Diphereline 3.75mg S.R.

1. NAME OF THE MEDICINAL PRODUCT Diphereline 3,75mg S.R. powder and solvent for suspension for injection, sustained release form. INN: triptorelin
2. QUALITATIVE AND QUANTITATIVE COMPOSITION. PHARMACEUTICAL FORM.

Powder (triptorelin, D,L lactide-coglycolide polymer, mannitol, Carmellose sodium, Polysorbate ) and solvent (water, mannitol) for suspension for injection (i.m.), sustained release form.
3. CLINICAL PARTICULARS

3.1. Therapeutic indications Prostate cancer. Treatment of the prostate cancer with metastases. Patients who have not previously received hormone therapy respond better to Diphereline. Precocious puberty ( before 8 years in girls and 10 years in boys ). Genital and extra genital endometriosis (stage I to IV ) Female infertility Supplementary treatment in combination with gonadotrophin to induce ovulation with a view to in vitro fertilisation and embryo transfer (I.V.F.E.T.). 3.2 Posology and method of administration. Warnings and precautions. Prostate cancer: Two regimens are possible: - one daily s.c. injection of immediate release Diphereline 0.1 mg for 7 days, on Day 8 one i.m. injection of Diphereline 3.75 mg S.R., repeated every 28 days. - from the outset , one i.m. injection of Diphereline 3.75 mg S.R., repeated every 28 days. Warnings and precautions: Clinical symptoms may worsen on starting the treatment. These cases merit medical supervision in patients with obstructed urinary tract and medullary compression. The response to the treatment may be evaluated in the bone by scintigraphy or CT scan and in prostate by ultrasonography and or CT scan in addition to clinical examination and rectal touch. Precocious puberty: Children weighing more than 20 kg: one i.m. injection of Diphereline 3.75 mg S.R., repeated every 28 days. Children weighing less than 20 kg: Half of the dose of Diphereline 3.75 mg S.R., repeated every 28 days. Endometriosis: The treatment must be started in the first five days of menstrual cycle. One i.m. injection of Diphereline 3.75 mg S.R., repeated every 28 days. Duration depends on the initial severity and the changes observed in clinical features during treatment. Treatment should not be continued for more than 6 months. It is not recommended a second course of treatment. Treatment of fibromynomas prior to surgery The treatment must be started in the first five days of menstrual cycle. One i.m. injection of Diphereline 3.75 mg S.R., repeated every 28 days. Treatment should not be continued for more than 3 months. 1

Warnings and precautions: Regular treatment results in constant hypogonadotrophic amenorrhoea. A metrorrhagia in the course of treatment, other than in first month, is abnormal, and if the levels of estradiol are less than 50 pg/ml , possible associated organic lesions should be sought. Female infertility One i.m. injection of Diphereline 3.75 mg S.R. on the second day of the cycle. Gonadotropins should be started after the pituitary desensitisation ( plasma estrogens less than 50 pg/ml ), generally 15 days after injection of Diphereline. Warnings and precautions: the follicular retrieval may increase markedly in some predisposed patients and particularly in those with polycystic ovarian disease. The induced of ovulation should be monitored under rigorous medical supervision with strict and regular biological and clinical controls: fast plasma estrogen assay and ultrasonography. If the ovarian response is excessive, it is recommended to interrupt the stimulation cycle. 3.3. Contraindications Should never be used during pregnancy.

3.4 Undesirable effects In men : Urinary symptoms, bone pain of metastatic origin and symptoms associated with medullary compression may be exacerbated when plasma testosterone is transiently increased at the start of the treatment. These treatments disappear in 1-2 weeks. The most frequent undesirable effects during the treatment ( hot flushes, decreased libido, and impotence ) are related to the decrease of testosterone levels. In woman: The symptoms of endometriosis may be exacerbated when plasma estradiol is transiently increased at the start of the treatment. Metrorrhagia may occur in the month following the first injection. When used to treat infertility, the combination with gonadotrophins may result in ovarian hyperstimulation. The most frequent undesirable effects during the treatment (hot flushes, vaginal dryness, and impotence) are related to the pituitary ovarian blockade. 4. PHARMACOLOGICAL PROPERTIES 4.1. Pharmacodynamic Pharmacotherapeutic group: Gonadotrophine releasing hormone analogue ( ATC code: L 02 A E). Triptorelin is a synthetic decapeptide analogue of natural GnRH . After initial stimulation , , the prolonged administration of triptoreline inhibits gonadotrope secretion with consequent suppression of testicular and ovarian function. Prostate cancer The prolonged administration of triptoreline may initially increase LH and FSH ( flare up ) and consequently testosterone levels. 2-3 weeks after, LH and FSH decrease to concentrations that results in castration. Precocious puberty The inhibition of the pituitary gonadotrophic hyperactivity in both sex leads to the suppression of LH peak after LHRH stimulation test and consequently to the suppression of estradiol or testosterone and 2

to an improvement in the height age/bone ratio and final height Endometriosis The prolonged administration of triptoreline supresses estradiol secretion and thus enables resting of ectopic endometrial tissue. Female infertility The prolonged administration of triptoreline supresses LH and FSH, ensuring therefore the suppression of the intercurrent endogenous LH peak enabling enhanced quality of folliculogenesis and increased follicular retrieval. 4.2. Pharmacokinetic Following i.m. injection of Diphereline 3.75 mg S.R., an initial phase of active substance release is observed, followed by a further phase of regular release of 46.6 ng per day with a mean plasmatic C of 0.32 ng/ml . This is due to the new galenic form of microspheres where is scattered the active substance. Bioavailability = 53 %. 5. NATURE AND CONTENTS OF CONTAINER Powder in a vial and ampoule containing the solvent. Box containing 1 vial and 1 ampoule with 1 syringe and 2 needles.
6. MARKETING AUTHORISATION HOLDER BEAFOUR IPSEN PHARMA 24 rue Erlanger 75781 PARIS CEDEX 16

Representative in Albania: PharmaSwiss SA, Rruga Vaso Pasha, Pallati i Ri, Nr.20, Kati III, Tirane