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Action on Gonadotropic Hormone Suppression: In patients with endometriosis, uterine myoma or premenopausal breast cancer, subcutaneous injection of Leuprorelin Acetate once every 4 weeks generally causes serum estradiol to fall to a value near the menopausal level. Thus, this drug produces an ovarian function suppressing effect, with resultant inhibition of normal ovulation and cessation of menstruation.
In patients with prostate cancer, subcutaneous administration of Leuprorelin Acetate once every 4 weeks causes serum testosterone to fall below the castration level, indicating a pharmacological castrating effect.
In girl and boy patients with central precocious puberty, subcutaneous administration of leuprorelin acetate, once every 4 weeks, reduces the serum level of gonadotropic hormone to the prepubertal level, exhibiting an action of delaying the progression of secondary sex characteristics.
Clinical Studies: Endometriosis: In clinical studies in which 1.88 mg or 3.75 mg of Leuprorelin Acetate was administered subcutaneously to patients with endometriosis six times at 4-week intervals, the global improvement rating at week 24 was as shown in the following table. With administration of 3.75 mg, the improvement rate (marked improvement + improvement) was 79.9%. (See Table 2.)
Click on icon to see table/diagram/imageAs compared with 3.75 mg, the clinical effect of 1.88 mg was slightly lower. However, it was suggested that when compared based on body weight, nearly the same improvement rate would be obtained where the body weight is less than 50 kg.
In further clinical studies in which 1.88 mg of Leuprorelin Acetate was administered subcutaneously six times at 4-week intervals to patients with endometriosis weighing less than 50 kg, the improvement rate (marked improvement + improvement) was 82.0% (41/50 patients). The double-blind comparative study in patients with endometriosis has proved the usefulness of ENANTONE.
Uterine Myoma: In a clinical study in which 1.88 mg or 3.75 mg of Leuprorelin Acetate was administered subcutaneously to patients with uterine myoma four or six times at 4-week intervals, the global improvement rating (marked improvement + improvement) and the marked improvement rating at 4 weeks after the final administration, excluding indeterminable cases, were 83.5% (259/310 patients) and 39.7% (123/310 patients), respectively.
The following table shows the improvement rate (marked improvement + improvement) in stratified analysis by dose, body weight and preadministration size of uterus (by vaginal examination). In patients with relatively heavy weight (55 kg or more) and those with markedly enlarged uterus (fist size or larger), the improvement rate was higher in 3.75 mg group than in 1.88 mg group. (See Table 3.)
Click on icon to see table/diagram/imageThe double-blind comparative study in patients with uterine myoma has proved the usefulness of ENANTONE. In the meantime, in a dose-setting study in which this drug was administered four times in doses of 0.94 mg, 1.88 mg, 3.75 mg and 5.63 mg, adverse reactions including changes in laboratory values were observed in 35 of 48 patients (72.9%), 36 of 45 patients (80.0%), 39 of 43 patients (90.7%) and 43 of 49 patients (87.8%), respectively.
Premenopausal Breast Cancer: In a clinical study in which 3.75 mg of Leuprorelin Acetate was administered subcutaneously to patients with premenopausal breast cancer three times at 4-week intervals, the effectiveness rate (CR + PR) at week 12 in complete cases and evaluable cases were 30.4% (14/46 patients) and 28.6% (14/49 patients), respectively. In addition, this drug continued to be used alone after week 12, and the effectiveness rate※ (CR + PR) in complete cases and evaluable cases covering those for which evaluation could be made for long-term administration and those for which evaluation was finished at week 12 were 37.0% (17/46 patients) and 34.7% (17/49 patients), respectively. (※Evaluation based on "Best response" noted in the entire observation period.) [Evaluation according to the "Criteria for evaluation of therapeutic effect in advanced and recurrent breast cancer" (CR: Complete Response (markedly effective), PR: Partial Response (effective)).]
In a randomized controlled study conducted abroad (in Europe) in which subcutaneous injection of Leuprorelin Acetate 11.25 mg at 3-month intervals or CMF therapy was given to patients who were positive for lymph node metastasis and were in status of post (premenopausal/perimenopausal breast cancer) surgery, recurrence-free survival rates were shown as follows. (See Table 4.)
Click on icon to see table/diagram/imageProstate Cancer: In a clinical study in which 3.75 mg of Leuprorelin Acetate was administered subcutaneously to patients with prostate cancer three times at 4-week intervals, the effectiveness rate (CR + PR) at week 12 in complete cases was 53.9% (55/102 patients) and that in evaluable cases was 48.2% (55/114 patients). In a long-term clinical study in which this drug was subcutaneously administered 5 to 46 times at 4-week intervals to patients who were given continuous treatment with this drug alone, the effectiveness rate※ (CR + PR) of complete cases in evaluable cases was 51.7% (15/29 patients). (※Evaluation based on "Best response" noted in the entire observation period.) [Evaluation according to the "Criteria for evaluation of therapeutic effect in medicinal treatment for prostate cancer" (CR: Complete Response (markedly effective), PR: Partial Response (effective)).]
The comparative clinical study in patients with prostate cancer has proved the usefulness of ENANTONE.
Central Precocious Puberty: In a clinical study in which 30 μg/kg to 90 μg/kg of Leuprorelin Acetate was administered subcutaneously to patients with central precocious puberty once every 4 weeks, the effectiveness rates at week 24, week 48, week 96 and week 114 were as shown in the following table: See Table 5.
Click on icon to see table/diagram/imagePharmacokinetics: Endometriosis: Blood concentration: Figure 1 shows blood concentration in a study in which 1.88 mg or 3.75 mg, as leuprorelin acetate, was administered subcutaneously to patients with endometriosis in a total of six times at 4-week intervals. When 3.75 mg, as leuprorelin acetate, was administered subcutaneously to patients with endometriosis (77 patients) six times at 4-week intervals, the combined blood concentration of the unchanged compound and metabolite M-I* revealed no accumulation. (See Figure 1.)
* M-I: Tyr-D-Leu-Leu-Arg-Pro-NHC2H5.
Click on icon to see table/diagram/imageUrinary excretion: The following table shows the urinary excretion rates (%) of the unchanged compound and metabolite M-I at 24 hours after the first administration and 24 hours after the sixth administration, when 3.75 mg, as leuprorelin acetate, was administered subcutaneously to patients with endometriosis six times at 4-week intervals: See Table 6.
Click on icon to see table/diagram/imageUterine Myoma: The pharmacokinetics in patients with uterine myoma are considered to be the same as those in patients with endometriosis, which is the same estrogen dependent disease as uterine myoma and is occurring in nearly the same age group as uterine myoma.
Premenopausal Breast Cancer: When 3.75 mg, as leuprorelin acetate, was administered subcutaneously to patients with premenopausal breast cancer three times at 4-week intervals, the blood concentration of the unchanged compound was as shown in Figure 2. The blood concentrations at 4 weeks after the second and third administration were not higher than the level observed 4 weeks after the first administration. Thus, this drug is not likely to accumulate. (See Figure 2.)
Click on icon to see table/diagram/imageProstate Cancer: Blood concentrations: Figure 3 shows the blood concentration of the unchanged compound when a single subcutaneous dose of 3.75 mg, as leuprorelin acetate, was administered to patients with prostate cancer. The blood concentrations of the unchanged compound in subcutaneous administration of 3.75 mg, as leuprorelin acetate, to patients with prostate cancer (17 patients) three times at 4-week intervals, revealed no accumulation. (See Figure 3.)
Click on icon to see table/diagram/imageUrinary excretion: When a single dose of 3.75 mg, as leuprorelin acetate, was subcutaneously administered to patients with prostate cancer (2 patients), the urinary excretion rates of the unchanged compound and its metabolite M-I up to 28 days after administration were 2.9% and 1.5%, respectively.
Central Precocious Puberty: Blood concentrations: Figure 4 shows the blood concentrations of the unchanged compound after the first administration, when 30 μg/kg, as leuprorelin acetate, was given subcutaneously to patients with central precocious puberty twelve times at 4-week intervals. Judging from the trend of blood concentration of the unchanged compound, this drug is not considered to accumulate. (See Figure 4.)
Click on icon to see table/diagram/imageUrinary excretion: When a single dose of 30 μg/kg, as leuprorelin acetate, was subcutaneously administered to patients with central precocious puberty (1 patient), the urinary excretion rates of the unchanged compound and its metabolite M-I up to 28 days after administration were 1.8% and 7.1%, respectively.
Enantone 3-Month DPS 11.25 mg: Pharmacotherapeutic category: Gonadotropin releasing hormone analogues. ATC: L02AE02.
Pharmacology: Pharmacodynamics: Mechanism of action: Leuprorelin acetate, active substance of Enantone 11.25 mg, is a natural GnRH hormone analogue. Leuprorelin is much more active than natural GnRH and can be defined as a hypothalamic physiological decapeptide superagonist. Leuprorelin is not chemically related to steroids.
Pharmacodynamic effects: Enantone Depot 11.25 mg is formulated so as to allow, after the administration and for three months a continuous and uniform release of the active substance from the injection site. After the first administration of Enantone 11.25 mg a transitory increase of sexual steroids is observed, due to the stimulation of the pituitary secretion of gonadotropin (agonist effect). Within 3 weeks from the single administration a secretory inhibition of the hypophysis (antagonist effect) and a suppression of the gonadic activity is observed.
Clinical efficacy and safety: Males: In male this causes a decrease of testosterone to the characteristic values of castration, which continues for at least 14 weeks. With the repeated administration every three months, testosterone is suppressed for the whole duration of the treatment.
Females: In female the administration causes a condition of hypoestrogenism similar to the one registered during menopause. With the repeated administration every three months the condition of hypoestrogenism continues for the whole duration of the treatment, causing a fall of estradiol and progesterone, and inducing a condition of reversible castration.
These effects can be usefully used in hormone-dependent pathologies. As far as breast cancer is concerned, besides the presence of specific receptors of GnRH, a direct action of the GnRH analogues on the tumoral tissue was demonstrated, independent from the oestrogenic depletion.
Paediatric population: Reversible suppression of the pituitary gonadotropin release occurs with a consequent reduction of the levels of estradiol (E2) or of testosterone to values within the prepuberal range.
Initial gonadic stimulation (flare-up) may cause vaginal bleeding in girls who are already in the postmenarcheal stage at the beginning of the treatment. Bleeding from suspension may occur at the beginning of the treatment. The haemorrhage is normally interrupted when the treatment continues.
The following therapeutic effects can be demonstrated: Suppression of the basal and stimulated gonadotropin levels to prepuberal levels; Suppression of the prematurely augmented sex hormone levels, restoring of the prepuberal levels and stopping the precocious menstrual cycle; Stopping/involution of somatic pubertal development (Tanner stages); Improvement/normalisation of the chronological age and bone age ratio; Prevention of the progressive acceleration of bone age; Reduction of the speed of growth and its normalisation; Increasing final height.
The result of the treatment is suppression of the hypothalamic-pituitary-gonadal axis activated pathologically and prematurely according to the prepuberal age.
In a long term clinical study in children treated with leuprorelin in doses of up to 15 mg per month for > 4 years, the pubertal progression was shown to restart after the treatment was interrupted. The follow-up of 20 female subjects in adult age showed normal menstrual cycles in 80% and 12 pregnancies in 7 of the 20 subjects, including multiple pregnancies for 4 subjects.
Pharmacokinetics: Absorption: The drug administration by i.m. or s.c. route to rats (100 mg/kg) and to dogs (20 mg/kg) causes typical modifications in leuprorelin acetate plasmatic concentrations. In both species an initial increase with peaks after 3 hours is observed. A plateau is reached after 2 days and it is maintained for about 14 weeks. Then leuprorelin levels gradually decrease for a period varying from 2 to 3 weeks till the dosage limit is reached. These modifications in leuprorelin levels are identical in the two species (dog and rat). A comparison of leuprorelin acetate levels after i.m. or s.c. injection shows there are no significant differences in between the two species; therefore the bioavailability is identical for both administration route. In repeated administration trials no accumulation phenomena were observed.
In males after injection of Enantone, an initial phase of rapid release is observed. Within 2-3 hours the maximum concentrations are reached. The levels increase further and then decline and reach a steady state in between 3-7 days lasting for at least 117 ± 9 days.
Pharmacokinetic/pharmacodynamic relationships: In males the rapid increase of leuprorelin levels after the first injection produced an increase of plasmatic concentration of testosterone which in the following weeks decreases below the castration level of 50 ng/dl. This phenomenon was observed within 3 weeks (12-13 days) after the first administration of Enantone. The castration levels are maintained for 15 weeks on average.
In females the administration of Enantone every three months involves a suppression of the gonadal activity, which causes a hypogonadotropic amenorrhea.
Figure 5 shows the serum levels of leuprorelin in children during the first 6 months of treatment after sc administration of Enantone 11.25 mg/ml (2 injections). From the first injection, the serum levels increased, reaching their peak in the fourth month (294.79 pg/ml ± 105.42) and then underwent a slight reduction until the sixth month (229.02 pg/ml ± 103.33). (See Figure 5.)
Click on icon to see table/diagram/imageToxicology: Pre-clinical Safety Data: Effects in pre-clinical studies were only observed at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use. The maximum non-lethal single dose in mouse and rat administered via parenteral was higher than 100 mg/kg with the active substance alone.
DL50 of Enantone 11.25 mg is higher than 2000 mg/kg in intramuscular administration. In studies of chronic toxicity performed on monkeys, rats and mice, no unexpected toxic effects were recorded, but only pharmacodynamic effects to be ascribed to the product. In rats treated for 2 years, a trend of benign pituitary adenoma was observed (not statistically significant). These modifications, which are not related to humans, are to be ascribed to the animal species used and to the pharmacodynamics of the product.
Enantone 6-Month DPS 30 mg: Pharmacotherapeutic group: GnRH analogues. ATC code: L02AE02.
Pharmacology: Pharmacodynamics: Leuprorelin acetate, the active ingredient in ENANTONE 6 MONTH DPS, is a synthetic nona-peptide analogue of the naturally occurring hypothalamic gonadotropin releasing factor, GnRH. This peptide has a longer half-life compared to peptidase due to its increased resistance and is more potent than naturally occurring GnRH due to its increased binding affinity to the GnRH receptor by a factor of 80 to 100.
The application leuprorelin acetate in animals and humans resulted in an increase in the gonadotropic hormones LH (luteinizing hormone) and FSH (follicle-stimulating hormone) from the anterior lobe of the pituitary gland. These hormones stimulate the gonadal steroid synthesis.
In contrast to the physiological GnRH released from the hypothalamus in a pulsatile mode, leuprorelin acetate, also known as an GnRH agonist, works to block the GnRH receptors of the pituitary gland with chronic therapeutic use, and after an initial short-term stimulatory effect, causes them to become "desensitized" ("down-regulated"). As a consequence, reversible pituitary suppression of gonadotropin release occurs, followed by a decrease in testosterone levels, thereby influencing the growth of prostate cancer, which is normally stimulated by dihydrotestosterone (DHT) formed by reduction of testosterone in the prostate cells.
Chronic administration of leuprorelin acetate leads to a decrease in the number and/or sensitivity ("down-regulation") of the GnRH receptors present in the pituitary gland, resulting in a decrease in LH, FSH, and DHT levels, thereby reducing the testosterone level to the castration range within 2 to 4 weeks.
The hormone-decreasing and inhibitory effect of leuprorelin acetate on the growth of prostate cancer has also been demonstrated in animal studies.
Experimental and clinical studies demonstrated that 6-monthly treatment with ENANTONE 6 MONTH DPS results in the inhibition of gonadotropin release after an initial stimulatory effect.
In man the subcutaneous administration of ENANTONE 6 MONTH DPS causes an initial short-term rise in LH and FSH, accompanied by a transient increase in testosterone and DHT levels. As a short-term exacerbation of symptoms has been reported in the first few weeks of treatment in isolated cases, the administration of an appropriate anti-androgen should be considered in patients with prostate cancer.
Long-term administration of ENANTONE 6 MONTH DPS leads to a decrease in LH and FSH levels in all patients, thereby resulting in a decrease in androgen in these patients to levels comparable to those seen after bilateral orchiectomy. These changes usually occur two to three weeks after commencement of therapy, and are maintained during the entire course of treatment. If appropriate, a treatment with ENANTONE 6 MONTH DPS, which has to be administered every six months, represents a viable alternative to orchiectomy. To date, the maintenance of suppressed testosterone levels in the castration range with continuous administration of leuprorelin acetate has been confirmed for five years.
Clinical Efficacy: In a multicenter, randomized phase III study with leuprorelin acetate 11.25 mg 263 patients with locally advanced prostate cancer, classified as T3-T4, or pT3, N0; M0 were analyzed. For 3 years a combination of radiotherapy with long-term androgen withdrawal therapy was applied in 133 patients and a single 3-year androgen withdrawal therapy with leuprorelin acetate 11.25 mg in 130 patients.
Based on ASTRO (Phoenix) criteria the five-year progression-free survival in the combined group was 60.9% (64.7%) versus 8.5% (15.4%) in the group receiving hormone treatment alone [p=0.0001; (p=0.0005)]. According to the ASTRO definition the risk of progression was 3.8 times higher in the group receiving hormone therapy alone (95% CI [2.17; 6.49]).
The median clinical or biological progression-free survival according ASTRO definition was 641 days (95% CI [626; 812] in the hormone treatment alone group versus 2804 days (95% CI [2090;-]; p<0.0001) in the combined treatment group. There were further statistically significant differences with regard to loco-regional progression [HR 3.6 (95% CI [1.9; 6.8]; (p<0.0001)], metastatic progression (p=0.018) and metastatic free survival (p<0.018) for the combination therapy group compared to the group with androgen withdrawal therapy alone.
The results of this study indicate that 3 year androgen withdrawal therapy with leuprerelin acetate 11.25 mg in combination with radiotherapy is superior to a 3 year androgen withdrawal therapy alone.
The superiority of the combined androgen deprivation therapy with GnRH analogues compared to the single radiotherapy treatment of locally advanced prostate cancer was shown in the following study.
In the randomized RTOG trial no. 85-31, 977 patients with locally advanced prostate cancer, classified as T1-T3 with lymph node metastasis, disease extended beyond the capsule and or in the seminal vesicles, have been included. 488 patients received radiotherapy plus long-term androgen deprivation therapy with Goserelin and 489 patients received radiotherapy alone. The results obtained in the study were in favor of adjuvant hormone treatment in conjunction with radiotherapy. Ten-year progression-free survival was 37 % versus 23 % (p <0.001), progression-free survival with PSA level <1.5 ng/ml was 31 % versus 9 % (p <0.0001), local treatment failure was 23% versus 38% (p <0.0001) and metastatic dissemination 24% versus 39% (p <0.0001). Overall survival was 49% versus 39% (p=0.002) and disease-specific mortality was 16% versus 22% (p=0.0052).
The superiority of androgen deprivation therapy with GnRH analogues in combination with radiotherapy versus single radiotherapy treatment of localized prostate cancer in patients with intermediate-risk was shown in the following study.
The randomized RTOG phase III trial 94-08 was conducted on patients with localized prostate cancer stage T1b, T1c, T2a or T2b and a PSA-level ≤10 ng/ml. The subpopulation of patients with intermediate-risk, defined with Gleason score of 7 or Gleason-Score ≤6 in conjunction with PSA-value >10 ng/ml up to 20 ng/ml or clinical stage T2b, includes 524 patients in the group of short-term androgen deprivation therapy plus radiotherapy for 4 months, 2 months before and 2 months concurrent with the radiotherapy, and 544 patients in the group of radiotherapy single treatment. From the subpopulation with intermediate risk, the combined treatment of androgen deprivation therapy with Goserelin and radiotherapy was superior to the single radiotherapy treatment. The 10-year overall survival was 61% versus 54% [HR 1.23, 95% CI (1.02 - 1.49; p=0.03)]. Disease-specific mortality was 3% versus 10% [HR 2.49, 95% CI (1.50 - 4.11; p=0.004)] and the biochemical failure was 28% versus 45% [HR 1.79, 95% CI (1.45 - 2.21; p <0.001)].
The evidence for the treatment of localized prostate cancer in patients with high-risk is based on published trials of radiotherapy in combination with GnRH analogues including leuproreline acetate. Clinical data from 5 published trials have been analyzed (EORTC 22863, RTOG 85-31, RTOG 92-02, RTOG 8610 und D'Amico et al., JAMA 2004), from which all have shown the advantage of the combined treatment with GnRH analogues and radiotherapy. The published trials did not allow a clear distinction between patients with locally advanced or high-risk localized prostate cancer.
Clinical data have shown that a radiotherapy followed by 3 years androgen deprivation therapy is preferred compared to the radiotherapy followed by 6 months androgen deprivation therapy.
Medical guidelines recommend 2 to 3 years androgen deprivation therapy for patients with cancer classified as T3 to T4, who receive radiotherapy.
In clinical trials, the benefits of additional drug administration, such as inhibitors of the androgen synthesis (e.g. abirateronacetate), androgen-receptor inhibitors (e.g. enzalutamid), taxane (e.g. docetaxel or cabazitaxel) or radiotherapeutics (e.g. radium-223) in addition to GnRH agonists, such as leuprorelin acetate, could be shown in patients with metastatic castration-resistant prostate cancer.
Pharmacokinetics: Release: The active ingredient leuprorelin acetate is continuously released from the lactic acid polymer for a period of 6 months after injection of ENANTONE 6 MONTH DPS. The carrier polymer is absorbed over time in a similar fashion to surgical suture material.
Absorption: After single s.c. injection of ENANTONE 6 MONTH DPS serum levels of leuprorelin rise quickly in patients with prostate carcinoma with a subsequent decrease to a plateau within a few days. Within 1.8 hours mean maximum serum levels of 102 ng/ml are measured. In the plateau phase detectable serum levels were found until up to >26 weeks after administration. In some patients, leuprorelin levels have been observed for up to 30 weeks. (See Figure 6.)
Click on icon to see table/diagram/imageAn initial re-increase of testosterone levels was observed in median after approx. 200 days in case no subsequent injection was administered.
Distribution and Elimination: The distribution volume of leuprorelin is 36 l in men; total clearance is 139.6 ml/min (measured under treatment with Enantone S.R. 3.75 mg).
With repeated administration, a persistent suppression of testosterone levels to the castration range occurs, without the testosterone levels undergoing a transient rise, as after the first injection.
Patients with renal impairment: In patients with impaired renal function, (Creatinine value 1,4 ml bis 2 mg/dl) the leuprorelin serum levels equals the level in patients with normal renal function. In Patients with severe renal function (Creatinine value >2 mg/dl) elevated levels of leuprorelin levels may occur. However, this observation appears to be of no clinical relevance. No effects on the leuprorelin serum level is shown in patients with impaired liver function.
Toxicology: Preclinical safety data: Preclinical studies with leuprorelin acetate show impact on the reproductive system in both sexes, which are expected as a result of the known pharmacological effect. These effects are in principle reversible after a recovery phase (see Pharmacodynamics as previously mentioned).
Leuprorelin acetate shows no teratogenic effect. Due to the pharmacological effect on the reproductive system embryotoxicity and lethality appeared in rabbits.
Carcinogenicity studies have been performed in rats and mice over 24 months. After subcutaneous injection a dose-dependent increase in benign pituitary hyperplasia and benign pituitary adenomas at dosages of 0.6 mg to 4 mg/kg/day was observed in rats. No such effect was observed in mice, so that the effect in rats can be considered as species-specific.
Leuprorelin acetate had no mutagenic effect in a series of in vitro and in vivo studies.
