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Pharmacology: Pharmacodynamics: Triptorelin is a synthetic decapeptide analogue of natural GnRH (gonadotrophin-releasing hormone).
Studies conducted in humans and in animals have shown that, after the initial stimulation, prolonged administration of triptorelin inhibits gonadotrophin secretion with consequent suppression of testicular and ovarian function.
3.75 mg: Further studies in animals have suggested another mechanism of action: direct effects on the gonads by decreasing the sensitivity of peripheral receptors to GnRH.
11.25 mg: The administration Diphereline P.R 11.25 mg may initially increase blood LH and FSH levels and may consequently increase initial testosterone level (flare-up) in men and oestradiol level in women. Continuing the treatment decreases LH and FSH levels leading to decreased testosterone and oestradiol levels similar to those observed after castration within about 20 days after the injection and for as long as the active substance is released.
Prostate cancer: A randomized phase III study of 970 patients with prostate cancer locally advanced (T2c-T4) has investigated whether radiation therapy associated with short term androgen deprivation therapy (6 months, n = 483) was non-inferior to radiotherapy associated with long term androgen deprivation therapy (3 years, n = 487). The GnRH agonist was triptorelin (62.2%) or other GnRH agonists (37.8%) and the trial was not further stratified by the type of agonist.
Overall, total mortality at 5 years was 19.0% and 15.2% respectively in the "short term hormonal treatment" and "long term hormonal treatment" groups, with a relative risk of 1.42 (CI-sided 95, 71% = 1.79; 95.71% CI = [1.09; 1.85], p = 0.65 for noninferiority and p = 0.0082 for post-hoc test of difference between groups of treatment). The 5-year mortality specifically related to the prostate was 4.78% and 3.2% respectively in the "short term hormonal treatment" and "long term hormonal treatment" groups, with a relative risk of 1.71 (CI 95% [1.14 to 2.57], p = 0.002).
The post hoc analysis in the subgroup triptorelin also show the advantage of the long term treatment versus the short term treatment on overall mortality (relative risk 1.28; 95.71% CI = [0.89 ; 1.84], p = 0.38 and p = 0.08 respectively for non-inferiority post-hoc tests and for difference between treatment groups).
3.75 mg: The administration of a daily dose of triptorelin may initially increase LH and FSH blood levels (flare up) and consequently increase testosterone levels. Continuing the treatment decreases LH and FSH 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.
This study shows that the combination of radiotherapy and long term androgen deprivation therapy (3 years) is preferable to a combination of radiotherapy and short term androgen deprivation therapy (6 months).
11.25 mg: An opened, not controlled and multicentric phase 3 clinical trial involving 126 patients with advanced prostate cancer has been conducted during 6 months in order to assess the efficacy of subcutaneous administration of Diphereline P.R. 11.25 (one administration every 3 months). After four weeks 97.6% of subjects were castrated (testosterone levels <50 ng/dL) (95% CI: [93.2; 99.5]) and castration was maintained at Month 6 in 96.6% of subjects (95% CI: [91.6; 99.1]) (coprimary endpoints). The probability for a subject to be castrated within the first month of treatment and to remain castrated at each measurement up to 6 months was 96% (95% CI [0.92, 0.99]) (see Figure 1).
Click on icon to see table/diagram/imageDuring the treatment by triptorelin, median PSA levels were reduced by 64.2% at Month 1 and by 96% at Month 6 (secondary endpoint). Median PSA values remained within normal range (0-4 ng/mL) from Month 2 until the end of the study.
In patients with locally advanced prostate cancer several randomized long-term clinical trials provide evidence for the benefit of androgen deprivation therapy (ADT) in combination with radiotherapy (RT) compared to RT alone (RTOG 85-31, RTOG 86-10, EORTC 22863, D'Amico et al., JAMA, 2008).
Overall quality of life using QLQ-C30 did not differ significantly between the two groups (P = 0.37).
Evidence for the indication of high-risk localised prostate cancer is based on published studies of radiotherapy combined with GnRH analogues. Clinical data from five published studies were analyzed (EORTC 22863, RTOG 85-31, RTOG 92-02, RTOG 86-10, and D'Amico et al., JAMA, 2008), which all demonstrate a benefit for the combination of GnRH analogue with radiotherapy. Clear differentiation of the respective study populations for the indications locally advanced prostate cancer and high-risk localised prostate cancer was not possible in the published studies.
For patients with metastatic prostate cancer castration-resistant, clinical trials have shown the benefice of adding androgen biosynthesis inhibitors as abiraterone acetate or inhibitors of signaling pathway of androgen receptors as enzalutamide to the treatment by a GnRH analog as triptorelin.
Endometriosis: Prolonged treatment with triptorelin suppresses oestradiol secretion and thus enables resting of ectopic endometrial tissue.
3.75 mg: Uterine fibromyomas: Studies conducted have shown a regular and pronounced decrease in the volume of certain uterine fibromyomas. This decrease is maximum during the third month of treatment.
Triptorelin treatment may induce amenorrhea after the first month of treatment in most patients. It may correct a possible anaemia resulting from menorrhagia and/or metrorrhagia.
Breast cancer: Clinical studies performed in premenopausal women with endocrine responsive early stage breast cancer have been conducted with triptorelin in order to suppress oestradiol ovarian secretion, the main source of oestrogens. Based on studies performed in healthy women and women with endometriosis, the effect of triptorelin is achieved 3 4 weeks after administration.
Two phase 3 studies (SOFT and TEXT) have explored the 5-year benefit of ovarian function suppression (OFS) in combination with tamoxifen (T) or an aromatase inhibitor (exemestane - E) in premenopausal women with endocrine responsive early stage breast cancer.
Triptorelin was the main treatment used to achieve OFS (91.0% of randomised subjects in the SOFT study, and 100% in the TEXT study). The remaining 9% of women in the SOFT study had bilateral oophorectomy or bilateral ovarian irradiation.
SOFT study results: The SOFT study was designed to answer the question of the added value of OFS to tamoxifen as adjuvant treatment of premenopausal women with endocrine responsive early stage breast cancer.
A total of 3047 women were analysed (1015 women in the T+OFS, 1018 women in the T alone and 1014 women in the E+OFS arm).
At a median follow-up of 67 months (5.6 years), treatment with T+OFS non significantly reduced the hazard of a Disease Free Survival (DFS) event versus T alone (HR=0.83; 95% CI, 0.66 to 1.04; p=0.10). The estimated 5-year DFS was 86.6% (95% CI, 84.2% to 88.7%) among women patients assigned to T+OFS compared with 84.7% (95% CI, 82.2% to 86.9%) for women assigned to T alone.
However, after adjustment for prespecified covariates in the multivariate Cox model, women assigned treatment with T+OFS had a significantly reduced hazard of a DFS event compared with women assigned T alone, with a reduction of 22% (HR=0.78; 95% CI, 0.62 to 0.98; p=0.03).
Women assigned treatment with T+OFS had a non-significantly reduced hazard of a breast cancer event compared with women assigned T alone (HR=0.81; 95% CI, 0.63 to 1.03; p=0.09). The estimated 5-year Breast Cancer Free Interval (BCFI) was 88.4% (95% CI, 86.1% to 90.3%) for women assigned treatment with T+OFS compared with 86.4% (95% CI, 84.0% to 88.5%) for women assigned T alone.
However, after adjusting for pre-specified covariates in the multivariable Cox model, women assigned T+OFS had a significantly reduced hazard of a BCFI event compared with women assigned T with a reduction of 25% (HR=0.75; 95% CI, 0.59 to 0.96; p=0.02).
The absolute benefit is higher in women who received adjuvant chemotherapy. The DFS rate at 5 years for women who received adjuvant chemotherapy was 80.7% in the T + OFS arm and 77.1% in the T arm only (HR=0.82; 95% CI, 0.64 to 1.07) with an absolute benefit of 3.6% for T+OFS.
In particular, the benefit of adding OFS was apparent for 5 year DFS in a post-hoc analysis for the subgroup of women less than 40 years old (HR=0.74; 95% CI, 0.53, 1.03) with an absolute benefit of 4.4% for T+OFS compared to T alone.
In the SOFT study, subjects assigned E+OFS had a statistically significantly reduced hazard of a DFS event, as compared with subjects assigned T alone (HR=0.68, 95% CI, 0.53 to 0.86). The estimated 5-year DFS rate was 89.0% (95% CI, 86.8% to 90.9%) among subjects assigned to E+OFS as compared with 84.7% (95% CI, 82.2% to 86.9%) among subjects assigned T alone.
Subjects assigned E+OFS had a statistically significantly reduced hazard of a breast cancer event as compared with subjects assigned T alone (HR=0.64; 95% CI, 0.49 to 0.83). The estimated 5-year BCFI was 90.9% (95% CI, 88.9% to 92.6%) among subjects assigned E+OFS compared with 86.4% (95% CI, 84.0% to 88.5%) among subjects assigned T alone.
Subjects assigned E+OFS had a statistically significantly reduced hazard of a distant recurrence as compared with subjects assigned T alone (HR=0.71; 95% CI, 0.52 to 0.96). The estimated 5-year Distant Recurrence Free Interval (DRFI) was 93.0% (95% CI, 91.2% to 94.5%) among subjects assigned E+OFS compared with 90.7% (95% CI, 88.6% to 92.4%).
The absolute benefit is higher in women who received adjuvant chemotherapy. The DFS rate at 5 years for women who received adjuvant chemotherapy was 83.8% in the E + OFS arm and 77.1% in the T arm only (HR=0.70, 95% CI, 0.53 to 0.92) with an absolute benefit of 6.7% for E+OFS. (See Figure 2.)
Click on icon to see table/diagram/imageIn the 3 arms SOFT study, women who received chemotherapy had a higher proportion of high risk clinical criteria of recurrence: 49.3% below age < 40, 56.9% with lymph nodes positive, 47.0% with breast tumour size > 2 cm and 33.7% with tumour grade 3.
Combined SOFT and TEXT study results: The primary objective of TEXT study was to evaluate the role of aromatase inhibitors (exemestane) in women treated with OFS compared with T+OFS including all women from SOFT and TEXT studies. A total of 4690 women were analysed: 2346 women in the E+OFS arm and 2344 women in the T+OFS arm.
At a median follow-up of 68 months (5.7 years), treatment with E+OFS statistically significantly reduced the hazard of a DFS event versus T+OFS (HR=0.72; 95% CI, 0.60 to 0.86; p=0.0002). The estimated 5-year DFS was 91.1% (95% CI, 89.7% to 92.3%) for women assigned to E+OFS compared with 87.3% (95% CI, 85.7% to 88.7%) for women assigned T+OFS. (See Figure 3.)
Click on icon to see table/diagram/imageWomen assigned E+OFS had a statistically significantly reduced hazard of a breast cancer event compared with women assigned T+OFS (HR=0.66; 95% CI, 0.55 to 0.80; P<0.0001). The estimated 5 year BCFI was improved at 92.8% (95% CI, 91.6% to 93.9%) for women assigned E+OFS compared with 88.8% (95% CI, 87.3% to 90.1%) for women assigned T+OFS.
11.25 mg: Pediatric population - precocious puberty: The inhibition of hypophyseal gonadotrophic hyperactivity in both sexes manifests as suppression of oestradiol or testosterone secretion, as a lowering of the LH peak and as improved Height Age/Bone Age ratio.
Initial gonadic stimulation may cause slight genital haemorrhages requiring medroxyprogesterone or cyproterone acetate treatment.
Pharmacokinetics: 3.75 mg: Following intramuscular injection of the sustained release form, an initial phase of release of the active substance is observed, followed by a further phase of regular release during 28 days (Cmax = 0.32 ± 0.12ng/ml) providing a mean, steady-state triptorelin release of 46.6 ± 7.1μg/day, with product bioavailability of approximately 53% over one month.
11.25 mg: Following intramuscular injection of Diphereline P.R. 11.25 mg in patients (men and women), a peak plasma concentration of triptorelin is observed about 3 hours after injection. After a declining concentration phase, which continues during the first month, circulating triptorelin levels remain constant until the end of the third month following the injection.
In the study conducted with subcutaneous administration in men, peak plasma concentration of triptorelin is rapidly reached after injection (median Tmax of 4.5h) and triptorelin is constantly released during the period of 91 days. Residual concentrations of triptorelin (Cmin) were 0.063 ng/ml three months after subcutaneous administration.
Toxicology: Preclinical safety data: 3.75 mg: 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.
The resorption of the powder is complete within 40-45 days.
11.25 mg: The molecule did not demonstrate any specific toxicity in animal toxicological studies. The effects observed are related to the pharmacological properties of the substance on the endocrine system.
The resorption of the product is complete in 120 days.
