decrease of gonadotrophin
and sex steroid levels. In men serum testosterone levels, initially raised in response to early luteinising hormone (LH) release, fall to castrate
levels in about 2-4 weeks.

Leuprorelin acetate is inactive when given orally.

A randomised, open-label, comparative multi-centre study was performed to compare the efficacy and safety of the 3.75 mg and 11.25 mg
depots of leuprorelin acetate. 48% of patients included had locally advanced disease (T3N0M0), 52% of patients had metastatic disease.
Mean serum testosterone level fell below the threshold for chemical castration (0.5 ng/ml) at one month of treatment, continuing to decrease
thereafter and stabilising at a value below the castration threshold. The decline in serum PSA mirrored that of serum testosterone in both
groups.
In an open, prospective clinical trial involving 205 patients receiving 3.75  mg leuprorelin acetate on a monthly basis as treatment for
metastatic prostate cancer, the long-term efficacy and safety of leuprorelin acetate was assessed. Testosterone levels were maintained below
the castrate threshold over the 63-month follow up period. Median survival time exceeded 42.5 months for those receiving monotherapy
and 30.9 months for those receiving leuprorelin acetate in combination with anti-androgens (this difference relating to baseline differences
between groups).

In a meta-analysis involving primarily patients with metastatic disease, no statistically significant difference in survival was found for patients
treated with LHRH analogues compared with patients treated with orchidectomy.

In another randomised, open-label, multi-centre comparative trial, leuprorelin acetate in combination with flutamide has been shown to
significantly improve disease-free survival and overall survival when used as an adjuvant therapy to radiotherapy in 88 patients with highrisk localised (T1-T2 and PSA of at least 10 ng/mL or a Gleason score of at least 7), or locally advanced (T3-T4) prostate cancer. The
optimum duration of adjuvant therapy has not been established. This US study used a higher dose of leuprorelin acetate (7.5 mg/month)
which is therapeutically equivalent to the European licensed dose.
The use of a LHRH agonist may be considered after prostatectomy in selected patients considered at high risk of disease progression.
There are no disease-free survival data or survival data with leuprorelin acetate in this setting.

Neoadjuvant leuprorelin acetate prior to radiotherapy has been shown to reduce prostate volume.

In children:

Reversible suppression of pituitary gonadotropin release occurs, with a subsequent decrease in oestradiol (E2) or testosterone levels to
values in the pre-pubertal range.

Initial gonadal stimulation (flare-up) may cause vaginal bleeding in girls who are already post-menarchal at start of treatment. Withdrawal
bleeding may occur at the start of treatment. The bleeding normally stops as treatment continues.

The following therapeutic effects can be demonstrated:

- Suppression of basal and stimulated gonadotropin levels to pre-pubertal levels;

- Suppression of prematurely increased sexual hormone levels to pre-pubertal levels and arrest of premature menstruation;

- Arrest/involution of somatic pubertal development (Tanner stages);

- Improvement/normalisation of the ratio of chronological age to bone age;

- Prevention of progressive bone age acceleration;

- Decrease of growth velocity and its normalization;

- Increase in final height.
Treatment result is the suppression of the pathologically, prematurely activated hypothalamic-pituitary-gonadal axis according to

pre-pubertal age.

In a long-term clinical trial in children treated with leuprorelin at doses up to 15mg monthly for > 4 years resumption of pubertal progression
were observed after cessation of treatment. Follow up of 20 female subjects to adulthood showed normal menstrual cycles in 80% and 12
pregnancies in 7 of the 20 subjects including multiple pregnancies for 4 subjects.
5.2 Pharmacokinetic properties

Leuprorelin acetate is well absorbed after subcutaneous and intramuscular injections. It binds to the LHRH receptors and is rapidly degraded.
An initially high plasma level of leuprorelin acetate peaks at around 3 hours after a PROSTAP 3 subcutaneous injection, followed by a
decrease to maintenance levels in 7 to 14 days. PROSTAP 3 provides continuous plasma levels for up to 117 days resulting in suppression
of testosterone to below castration level within 4 weeks of the first injection in the majority of patients.

The metabolism, distribution and excretion of leuprorelin acetate in humans have not been fully determined.

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Source: Medicines and Healthcare Products Regulatory Agency

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