DIPHERELINE 0.1 MG

SUMMARY OF PRODUCT CHARACTERISTICS

1.

TRADENAME OF THE MEDICINAL PRODUCT

DIPHERELINE 0.1 mg, powder and solvent for solution for injection (S.C.).

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Composition of the powder

Triptorelin ................................................................................... 0.0001 g

Mannitol ...................................................................................... 0.0100 g

For one dose

Composition of the solvent

Sodium chloride ........................................................................... 0.009 g

Water for injections q.s. .............................................................. 1 ml

For one ampoule

3.

PHARMACEUTICAL FORM

Powder and solvent for solution for injection (S.C.)

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Female infertility: Management of ovarian stimulation in association with the

gonadotrophins (hMG, FSH, hCG) in view of in vitro fertilisation and embrio

transfer (I.V.F.E.T.) and other assisted conception techniques.

4.2

Posology and method of administration

Prostate cancer

One daily injection of 0.1 mg triptorelin by subcutaneous route from Day 1 to

Day 7, before changing to the prolonged release form.

Female infertility

: in combination with gonadotrophins.

One daily subcutaneous injection from Day 2 of the menstrual cycle (at the same time

as ovarian stimulation starts) until the day before the day set for induction, i.e. an

average period of 10 to 12 days for each attempt.

4.3

Contra-indications

Hypersensitivity to GnRH, its analogues or to one of the constituents.

4.4

Special warnings and special precautions for use

Prostate cancer

Warnings on beginning treatment

It has been reported that clinical symptoms (particularly bone pain) may worsen on

beginning treatment but these cases are isolated and generally transient. These

cases justify a careful medical supervision during the first few weeks of treatment,

particularly in patients presenting with urinary tract obstruction and in those with

vertebral metastases (see Undesirable effects).

For the same reason, particular care should be taken when beginning treatment in

patients with premonitory signs of spinal cord compression.

A transitory increase in acid phosphatases may be observed at the beginning of

treatment.

Precautions for use

It may be advantageous to check blood testosterone levels periodically with an

accurate method as these should not exceed 1 ng /ml.

Female infertility

Warnings

Confirm

that

patient

pregnant

before

prescription

DIPHERELINE 0.1 mg.

follicular retrieval induced

injection of

triptorelin combined

with

gonadotrophins may increase markedly in some predisposed patients and particularly

in cases of polycystic ovarian disease.

The ovarian response to the triptorelin-gonadotrophin combination may differ with the

same doses from one patient to another one, and in certain cases, from one cycle to

another in the same patient.

Precautions for use

The induced ovulation should be monitored under rigorous medical supervision with

strict and regular biological and clinical controls: fast plasma oestrogen assay and

ultrasonography (see Undesirable effects).

If the ovarian response is excessive, it is recommended to interrupt the stimulation

cycle by discontinuing the gonadotrophin injections.

4.5

Interaction with other medicinal products and other forms of interaction

Not applicable.

4.6

Pregnancy and lactation

Pregnancy

At the present time, GnRH analogues are used in combination with gonadotrophins

to induce ovulation and therefore encourage pregnancy. Pregnancy is therefore not

an indication for these products.

However, experience has shown that after ovulation has been induced in a previous

cycle, some women become pregnant without realising it, and undertake a further

course to stimulate ovulation.

Data currently available concerning the effects of this type of product during

pregnancy are summarised below:

Animal studies have not shown the product to have any teratogenic effects. No

malformations are therefore expected in humans with this product as substances

that cause malformations in humans have been found to be teratogenic in well-

conducted animals studies in two species so far.

In clinical studies to date, the use of GnRH analogues in a limited number of

pregnant

women

resulted

malformations

foetotoxicity.

Nevertheless, further studies are required to study the consequences of exposure

during pregnancy.

4.7

Effects on ability to drive and use machines

Not applicable.

4.8

Undesirable effects

At the beginning of treatment

(see Warnings and Precautions for use)

In men

Urinary symptoms, bone pain of metastatic origin and symptoms associated with

spinal

cord

compression

from

vertebral

metastases

exacerbated

when

plasma

testosterone

initially

transiently

increased

beginning

treatment. These symptoms disappear in one to two weeks.

During the treatment

The most frequently reported undesirable effects (hot flushes, decreased libido, and

impotence) are related to the decrease in plasma testosterone levels resulting from

the pharmacological effects of the substance, and are similar to those observed with

other GnRH analogues. These effects have not been observed during short-term

treatment with DIPHERELINE 0.1 mg.

At the beginning of treatment

In women

When used to treat infertility, the combination with gonadotrophins may result in

ovarian hyperstimulation. Ovarian hypertrophy, pelvic and/or abdominal pains may be

observed (see Warnings and Precautions for use).

During the treatment

The most frequently reported effects, such as hot flushes, vaginal dryness, decreased

libido and dyspareunia, are related to pituitary-ovarian blockade.

These

effects

have

been

observed

during

short-term

treatment

with

DIPHERELINE 0.1 mg.

A few rare cases of headache, arthralgia and myalgia have been reported.

Allergic reactions such as urticaria, rash, pruritus and very occasionally Quincke's

oedema have been reported.

In both men and women

A few cases of nausea, vomiting, weight increase, hypertension, mood disorders,

visual disturbances, pain at the injection site and fever have been reported.

The prolonged use of GnRH analogues may lead to bone loss, a risk factor for

possible osteoporosis. These effects have not been observed during short-term

treatment with DIPHERELINE 0.1 mg.

4.9

Overdose

Not applicable.

5.

PHARMACOLOGICAL PROPERTIES

GONADOTROPHIN-RELEASING HORMONE ANALOGUE

(L 02 AE04: antineoplastic and immunomodulator).

5.1

Pharmacodynamic properties

Triptorelin is a synthetic decapeptide analogue of natural GnRH (gonadotrophin-

releasing hormone).

Studies

conducted

humans

animals

have

shown

that

after

initial

stimulation,

prolonged

administration

triptorelin

inhibits

gonadotrope

secretion with consequent suppression of testicular and ovarian function.

Further studies in animals have suggested another mechanism of action: direct effect

on the gonads by decreasing the sensitivity of peripheral receptors to GnRH.

Prostate cancer

The administration of a daily dose of triptorelin may initially increase LH and FSH

blood levels (flare up) and may consequently increase initial testosterone levels.

Continuing the treatment decreases LH and FSH levels to concentrations that result in

castration levels of steroids within 2-3 weeks and for as long as the product is

administered.

The treatment may improve functional and objective symptoms.

Female infertility

Prolonged treatment with triptorelin inhibits gonadotrope secretion (FSH and LH). The

treatment ensures therefore the suppression of the intercurrent endogenous LH peak

enabling enhanced quality of folliculogenesis and increased follicular retrieval.

5.2

Pharmacokinetic properties

In healthy adult volunteers

Following subcutaneous injection the resorption of triptorelin (0.1 mg) is quick

(tmax = 0.63

0.26 hr) with a peak plasma concentration (Cmax = 1.85

0.23 ng/ml).

Elimination is achieved with a biological half-life of 7.6

1.6 hr, after a 3 to 4 hours

distribution phase.

Total plasma clearance is: 161

28 ml/min.

Distribution volume is: 1562

158 ml/kg.

In patients with prostate cancer

With

subcutaneous

administration

(0.1

mg),

plasma

concentrations

oscillate

between maximum values of 1.28

0.24 ng/ml (Cmax) usually obtained one hour

after injection (tmax) and minimum values of 0.28

0.15 ng/ml (Cmin) obtained 24

hours after injection.

Biological half-life is on average 11.7

3.4 hr but varies according to patients, and

plasma clearance (118

32 ml/min) reflects slowing of elimination in these patients,

whilst

distribution volumes are

close

those

healthy volunteers (1130

210 ml/kg).

5.3

Preclinical safety data

The molecule did not demonstrate any specific toxicity in animal toxicological

studies. The effects observed were related to the pharmacological properties of the

substance on the endocrine system.

6.

PHARMACEUTICAL PARTICULARS

6.1

Incompatibilities

Not applicable.

6.2

Shelf-life

2 years

After first opening – use within 24 hours

After reconstitution – use within 24 hours

6.3

Special precautions for storage

Store at 25ºC

6.4

Nature and contents of container

Vial or ampoule (glass) containing the powder and ampoule (glass) containing the

solvent.

6.5

Instructions for use/handling

Not applicable.

7.

MARKETING AUTHORISATION HOLDER

IPSEN PHARMA, FRANCE

65 Quai Georges Gorge

92100 BOULOGNE-BILLACOURT ,France

AUTHORIZATION HOLDER

MEDISON PHARMA Ltd.

P.O.B 7090

, PETACH TIKVA

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02.11