Enantone 1-Month DPS 3.75 mg/Enantone 3-Month DPS 11.25 mg/Enantone 6-Month DPS 30 mg

Leuprorelin acetate.

Leuprorelin Acetate occurs as a white to yellowish white powder. It is freely soluble in water and acetic acid (100), soluble in methanol and ethanol (95), slightly soluble in ethanol (99.5) and sparingly soluble in acetonitrile. It is hygroscopic.
Structural formula (amino acids sequence): 5-oxo-Pro-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NH-CH₂-CH₃·CH₃COOH.
Chemical name: 5-Oxo-prolyl-histidyl-tryptophyl-seryl-tyrosyl-D-leucyl-leucyl-arginyl-N-ethyl-prolinamide monoacetate.
Molecular formula: C₅₉H₈₄N₁₆O₁₂ · C₂H₄O₂.
Molecular weight: 1269.45.
Enantone 1-Month DPS 3.75 mg: ENANTONE is a white lyophilizate supplied in a dual chamber pre-filled syringe as shown as follows: See Table 1.

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It consists of powder part and liquid part (1 ml vehicle for suspension). One ml of vehicle for suspension contains water for injection, and 50 mg of mannitol, 5 mg of carmellose sodium, and 1 mg of polysorbate 80 as inactive ingredients.
ENANTONE, when suspended with 1 ml of the attached vehicle for suspension, shows a pH value of 6.0 - 7.5 and an osmotic pressure ratio (relative to isotonic sodium chloride solution) of about 1.
Enantone 3-Month DPS 11.25 mg: White powder and clear, colourless solvent for suspension for injection.
One prefilled syringe contains leuprorelin acetate 11.25 mg.
Excipient with known effects: sodium.
Excipients/Inactive Ingredients: Powder: polylactic acid, mannitol.
Solvent: mannitol, sodium carmellose, polysorbate 80, water for injection.
Enantone 6-Month DPS 30 mg: Each dual chamber pre-filled syringe containing 352.9 mg sustained-release microcapsules and 1 ml suspension medium contains: 30.0 mg leuprorelin acetate, equivalent to 28.58 mg leuprorelin.
Excipients with known effect: one dual chamber pre-filled syringe contains 5.0 mg carmellose sodium.
Excipients/Inactive Ingredients: Sustained-release microcapsules: Poly (D,L-lactic acid) 270 mg, Mannitol (Ph. Eur.).
Suspension medium: Mannitol (Ph. Eur.), Carmellose sodium, Polysorbate 80, Acetic acid 99 % (to adjust the pH-value), Water for injections.

Enantone 1-Month DPS 3.75 mg: Pharmacology: Mechanism of Action: Repeated administration of either LH-RH in a massive dose or leuprorelin acetate, which is a highly potent LH-RH derivative, causes a transient pituitary-gonad system stimulating effect (acute effect) immediately after the first administration and then suppresses both the production and release of gonadotropin in the pituitary. It further suppresses the response of the ovary and testis to gonadotropin, resulting in a decrease in estradiol and testosterone producing action (chronic effect). The LH releasing activity of Leuprorelin Acetate is approximately equal to 100 times that of LH-RH, and its action of suppressing the pituitary-gonad function is stronger than that of LH-RH. Since Leuprorelin Acetate is a highly potent LH-RH derivative, its strong action of suppressing the pituitary-gonad function is attributed to its higher resistance to proteolytic enzymes and higher affinity for LH-RH receptors in comparison with LH-RH. Moreover, since ENANTONE is a sustained release preparation, it constantly releases Leuprorelin Acetate into the blood to effectively reduce the response of the ovary and testis, producing a highly favorable pituitary-gonad inhibitory action.
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.)

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As 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.)

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The 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.)

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Prostate 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.

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Pharmacokinetics: 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.

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Urinary 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.

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Uterine 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.)

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Prostate 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.)

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Urinary 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.)

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Urinary 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.)

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Toxicology: 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.)

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An 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.

Enantone 1-Month DPS 3.75 mg: Endometriosis; Decrease of myoma volume and/or amelioration of symptoms in uterine myoma with hypermenorrhea, hypogastralgia, low back pain, anemia, etc; Premenopausal breast cancer; Prostate cancer; Central precocious puberty.
Precautions for Indications: Uterine myoma: It should be noted that the treatment of uterine myoma with ENANTONE is not a radical treatment. Therefore, as a rule, this drug should be used as a means of providing conservative treatment until operation on patients requiring operation or providing premenopausal conservative treatment. For hypogastralgia and low back pain, the effect of this drug is not observed at the early period after administration. During such a period, therefore, appropriate symptomatic treatment should be given.
Premenopausal breast cancer: When starting treatment with ENANTONE, absence/presence of hormone receptor expression should be confirmed as a rule. When hormone receptor expression is confirmed to be negative, ENANTONE should not be used.
Enantone 3-Month DPS 11.25 mg: In male: Prostate cancer and its secondarisms.
In female: Genital and extragenital endometriosis (Phase I-IV); Breast cancer in pre and peri-menopausal women, where a hormone treatment is indicated; Uterine fibroids.
In children: Treatment of central precocious puberty (before age 9 in girls and before 10 years in boys).
Enantone 6-Month DPS 30 mg: ENANTONE 6 MONTH DPS is applied in male adults for treatment of the advanced hormone-dependent prostate carcinoma.
For the treatment of locally advanced hormone dependent prostate cancer; during and following radiation therapy.
For the treatment of localized hormone dependent prostate cancer in patients with intermediate- and high risk in combination with radiation therapy.

Enantone 1-Month DPS 3.75 mg: Endometriosis: Usually, for adults, 3.75 mg of Leuprorelin Acetate is subcutaneously administered once every 4 weeks. However, when the patient's weight is less than 50 kg, 1.88 mg may be used. The administration of this drug should be initiated on the first to fifth day after the start of menstrual period.
Uterine myoma: Usually, for adults, 1.88 mg of Leuprorelin Acetate is subcutaneously administered once every 4 weeks. However, for patients with heavy weight or those with markedly enlarged uterus, 3.75 mg is administered. The administration of this drug should be initiated on the first to fifth day after the start of menstrual period.
Prostate cancer and premenopausal breast cancer: Usually, for adults, 3.75 mg of Leuprorelin Acetate is subcutaneously administered once every 4 weeks.
Central precocious puberty: Usually, a dose of 30 μg/kg of Leuprorelin Acetate is subcutaneously administered once every 4 weeks. Depending upon the patient's condition, the dosage may be increased up to 180 μg/kg.
When using ENANTONE, this drug should be used after suspending it completely by transferring the whole quantity of the vehicle into the powder part, by pressing the plunger rod, with the injection needle held upward, with caution against foaming.
When ENANTONE is used, it becomes impossible to adjust the dosing quantity. Therefore, it should be used only when the patient requires the whole quantity at a time.
Precautions for Dosage and Administration: For all Indications: Since ENANTONE is a sustained release preparation with its action lasting 4 weeks, administration at an interval exceeding 4 weeks may lead to the recurrence of an increase in the serum level of gonadotropic hormone due to the pituitary-gonad system stimulating effect of this drug, resulting in a transient aggravation of the clinical condition. Therefore, the method of administering once every 4 weeks should be observed.
Endometriosis, Uterine Myoma: The incidence of adverse reactions generally tends to increase with an increase in dose. Thus, in setting the dose, careful attention should be paid to the body weight and the extent of enlargement of the uterus as shown previously. (See Pharmacology: Clinical Studies under Actions.)
Before starting treatment with ENANTONE, confirmation should be made that the patient is not pregnant. It is imperative the administration is initiated on the first to fifth day after the start of menstrual period. During the period of treatment with ENANTONE, the patient should be instructed to prevent conception with the use of a non-hormonal method.
A decrease in bone mass may occur owing to estrogen reducing effect of ENANTONE. Therefore, as a rule, this drug should not be administered to patients with endometriosis or uterine myoma for more than 6 months. (The safety of administration for more than 6 months has not been established.) When it is inevitable to administer this drug for a long period or to resume its administration, the drug should be carefully administered after the bone mass is examined as far as possible.
Premenopausal Breast Cancer: Before starting treatment, it should be confirmed that the patient is not pregnant. During the period of treatment with ENANTONE, the patient should be instructed to prevent conception with the use of a non-hormonal method.
A decrease in bone mass may occur owing to estrogen reducing effect of ENANTONE. Therefore, when this drug is administered for a long period, the drug should be carefully administered after bone mass is examined as far as possible.
Central Precocious Puberty: Caution should be exercised not to exceed the dose considered appropriate from the weight and symptoms, etc of the patient.
Enantone 3-Month DPS 11.25 mg: Dosage: Both in male and female the needed dosage is 11.25 mg of active principle (whole content of pre-filled syringe) to be administered once every 3 months.
The duration of the treatment of endometriosis is up to 6 months.
The duration of the treatment of uterine fibroids is up to 6 months.
Paediatric population: The treatment of children with leuprorelin acetate should be done under the general supervision of the paediatric endocrinologist.
The dosage regimen must be adapted individually.
The recommended initial dosage depends on body weight.
Children with body weight ≥20 kg: 1 ml (11.25 mg or the whole content of the prefilled syringe) once every 3 months as a single subcutaneous injection.
Children with body weight <20 kg: In these rare cases, the following dosage must be administered according to the clinical activity of the precocious puberty: 0.5 ml (5.63 mg or the half content of the prefilled syringe) once every 3 months as a single injection. The remainder of the suspension must be discarded. The child's weight gain should be monitored.
Depending to the activity of the central precocious puberty, it may be necessary to increase the dosage in the presence of inadequate suppression (clinical evidence, for example spotting or inadequate suppression of the gonadotropin in the GnRH test). The minimum effective dose to be administered every 3 months should therefore be determined using the GnRH test.
Sterile abscesses often occur at the injection site when leuprorelin acetate has been administered intramuscularly at higher dosages than recommended doses. Therefore, in such cases, the drug must be administered subcutaneously (see Precautions).
It is recommended that the lowest volumes possible for injections in children to decrease the problem associated with the intramuscular/subcutaneous injection.
The duration of the treatment depends on the clinical parameters at the beginning of or during the course of the treatment (prognosis of final height, rate of growth, bone age and/or bone age acceleration) and is decided by the paediatrician together with the guardian and, if applicable, the child being treated. Bone age should be monitored during treatment at 6-12 month intervals.
In girls over 12 years old with bone maturation and boys over 13 years old with bone maturation, treatment discontinuation should be considered taking into account clinical parameters.
In girls, pregnancy must be ruled out before treatment begins. The occurrence of pregnancy during treatment cannot usually be excluded. In such cases, the doctors should be contacted.
Notes: The dosing interval should be 90 ± 2 days to avoid the recurrence of precocious puberty symptoms.
Mode of administration: Enantone must be prepared, reconstituted and administered only by healthcare professionals familiar with these procedures. Before preparing the syringe, carefully wash the hands and wear protective gloves. Keep the syringe in an upright, vertical position during all preparation stages.
Screw the plunger into the end stopper until the stopper begins to turn.
The needle is free and covered with a regular cap. Do not touch the device around the needle.
Ensure that the needle is secure by screwing the needle cap clockwise. Do not over tighten.
Keeping the syringe upright, SLOWLY push the plunger until the middle stopper reaches the blue line in the centre of the syringe. NOTE: if the plunger is pushed too fast or beyond the blue line, some suspension may be lost out of the needle.
Gently tap the syringe on the palm of the hand while keeping the syringe upright to fully mix the particles and form a uniform suspension. The suspension will appear milky. NOTE: Avoid striking too hard to prevent the formation of bubbles.
If the particles adhere to the stopper, tap the syringe with the finger.
Remove the needle cap and advance the plunger to expel the air from the syringe.
At the time of injection, check the direction of the safety device (the black dot should point upwards).
Inject the contents of the syringe subcutaneously or intramuscularly like a normal injection.
AFTER INJECTION, remove the needle from the patient and immediately activate the safety device to cover the needle, pushing the wing upwards with a finger until it clicks, indicating that the device is fully extended and the needle covered.
Enantone 6-Month DPS 30 mg: Posology: 352.9 mg sustained-release microcapsules containing 30.0 mg leuprorelin acetate suspended in 1 ml suspension medium are administered subcutaneously (s.c.) once every six months.
ENANTONE 6 MONTH DPS can be used as neo-adjuvant or adjuvant therapy in combination with radiotherapy for locally advanced hormone dependent prostate cancer and for localized prostate cancer in patients with intermediate- and high risk.
Paediatric population: There are currently no data available for the use of ENANTONE 6 MONTH DPS in children.
Method of administration: ENANTONE 6 MONTH DPS should be prepared, reconstituted and administered only by healthcare professionals who are familiar with these procedures.
The suspension of ENANTONE 6 MONTH DPS should be prepared fresh each time before administration. (For instructions for the preparation of the dual chamber prefilled syringe before administration, see Special precautions for disposal under Cautions for Usage.)
ENANTONE 6 MONTH DPS is administered subcutaneously once every six months. The application interval should be 168 days to maximum 182 days (24 to 26 weeks).
The injection site should be changed every six months. The subcutaneous injection can be given in the abdominal skin, the buttocks, or the upper thigh, for example.
Generally, the treatment of advanced, hormone-sensitive prostate cancer with ENANTONE 6 MONTH DPS is a long-term treatment.
The treatment with a GnRH (Gonadotropin-Releasing-Hormone) analogous of patients which have a prostate carcinoma, can be continued after a castration resistance has been reached. The relevant guidelines have to be considered.
Clinical data have shown that an androgen withdrawal therapy with 3-year duration and following radiotherapy is preferable to a 6-month treatment of locally advanced hormone dependent carcinoma of the prostate (see also Pharmacology: Pharmacodynamics under Actions). In medical guidelines for patients (T3-T4) who receive radiotherapy an androgen withdrawal therapy with a treatment time of 2-3 years is recommended.
Combination of radiotherapy and 4 - 6 months androgen deprivation therapy with GnRH analogues is recommended for localized prostate cancer with intermediate risk, and for tumours with high-risk profile, a combination with 2 - 3 years androgen deprivation therapy is recommended.
According to animal experimental findings, it is essential to avoid accidental intra-arterial injection (thrombosis of small vessels distal to the administration site).

Enantone 3-Month DPS 11.25 mg: In the event of overdose, the patient must be carefully monitored and a symptomatic and support treatment must be established.
Enantone 6-Month DPS 30 mg: To date, no clinical symptoms of toxicity have been reported. In case of overdose, the patients should be closely monitored and receive symptomatic and supportive treatment.
Even when administered in daily doses of up to 20 mg for a period of two years, like applied in the first clinical studies, no new side effects or side effects different from those observed with a daily dose of 1 mg or with a dose of 30 mg administered every 6 months have been reported.

Enantone 1-Month DPS 3.75 mg: Endometriosis, Uterine Myoma, Central Precocious Puberty: Patients with a history of hypersensitivity to any of the ingredients of this drug or synthetic LH-RH or LH-RH derivatives.
Pregnant women or women having possibilities of being pregnant, or nursing mothers (see Use in Pregnancy & Lactation).
Patients with abnormal genital bleeding of indeterminable nature: There is a possibility of malignant disease.
Premenopausal Breast Cancer: Patients with a history of hypersensitivity to any of the ingredients of this drug or synthetic LH-RH or LH-RH derivatives.
Pregnant women or women having possibilities of being pregnant, or nursing mothers (see Use in Pregnancy & Lactation).
Prostate Cancer: Patients with a history of hypersensitivity to any of the ingredients of this drug or synthetic LH-RH or LH-RH derivatives.
Enantone 3-Month DPS 11.25 mg: Hypersensitivity to active substance or any of excipients listed in Description or to any other synthetic GnRH analogues or derivatives.
Pregnancy.
Breast-feeding.
Contraindicated in the presence of undiagnosed vaginal bleeding.
Enantone 6-Month DPS 30 mg: Hypersensitivity to leuprorelin or other synthetic GnRH analogues, polylactic acid or to any of the ingredients of the suspension medium listed in Description.
Demonstrated non-hormone-dependent carcinoma.
ENANTONE 6 MONTH DPS is not intended for the use in women and is generally contraindicated during pregnancy and lactation.

Enantone 1-Month DPS 3.75 mg: Careful Administration: ENANTONE should be administered with care in the following patients.
Endometriosis, Uterine Myoma, Premenopausal Breast Cancer: Patients with submucous myoma: Bleeding symptom may be aggravated. (See Important Precautions as follows.)
Prostate Cancer: Patients who have already had renal dysfunction due to spinal cord compression or ureteral obstruction or those who may be at a risk of developing such manifestations: There is a possibility that the symptoms of underlying disease are aggravated with the elevation of serum testosterone level in the early period after the first administration.
Important Precautions: Endometriosis: In administration of ENANTONE, care should be taken to differentiate a similar disease (malignant tumor, etc.) from endometriosis. If, during administration of ENANTONE, any growing phyma is found or no improvement is seen in the clinical symptom, the administration should be discontinued.
In the early period after the first administration of ENANTONE, a transient elevation of the serum level of estrogen may occur owing to the stimulating effect of ENANTONE, as a highly active LH-RH derivative, on the pituitary-gonad system, resulting in a transient aggravation of clinical condition. However, such an aggravation usually disappears in the course of continued administration.
Since a depressed state like climacteric disturbance may occur, the patient's condition should be closely observed. (See Clinically significant adverse reactions under Adverse Reactions.)
Uterine Myoma: In administration of ENANTONE, care should be taken to differentiate a similar disease (malignant tumor, etc.) from uterine myoma. If, during administration of ENANTONE, any growing phyma is found or no improvement is seen in the clinical symptom, the administration should be discontinued.
In administration of ENANTONE to patients with submucous myoma, bleeding symptom may worsen. Therefore, close observation should be made, and if any abnormality is observed, appropriate measures should be taken. In addition, the patients should be instructed to contact the attending physician in case of any aggravation of the bleeding symptom.
In the early period after the first administration of ENANTONE, a transient elevation of the serum level of estrogen may occur owing to the stimulating effect of ENANTONE, as a highly active LH-RH derivative, on the pituitary-gonad system, resulting in a transient aggravation of clinical condition. However, such an aggravation usually disappears in the course of continued administration.
Since a depressed state like climacteric disturbance may occur, the patient's condition should be closely observed. (See Clinically significant adverse reactions under Adverse Reactions.)
Premenopausal Breast Cancer: Since ENANTONE is an agent for endocrine therapy, use of this drug for premenopausal breast cancer should be limited to patients for whom treatment with ENANTONE is considered appropriate under the supervision of a physician who has adequate knowledge and experience in medication for cancer.
In the early period after the first administration of ENANTONE, a transient elevation of the serum level of estrogen may occur owing to the stimulating effect of ENANTONE, as a highly active LH-RH derivative, on the pituitary-gonad system, resulting in a transient aggravation of bone pain, etc. In such a case, symptomatic treatment should be given.
If antitumor effect is not obtained with ENANTONE and any progression of the tumor is observed, the administration should be discontinued.
Since a depressed state like climacteric disturbance may occur, the patient's condition should be closely observed. (See Clinically significant adverse reactions under Adverse Reactions.)
Prostate Cancer: Since ENANTONE is an agent for endocrine therapy, use of this drug for prostate cancer should be limited to patients for whom treatment with ENANTONE is considered appropriate under the supervision of a physician who has adequate knowledge and experience in medication for cancer.
In the early period after the first administration of ENANTONE, a transient elevation of the serum level of testosterone may occur owing to the stimulating effect of ENANTONE, as a highly active LH-RH derivative, on the pituitary-gonad system, resulting in a transient aggravation of bone pain, etc. In such a case, symptomatic treatment should be given. Since ureteral obstruction or spinal cord compression may occur, this drug should be carefully administered and close observation should be made during the first month after initiation of administration, and if any of such symptoms occurs, appropriate measures should be taken.
Central Precocious Puberty: In the early period after the first administration of ENANTONE, a transient elevation of the serum level of gonadotropic hormone may occur owing to the stimulating effect of ENANTONE, as a highly active LH-RH derivative, on the pituitary-gonad system, resulting in a transient aggravation of clinical condition. However, such an aggravation usually disappears in the course of continued administration.
During the treatment with ENANTONE, LH-RH test should be performed at regular intervals. When suppression of the action of LH and FSH in blood is not achieved, the administration of this drug should be discontinued.
Other Precautions: It has been reported that the benign pituitary adenoma was observed in rats in a study in which this drug was administered subcutaneously in doses of 0.8, 3.6 and 16 mg (as leuprorelin acetate)/kg at 4-week intervals for 1 year and another study in which an aqueous injectable solution of Leuprorelin Acetate was similarly administered in doses of 0.6, 1.5 and 4 mg/kg/day for 2 years.
Use in Children: Central Precocious Puberty: The safety of ENANTONE in prematures, newborns and nursing infants has not been established.
Enantone 3-Month DPS 11.25 mg: Epidemiological data have shown that inhibiting the production of an endogenous sex hormone that occurs during androgen or estrogen deprivation therapy (for example, in menopausal women) is associated with metabolic changes (for example, reduction of glucose tolerance or worsening of pre-existing diabetes) as well as an increased risk of cardiovascular diseases. However the prospective data did not confirm the link between GnRH analogues treatment and increased cardiovascular mortality. Patients at high risk of metabolic changes or syndromes or cardiovascular diseases must be adequately monitored. ENANTONE 3 MONTH DPS, may be associated with increased risk of diabetes and certain cardiovascular diseases (including heart attack, sudden cardiac death or stroke) in men receiving these medications for the treatment of prostate cancer.
Androgen deprivation therapy may lead to QT interval prolongation. In patients with a history of QT interval prolongation or with risk factors for QT interval prolongation, and in patients receiving concomitant drugs that may prolong the QT interval (see Interactions), before beginning the treatment with Enantone the physicians must evaluate the risk-benefit ratio of each medicinal product, including the possibility of Torsades de pointes.
Seizures have been reported in post-marketing report in patients receiving leuprorelin acetate and these events have been reported in both children and adults, with or without history of epilepsy, seizure disorders, or risk factors for seizures.
There is an increased risk of incident depression (which can be severe) in patients receiving GnRH agonists, such as leuprolide. Patients should be informed accordingly and treated appropriately if symptoms occur.
Idiopathic intracranial hypertension: Cases of idiopathic intracranial hypertension (pseudotumor cerebri) have been reported in patients taking leuprorelin. Patients should be warned of the signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, visual disturbances and tinnitus. In case of idiopathic intracranial hypertension, consideration should be given to discontinuing the administration of leuprorelin.
In Males: In the early stage of prostate cancer treatment initial phase with GnRH analogues, some cases of transitory worsening of the clinical symptomatology may occur, such as urinary tract obstruction and haematuria (as urinary symptoms) following a temporary increase in testosterone levels. In patients with compression of the spinal cord due to spinal cord metastasis, bone pain, weakness of the lower extremities and transitory paresthesia (as neurological symptoms) may occur (see Adverse Reactions). This warrants particularly careful medical supervision during the first few weeks of treatment for the patient with urinary tract obstruction and for those with vertebral metastasis. For the same reason, subjects who have warning signs of bone marrow compression should be carefully monitored at the beginning of treatment.
In the initial period of treatment, a transitory increase in acid phosphatase may be observed.
These manifestations are usually transitory and disappear in one or two weeks from the beginning of treatment.
It may be useful to periodically check for testosteronaemia, that should not exceed 1 ng/ml, PSA and acid phosphatase, which may transiently increase in the first weeks of treatment. The therapeutic response can be evaluated in the bone by means of scintigraphy and/or tomographic examination; prostate response will be assessed by ultrasound and/or tomography (as well as clinical tests and rectal examination).
In the event of prolonged androgenic deprivation, bilateral orchiectomy or administration of GnRH analogues, it may be worthwhile periodically verifying the bone densitometry values as it can produce a state of hypoandrogenism, which induces a reduction of the bone mineral density. In patients who present additional risk factors, this may lead to osteoporosis and an increased risk of bone fractures.
Cardiovascular illnesses: There have been reports of an increased risk of onset of myocardial infarct, sudden cardiac death and stroke associated with the use of GnRH agonists in men. On the basis of the probabilities reported, the risk seems low and must be assessed carefully on the basis of the cardiovascular risk factors at the time of the set-up of the treatment for patients with prostate cancer. The patients treated with GnRH agonists must be checked for symptoms and signs which suggest development of a cardiovascular illness and must be managed in accordance with current clinical practice.
In Females: In females with endometriosis and uterine fibroids, the occurrence of severe metrorrhagia during the treatment is considered abnormal and involves checking plasma oestradiol levels which, if less than 50 pg/ml, requires further investigation for the identification of any associated organic lesions. Prior to administering Lupron (leuprolide acetate), severe undiagnosed vaginal bleeding (see Contraindications) should be investigated, diagnosis must be confirmed and appropriate treatment given. In the event of severe vaginal bleeding during treatment, the patient should be closely monitored and appropriately treated if necessary.
Prior to treatment, women of childbearing potential should be carefully monitored to rule out pregnancy (see Contraindications). Non-hormonal contraception must be used during treatment. These methods should be maintained until the menstrual cycle is resumed.
In case of prolonged estrogen deprivation, bilateral ovariectomy, ovarian ablation or administration of GnRH, it may be useful to verify periodically the values of bone densitometry as it can produce a state of hypoestrogenism, that can also occur in patients who have undergone a bilateral ovariectomy or ovarian ablation, which causes a reduction of the bone mineral content. In patients who present additional risk factors, it may lead to osteoporosis and an increased risk of bone fractures.
Treatment duration should be limited to 6 months in the treatment of endometriosis and uterine fibroids because its use is associated with an increased risk of bone mineral loss. If retreatment is necessary, changes in bone parameters should be closely monitored. Initially, after the first administration of the drug, temporary worsening of clinical picture may occur. However, these symptoms disappear as the treatment continues.
Effects on Driving and Using Machines: Enantone may affect the ability to drive or operate machinery because it can cause visual disturbances and dizziness.
Use in Children: In Girls: In girls with precocious puberty, the gonadic stimulation may be responsible for small amounts of genital bleeding after the first injection which requires the addition of appropriate treatment only if these occur beyond the first month of treatment. Before starting treatment, girls of childbearing age must be tested to rule out pregnancy (see Contraindications).
In Infancy: The inhibition of pituitary gonadotropic activity manifests in both sexes as suppression of oestradiol secretion or testosterone secretion, with the lowering of LH peak and improvement in the growth age/bone age ratio.
Since the child is growing, it is recommended to regularly check that the oestradiol/testosterone levels remain low, especially if their weight is approaching 20 kg.
Before starting therapy, a precise diagnosis of idiopathic and/or neurogenic central precocious puberty is necessary. Therapy consists of long-term individually regulated treatment. Enantone should be carefully administered at regular quarterly intervals. Exceptional delay of the injection date of a few days (90 ± 2 days) does not affect the results of therapy.
In the case of sterile abscess of the injection site (mainly reported after injection of a higher than recommended dosage), the absorption of leuprorelin acetate from the depot may be decreased. In this case hormonal parameters (testosterone, oestradiol) should be checked at 2-week intervals (see Dosage & Administration).
In patients with progressive brain tumours, caution should be exercised if the risk from a clinical point of view is substantially greater than the benefits.
Bleeding and vaginal discharge after the first injection may indicate suspending hormone therapy in girls. Vaginal bleeding lasting beyond the first/second month of treatment must be investigated.
Bone mineral density (BMD) may decrease during central precocious puberty therapy with GnRH agonists. However, after treatment discontinuation, subsequent maturation of bone mass is preserved and the peak growth of bone mass in late adolescence does not appear to be affected by treatment.
Slippage of the femoral epiphysis may occur after stopping GnRH treatment. The suggested theory is that low oestrogen concentrations during treatment with GnRH agonists weaken the epiphyseal plate. Increasing the rate of growth after stopping treatment results in a reduction in the cutting force required for the dislocation of the epiphysis.
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, so it is essentially "sodium free".
Enantone 6-Month DPS 30 mg: Patients with hypertension should be monitored closely.
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.
After surgical castration, treatment with ENANTONE 6 MONTH DPS does not lead to further reduction of testosterone levels.
Administration of ENANTONE 6 MONTH DPS leads to an initial short-term increase in the serum level of testosterone, potentially resulting in a transient exacerbation of certain disease symptoms. Patients with potential neurological complications, spinal metastases, or urinary tract obstruction should be monitored closely during the first few weeks of treatment.
In the initial phase of therapy the adjuvant administration of a suitable anti-androgen is to be considered to alleviate the symptoms potentially associated with the initial increase in testosterone levels and to attenuate the exacerbated clinical symptoms.
The success of the treatment should be monitored regularly (particularly in the presence of signs of progression despite adequate treatment) by means of clinical examinations (rectal palpation of the prostate gland, ultrasound, bone scan, computed tomography) and investigations of phosphates and the prostate-specific antigen (PSA) as well as serum testosterone.
A long-term androgen deprivation therapy with GnRH analogues or orchiectomy is associated with an increased risk of bone demineralisation. In patients with high risk it may lead to osteoporosis and increased risk for bone fracture.
Metabolic modification and cardiovascular risk: Epidemiological data have shown that the inhibition of endogenic sexual hormone production such as a gonadotropin deprivation (e.g., during menopause) during therapy with GnRH analogues results in a metabolic change (reduction in glucose tolerance or aggravation of pre-existing diabetes mellitus) and that there can be an increased risk for cardiovascular diseases (see Adverse Reactions). However, prospective data does not confirm a correlation between the treatment with GnRH analogous and an increased cardiovascular mortality. An appropriate monitoring of diabetic patients and patients with increased risk of metabolic or cardiovascular disorders treated with ENANTONE 6 MONTH DPS is recommended.
Androgen deprivation therapy may prolong the QT interval. In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see Interactions) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating ENANTONE 6 MONTH DPS.
After the launch of leuprorelin acetate seizures were monitored and reported in children and adults with or without a history of epilepsy, seizures or risk factors for seizures.
The use of ENANTONE 6 MONTH DPS can lead to positive results in doping tests.
ENANTONE 6 MONTH DPS contains less than 1 mmol sodium (23 mg) per one dual chamber prefilled syringe.
Idiopathic intracranial hypertension: Idiopathic, intracranial hypertension (pseudotumor cerebri) was reported in patients receiving leuprorelin. The patients should be informed of signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, visual disturbance, and tinnitus. Discontinuation of leuprorelin should be considered if idiopathic intracranial hypertension occurs.
Abuse and dependence: The risk of dependence to leuprorelin acetate is very low, as only medical professions perform the application. Leuprorelin acetate abuse would only suppress endogenic production.
Effects on ability to drive and use machines: In view of the tiredness that may occur in a few patients especially at the start of treatment, which can also be caused by the underlying tumour, this medicinal product, even when used as directed, may alter reactivity to such an extent that the ability to drive or to operate machines is impaired. This applies even more in combination with alcohol.

Enantone 1-Month DPS 3.75 mg: Endometriosis, Uterine Myoma, Premenopausal Breast Cancer, Central Precocious Puberty: ENANTONE should not be administered to pregnant women, women having possibilities of being pregnant, or nursing mothers. Abortion due to LH-RH derivatives has been reported. In animal studies of this drug, increased fetal death rate and low fetal body weight were observed (in rats and rabbits), and an increasing tendency for abnormal formation of fetal skeleton was observed (in rabbits). The transfer of Leuprorelin Acetate to mother's milk was also observed in rats.
Enantone 3-Month DPS 11.25 mg: Pregnancy: Enantone must not be administered during pregnancy (see Contraindications). Women of childbearing potential must use non-hormonal contraceptive measures during the treatment and until the menstrual cycle is resumed. Prior to treatment, women of childbearing potential should be carefully monitored to rule out an ongoing pregnancy.
Breastfeeding: Enantone should not be used during breastfeeding (see Contraindications).
Enantone 6-Month DPS 30 mg: ENANTONE 6 MONTH DPS is not intended for the use in women and is generally contraindicated during pregnancy and lactation.
Fertility in men: Clinical and pharmacological studies in men showed that the depression of fertility was completely reversible 24 weeks at the latest after discontinuation of continuous leuprorelin acetate application.

Enantone 1-Month DPS 3.75 mg: The following table shows the incidence of adverse reactions, including abnormalities in laboratory data, according to the indicated diseases and phase of investigation. (See Table 7.)

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The adverse reactions listed as follows have been observed in the previously mentioned investigations, spontaneous reports, etc.
Since ENANTONE is a sustained release preparation, the patient's condition should be observed while the effect of this drug lasts after the final dosing.
Clinically significant adverse reactions: For all indications: Since interstitial pneumonia, accompanied by fever, coughing, dyspnea, abnormal chest X-ray, etc. may occur (< 0.1%), the patient's condition should be closely observed. If any abnormality is observed, appropriate measures, such as treatment with adrenal cortical hormones, should be taken.
Since anaphylaxis may occur (< 0.1%), careful inquiry should be made, and close observation should be made after the administration of ENANTONE. If any abnormality is observed, appropriate measures should be taken.
Hepatic dysfunction or jaundice, with increased AST (GOT), ALT (GPT) etc., may occur (frequency unknown). Therefore, close observation should be made, and if any abnormality is observed, appropriate measures should be taken.
Development or aggravation of diabetes may occur (frequency unknown). If any abnormality is observed, appropriate measures should be taken.
Pituitary apoplexy has been reported in patients with pituitary adenoma (frequency unknown). Therefore, if headache, vision impairment, visual field disorder, etc. are observed immediately after the first dose of ENANTONE, appropriate measures, such as surgical treatment, should be taken after conducting examination.
Thromboembolic event, such as myocardial infarction, cerebral infarction, venous thrombosis, pulmonary embolism, may occur (frequency unknown). Therefore, close observation should be made, and if any abnormality is observed, appropriate measures, such as discontinuation of administration, should be taken.
Endometriosis, Uterine Myoma, Premenopausal Breast Cancer: Since a depressed state like climacteric disturbance resulting from estrogen reducing effect of ENANTONE may occur (0.1% - < 5%), the patient's condition should be closely observed.
Prostate cancer: Since a depressed state may occur (< 0.1%), the patient's condition should be closely observed.
Elevation of serum testosterone level due to the stimulating effect of ENANTONE on the pituitary-gonad system may bring about a transient aggravation of bone pain, ureteral obstruction or spinal cord compression (≥ 5%). If any of such symptoms occurs, appropriate measures, such as pertinent symptomatic treatment, should be taken.
Since cardiac failure may occur (0.1 - < 5%), close observation should be made. If any abnormality is observed, appropriate measures, such as discontinuation of administration, should be taken.
Clinically significant adverse reactions: Endometriosis, uterine myoma, premenopausal breast cancer, central precocious puberty: See Table 8.

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Prostate Cancer: See Table 9.

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Enantone 3-Month DPS 11.25 mg: Undesirable effects are mainly due to the specific pharmacological action of the medicinal product, that is, the endocrine changes caused by the product (suppression of testosterone secretion in men and menopausal similar to hypoestrogenism in women).
The following undesirable effects are based on the clinical trials experience and post-marketing experience. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), not known (the frequency cannot be defined on the basis of the available data).
All patient populations: See Table 10.

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All adult populations: See Table 11.

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Adult women: The most recurrent undesirable effects are associated with hypoestrogenism. Oestrogen levels return to normal when treatment is stopped. The state of hypoestrogenism leads to a slight reduction of bone density during the treatment, which is sometimes not reversible (see Precautions). (See Tables 12, 13 and 14.)

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Vaginal haemorrhage may occur during the therapy as a result of acute degeneration of the submucosal fibroids (see Precautions).
Adult men: In the early stage of therapy there is a short-term increase in sex hormone levels ("Flare-up" phenomenon). Adverse events that may occur particularly at the beginning of treatment include urinary tract obstruction (as urinary symptoms); bone pain, weakness in the lower extremities, and paraesthesia (as neurological symptoms) may also occur in patients with compression of the spinal column (see Precautions). (See Table 15.)

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Paediatric population: In the early stage of therapy there is a short-term increase in sex hormone levels ("Flare-up" phenomenon) followed by a drop to the values of the prepuberal range. Adverse events, particularly at the start of treatment, may occur due to this pharmacological effect. (See Table 16.)

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Enantone 6-Month DPS 30 mg: Administration of ENANTONE 6 MONTH DPS regularly leads to an initial short-term increase in the serum level of testosterone (Flare phenomenon), potentially resulting in a transient exacerbation of certain disease symptoms. The treatment may lead to onset or increase of urinary tract obstruction and its consequences (e.g., haematuria). In patients with bone metastasis bone pain may occur. In patients with bone marrow suppression, muscle weakness, myasthenia of the leg, and lymphedema may occur. This exacerbation of symptoms usually subsides spontaneously on continued therapy with ENANTONE 6 MONTH DPS, without leading to the need to discontinue ENANTONE 6 MONTH DPS.
Due to suppression of sex hormones adverse reactions may be observed. Frequencies of adverse reactions are defined in the following categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). (See Table 17.)

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Note: Response to ENANTONE 6 MONTH DPS can be verified by monitoring serum testosterone, acid phosphatase, and PSA levels. Specifically, there occurs an initial temporary rise in the testosterone level at the start of treatment, followed by a decrease within a period of two weeks. After two to four weeks testosterone levels are reached similar to those observed after bilateral orchiectomy and persisting in the castration range throughout the entire treatment period.
In the initial phase of therapy with ENANTONE 6 MONTH DPS, a transient rise in acid phosphatase may occur. However, acid phosphatase values usually return to normal or near-normal within a few weeks.
In case of very common occurring tip abscesses testosterone levels should be monitored, as a possible elevation of testosterone may result from inadequate leuprorelin absorption from the depot.

Enantone 1-Month DPS 3.75 mg: Endometriosis, Uterine myoma: Precautions for coadministration: ENANTONE should be administered with care when coadministered with the following drugs. (See Table 18.)

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Enantone 3-Month DPS 11.25 mg: Since androgenic deprivation treatment may prolong the QT interval, the concomitant use of Enantone with medicinal products known to prolong the QT interval or associated with Torsades de Pointes, such as class IA antiarrhythmic medicinal products (e.g. quinidine, disopyramide) or class III ones (e.g. amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin and antipsychotics should be carefully investigated (see Precautions).
Enantone 6-Month DPS 30 mg: Since androgen deprivation treatment may prolong the QT interval, the concomitant use of ENANTONE 6 MONTH DPS with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see Precautions).

Enantone 1-Month DPS 3.75 mg: Precautions Concerning Use: Route of Administration: ENANTONE should be used only by the subcutaneous route. Intravenous injection of ENANTONE may induce thrombosis.
Method of Administration: A needle for injection of 25 gauge or not finer should be used.
For subcutaneous injection, the following cautions should be exercised.
1. The site for subcutaneous injection should be the brachial, abdominal or gluteal region.
2. The injection site should be changed each time. The repeated injection should not be given at the same site.
3. The check should be made to see that the needle is not piecing a blood vessel.
4. The patients should be instructed not to massage the injection site.
Preparation: The injectable solution should be prepared at the time of use and be used immediately after suspending.
If any sedimentation is noticed in the suspension of vial product, such suspension should be used after swirling gently, avoiding formation of bubbles, to re-suspend the particles uniformly.
Mode of administration: Screw the plunger rod into the end stopper until the end stopper begins to turn.
Check if the needle is tight by twisting the needle cap clockwise. Do not overtighten.
While holding the syringe upright, depress the plunger SLOWLY by pushing the plunger rod 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.
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.
If the microspheres adhere to the stopper, tap the syringe by the finger.
Remove the needle cap and advance the plunger to expel the air from the syringe.
At the time of injection, check the direction of the safety device (with round mark face up).
Inject the entire contents of the syringe subcutaneously as it would be for a normal injection.
AFTER INJECTION, withdraw the needle from the patient and immediately activate the safety device to cover the needle by pushing the arrow forward with a finger, until a CLICK is heard and the device is fully extended and the needle is covered.
Enantone 3-Month DPS 11.25 mg: Special precautions for handling and disposal: Any unused medicinal product or waste should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.
Enantone 6-Month DPS 30 mg: Special precautions for disposal and other instructions for handling: Prepare the injectable suspension only at the time of administration, and use immediately. Any unused medicinal product or waste material should be disposed in accordance with local requirements. Do not dispose medicinal products into the drain water.
Instructions for the preparation of the ENANTONE 6 MONTH DPS suspension: 1) Insert plunger rod by turning it in.
2) Hold dual chamber syringe vertically with the top (cannula) upright.
3) By means of the plunger rod push the stopper system carefully to reach the blue marking. In this way the vehicle is enabled to enter the front chamber via the bypass.
4) At this stage the plunger rod must not be pulled back any more.
5) Continue to hold the dual chamber syringe vertically with the injection needle upright and move it to right and left to shake it or knock it at the hand joint to produce a milky suspension of the microcapsules in the vehicle. (Do not hold the syringe horizontally or downwards because in that case vehicle might escape.)
6) Prior to injection remove the needle sheath by pulling it off, not by turning it off. Subsequently, carefully remove the remaining air above the suspension by pressing it off the syringe.
The syringe is now ready for injection.
An aspiration is possible with subcutaneously applied cannula.
Handling after injection: 7) Slide the safety device of the needle according the arrow marks forward until it audibly/noticeable engages.
8) Dispose syringe properly.
Incompatibilities: Not applicable. ENANTONE 6 MONTH DPS should not be injected at the same time as other medicinal products.

Enantone 3-Month DPS 11.25 mg: Do not refrigerate or freeze.
Store in the original container in order to protect the medicinal product from light.
Shelf life: Once reconstituted, the suspension has to be administered immediately.
Enantone 6-Month DPS 30 mg: Shelf-life: In case a discoloration of the sustained-release microcapsules occurs and/or turbidity of suspension medium is observed before preparation of the suspension, the dual-chamber prefilled syringe must not be used. Preparation for injection results in an opaque suspension.
Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C. From a microbiological point of view, the product should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
Before injection, the suspension has to be shaken again.

Cancer Hormone Therapy / Trophic Hormones & Related Synthetic Drugs

L02AE02 - leuprorelin ; Belongs to the class of gonadotropin releasing hormone analogues. Used in endocrine therapy.

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