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

Active substance: LEUPRORELIN ACETATE

View full screen / Print PDF » Download PDF ⇩

Transcript
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, glacial acetic acid up to 0.05 mg in 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
4.1





CLINICAL PARTICULARS
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.

(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.


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 safety and efficacy of PROSTAP 3 in children has not yet been established.

Administration

INSTRUCTIONS ON HOW TO MIX AND ADMINISTER

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

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

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

upside

skin

AFTER INJECTION

Round mark

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. Inject
the entire contents of the syringe subcutaneously or intramuscularly as you
would for a normal 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.

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.




















FRONT




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.
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.
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.
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.


ARTWORK
THIS ARTWORK IS PROPERTY OF:

TAKEDA

PDF 1.5

ISSUE DATE OPERATOR

29/08/14 RI007M

6099995.02



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.

Realized by:

QUALITY SYSTEM - ISO 9001:2008

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

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).

SEPARATIONS: ( BLACK )

DRAFT

03

MEASURE (mm): 210X680 (FOLD 50X105)
FONT TYPE: HELVETICA Size: 8 PT
PREVIOUS CODE: 6099995.01
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






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.
4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.
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.



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.

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.

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.
4.8 Undesirable effects

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

Adverse events which have been reported infrequently include peripheral oedema, pulmonary embolism, hypertension, palpitations, fatigue, muscle weakness, diarrhoea, nausea, vomiting, anorexia, fever/chills, headache (occasionally severe), hot flushes, arthralgia, myalgia, dizziness, insomnia, mood changes, depression, paraesthesia, visual disturbances, weight changes, hepatic dysfunction, jaundice, and increases in liver function test values (usually transient).
Reactions at the injection site e.g. induration, erythema, pain, abscesses, swelling, nodules, ulcers and necrosis have been rarely reported. Changes in blood
lipids and alteration of glucose tolerance have also been reported which may affect diabetic control. Thrombocytopenia and leucopenia have been reported
rarely. Anaemia has been reported in patients receiving GnRH analogues. Hypersensitivity reactions including rash, pruritus, urticaria, and rarely, wheezing
or interstitial pneumonitis have also been reported. Anaphylactic reactions are rare.


Spinal fracture, paralysis, hypotension and worsening of depression have been reported (see Section 4.4).



A reduction in bone mass may occur with the use of GnRH agonists.



Very rare cases of pituitary apoplexy have been reported following initial administration in patients with pituitary adenoma.



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.



Impotence and decreased libido will be expected with PROSTAP 3 therapy.

The administration of PROSTAP 3 is often associated with hot flushes and sometimes sweating.

Orchiatrophy and gynaecomastia have been reported occasionally.


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).


Breast tenderness or change in breast size may occur occasionally. Hair loss has also been reported occasionally.


Vaginal haemorrhage may occur during therapy due to acute degeneration of submucous fibroids (see Section 4.4).


In Children: Commonly reported adverse events are emotional lability, headache, abdominal pain/abdominal cramps, nausea/vomiting, acne, vaginal bleeding, spotting, discharge and injection site reactions. General allergic reactions (fever, rash, e.g. itching, anaphylactic reactions) are very rare. As with other
medicinal products of this class, very rare cases of pituitary apoplexy have been reported following initial administration in patients with pituitary adenoma.



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.

5
5.1






PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Gonadotrophin-Releasing Hormone Analogues



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.




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.

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 high-risk 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 diseasefree survival data or survival data with leuprorelin acetate in this setting.

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

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.
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
6.1











PHARMACEUTICAL PARTICULARS
List of excipients
PROSTAP 3 Powder
Poly (D-L lactic acid)
Mannitol (E421)
Sterile Solvent
Carmellose sodium
Mannitol (E421)
Polysorbate 80
Glacial Acetic Acid (for pH adjustment)
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

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.
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: 26/09/2014
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



BACK
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

29/08/14 RI007M

6099995.02

SEPARATIONS: ( BLACK )

DRAFT

03

MEASURE (mm): 210X680 (FOLD 50X105)
FONT TYPE: HELVETICA Size: 8 PT
PREVIOUS CODE: 6099995.01
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

6099995.02

Expand view ⇕

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.

Hide
(web4)