Enantone L.P.

ENANTONE L.P. 3.75 mg/11.25 mg/30 mg is a sterile, lyophilized, white, odorless PLA (poly DL-lactic acid) microsphere powder for subcutaneous or intramuscular injection after reconstitution with the sterile vehicle to provide a 1 month (3.75 mg)/3 month (11.25 mg)/6 month (30 mg) depot injection.
For Dual Chamber Pre-filled Syringe (DPS) with a needle (25 G for 3.75 mg/23 G for 11.25 mg and 30 mg): Each DPS contains 3.75 mg/11.25 mg/30 mg leuprorelin acetate, respectively, and 1 ml sterile vehicle. The DPS is a dual chamber syringe with white powder in the front chamber and clear, colorless fluid in the rear chamber.
Excipients/Inactive Ingredients: 3.75 mg: PLGA-W [CoPoly (DL-Lactic acid/Glycolic acid) 75:25 mol%], Mannitol, Methylene Chloride, Polyvinyl Alcohol, Water for injection, Carboxymethylcellulose Sodium and Polysorbate 80.
11.25 mg: Polylactic acid, Mannitol, Methylene Chloride, Polyvinyl Alcohol, Carboxymethylcellulose Sodium, Polysorbate 80 and Water for injection.
30 mg: PLA(6M), Mannitol, Water for injections, Methylene Chloride, Polyvinyl Alcohol, Glacial Acetic Acid, CMC-Na, Polysorbate 80 and Nitrogen.

Pharmacotherapeutic group: Antineoplastics - Endocrine Therapy - GnRH analogues. ATC code: L02AE02.
Pharmacology: Pharmacodynamics: 3.75 mg/11.25 mg: Enantone L.P. 3.75 mg/11.25 mg contains leuprorelin acetate, a synthetic nonapeptide analogue of naturally occurring gonadotrophin-releasing hormone (GnRH) which possesses greater potency than the natural hormone. Leuprorelin acetate is a peptide and therefore, unrelated to the steroids. Chronic administration results in an inhibition of gonadotrophin production and subsequent suppression of ovarian and testicular steroid secretion. This effect is reversible on discontinuation of therapy.
Administration of leuprorelin acetate results in an initial increase in circulating levels of gonadotrophins which leads to a transient increase in gonadal steroid levels in both men and women. Continued administration of leuprorelin acetate results in a decrease in gonadotrophin and sex steroid levels. In men, serum testosterone levels, initially raised in response to early luteinising hormone (LH) release, fall to castrate levels in about 2-4 weeks.
Leuprorelin acetate is inactive when given orally.
In children: Reversible suppression of pituitary gonadotropin release occurs, with a subsequent decrease in oestradiol (E2) or testosterone levels to values in the pre-pubertal range.
Initial gonadal stimulation (flare-up) may cause vaginal bleeding in girls who are already post-menarchal at start of treatment. Withdrawal bleeding may occur at the start of treatment. The bleeding normally stops as treatment continues.
The following therapeutic effects can be demonstrated: Suppression of basal and stimulated gonadotropin levels to pre-pubertal levels; Suppression of prematurely increased sexual hormone levels to pre-pubertal levels and arrest of premature menstruation; Arrest/involution of somatic pubertal development (Tanner stages); Improvement/normalisation of the ratio of chronological age to bone age; Prevention of progressive bone age acceleration; Decrease of growth velocity and its normalization; Increase in final height.
Treatment result is the suppression of the pathologically, prematurely activated hypothalamic-pituitary-gonadal axis according to pre-pubertal age.
In a long-term clinical trial in children treated with leuprorelin at doses up to 15 mg monthly for >4 years resumption of pubertal progression were observed after cessation of treatment. Follow up of 20 female subjects to adulthood showed normal menstrual cycles in 80% and 12 pregnancies in 7 of the 20 subjects including multiple pregnancies for 4 subjects.
30 mg: Leuprorelin acetate, the active ingredient in ENANTONE L.P. 30 mg, is a synthetic analogue of the naturally occurring hypothalamic releasing factor, LHRH, which works to control the release of 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 LHRH released from the hypothalamus in a pulsatile mode, leuprorelin acetate, also known as an LHRH agonist, works to block the LHRH 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 LHRH 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.
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 L.P. 30 mg results in the inhibition of gonadotropin release after an initial stimulatory effect.
In the man the subcutaneous administration of ENANTONE L.P. 30 mg 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 L.P. 30 mg 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 L.P. 30 mg, 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 Studies: 3.75 mg/11.25 mg: Prostate cancer: A randomised, open-label, comparative multi-centre study was performed to compare the efficacy and safety of the 3.75 mg and 11.25 mg depots of leuprorelin. 48% of patients included had locally advanced disease (T3N0M0), 52% of patients had metastatic disease. Mean serum testosterone level fell below the threshold for chemical castration (0.5 ng/ml) at one month of treatment, continuing to decrease thereafter and stabilising at a value below the castration threshold. The decline in serum PSA mirrored that of serum testosterone in both groups.
In an open, prospective clinical trial involving 205 patients receiving 3.75 mg leuprorelin on a monthly basis as treatment for metastatic prostate cancer, the long-term efficacy and safety of leuprorelin was assessed. Testosterone levels were maintained below the castrate threshold over the 63-month follow up period. Median survival time exceeded 42.5 months for those receiving monotherapy and 30.9 months for those receiving leuprorelin in combination with anti-androgens (this difference relating to baseline differences between groups).
In a meta-analysis involving primarily patients with metastatic disease, no statistically significant difference in survival was found for patients treated with GnRH analogues compared with patients treated with orchidectomy.
In another randomised, open-label, multi-centre comparative trial, in prostate cancer patients leuprorelin in combination with flutamide has been shown to significantly improve disease-free survival and overall survival when used as an adjuvant therapy to radiotherapy in 88 patients with high-risk localised (T1-T2 and PSA of at least 10 ng/mL or a Gleason score of at least 7), or locally advanced (T3-T4) prostate cancer. The optimum duration of adjuvant therapy has not been established. This US study used a higher dose of leuprorelin (7.5 mg/month) which is therapeutically equivalent to the European licensed dose.
The use of a GnRH agonist may be considered after prostatectomy in selected patients considered at high risk of disease progression. There are no disease-free survival data or survival data with leuprorelin in this setting.
11.25 mg: Premenopausal breast cancer: The following table shows the antitumor effect (the effectiveness rate) and the inhibition rate of serum estradiol concentration at the menopausal level observed in a clinical study in which 11.25 mg as Leuprorelin Acetate was subcutaneously administered to premenopausal breast cancer patients once every 12 weeks (concomitantly with tamoxifen citrate 20 mg/day). (See Table 1.)

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The recurrence-free survival rate in the clinical studies in which 11.25 mg as Leuprorelin Acetate was administered up to 96 weeks to 70 of the previously mentioned patients in status of post (premenopausal breast cancer) surgery was 93.5% (two-sided 95% confidence interval: 87.23 to 99.74%).
In a randomized controlled, non-inferiority design study conducted in Germany and the Ukraine in which Leuprorelin Acetate 11.25 mg at 3-month intervals or cyclophosphamide, methotrexate, fluorouracil (CMF) therapy was given to pre- and peri-menopausal women with breast cancer (T1-3, N+M0), positive estrogen receptor status (ER+) and curative approach of surgery within six weeks prior to enrolment progression-free survival rates were shown as follows. (See Table 2.)

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Pharmacokinetics: 3.75 mg: Studies show that single intramuscular or subcutaneous doses of leuprorelin acetate over the dose range 3.75 to 15 mg results in detectable levels of leuprorelin acetate for more than 28 days, good bioavailability, a consistent and predictable pharmacokinetic profile, and biological efficacy at plasma levels of less than 0.5 ng/ml. The pharmacokinetic profile is similar to that seen in animal studies using the compound, with an initial high level of drug released from the microcapsules during reconstitution and injection followed by a plateau over a 2-3 week period before levels gradually become undetectable. There appears to be no significant difference between the routes of administration (im vs sc) in biological effectiveness or pharmacokinetics.
The metabolism, distribution and excretion of leuprorelin acetate in humans have not been fully determined.
Children with Central Precocious Puberty (CPP): Following a single subcutaneous administration of leuprorelin acetate 1 month depot at a dosage of 30 mcg/kg body-weight, peak serum levels of 7.81 ± 3.59 ng/mL were attained at about 1 hour after administration. Serum levels declined rapidly to 0.15 ± 0.06 ng/mL by day 1 after administration and remained below 0.07 ng/mL from day 3 for 4 weeks (Figure 1). The AUC 0-672 was 105.78 ± 52.40 ng.hr/mL. (See Figure 1.)

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11.25 mg: Leuprorelin acetate is well absorbed after subcutaneous injection. It binds to the luteinising hormone-releasing hormone (LHRH) receptors and is rapidly degraded. An initially high plasma level of leuprorelin acetate peaks at around 3 hours after Enantone L.P. 11.25 mg injection, followed by a decrease to maintenance levels in 7 to 14 days. Enantone L.P. 11.25 mg provides continuous plasma levels for up to 117 days resulting in suppression of testosterone to below castration level within 4 weeks of the first injection in the majority of patients.
The metabolism, distribution and excretion of leuprorelin acetate in humans have not been fully determined.
In children: Figure 2 presents the leuprorelin serum levels in children during the first 6 months of treatment following s.c. administration of leuprorelin acetate 3-month depot (two injections).
From the first injection, the leuprorelin serum levels increase reaching maximal serum levels at month 4 (294.79 pg/ml ± 105.42) and slightly decrease until month 6 (229.02 pg/ml ± 103.33). (See Figure 2.)

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Premenopausal breast cancer: When 11.25 mg, as leuprorelin acetate, was administered subcutaneously to patients (in status of post surgery) with premenopausal breast cancer two times at 12-week intervals (concomitantly with tamoxifen citrate 20 mg/day), the blood concentration (the unchanged compound and its metabolite M-I) was as shown as follows. The blood concentrations of leuprorelin including its metabolite M1 attained steady state at week 16 after administration, and remained at approximately 0.2 ng/mL up to week 24. (See Figure 3.)

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30 mg: The active ingredient leuprorelin acetate is continuously released from the lactic acid polymer for a period of 6 months after injection of the ENANTONE L.P. 30 mg depot suspension. The carrier polymer is absorbed over time in a similar fashion to surgical suture material.
After single s.c. injection of ENANTONE L.P. 30 mg serum levels of leuprorelin rise quickly with a subsequent decrease to a plateau within a few days. Within two 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. Fig. 4 shows the course of leuprorelin levels after a single administration of ENANTONE L.P. 30 mg.
An initial re-increase of testosterone levels was observed in median after approx. 200 days in case no subsequent injection was administered. (See Figure 4.)

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The distribution volume of leuprorelin is 36 l in men; total clearance is 139.6 ml/min (measured under treatment with Enantone Monthly Depot).
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.
In patients with impaired renal function, higher leuprorelin serum levels were measured in some cases whereas in patients with hepatic dysfunction lower values were found. However, this observation appears to be of no clinical relevance.
Toxicology: Preclinical safety data: 3.75 mg/11.25 mg: Animal studies have shown that leuprorelin acetate has a high acute safety factor. No major overt toxicological problems have been seen during repeated administration. Whilst the development of pituitary adenomas has been noted in chronic toxicity studies at high doses in some animal species, this has not been observed in long-term clinical studies. No evidence of mutagenicity or teratogenicity has been shown. Animal reproductive studies showed increased foetal mortality and decreased foetal weights reflecting the pharmacological effects of this GnRH agonist.
30 mg: 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 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.

3.75 mg & 11.25 mg: Prostate cancer: Metastatic prostate cancer; Locally advanced prostate cancer, as an alternative to surgical castration; As an adjuvant treatment to radiotherapy in patients with high-risk localized or locally advanced prostate cancer; As an adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression.
Endometriosis at genital and extragenital localization (From stage I to stage IV).
Premenopausal breast cancer.
3.75 mg: Uterine Fibroids (Leiomyomata); Central precocious puberty (CPP).
11.25 mg: Symptomatic laparoscopically confirmed endometriosis, when suppression of ovarian hormone production is indicated, provided the disease does not primarily require surgery.
Preoperative flattening of the endometrium before planned operative hysteroscopic intervention, e.g. endometrium ablation or resection.
Symptomatic Uterine Fibroids (Leiomyomata), when suppression of ovarian hormone production is indicated, as a preoperative measure for the volume reduction of individual fibroids in fibroid nucleation or hysterectomy.
Treatment of central precocious puberty (girls under 9 years of age, boys under 10 years of age).
30 mg: Advanced Prostate Cancer.

3.75 mg/11.25 mg: Treatment with Prostate cancer: After reconstitution, 3.75 mg/11.25 mg of leuprorelin acetate (ENANTONE L.P. 3.75 mg/11.25 mg) is administered once a month (for 3.75 mg) and ONCE EVERY THREE MONTHS (for 11.25 mg) as a single subcutaneous or intramuscular injection.
The majority of patients will respond to a 3.75 mg/11.25 mg dose. ENANTONE therapy should not be discontinued when remission or improvement occurs. Response to ENANTONE L.P. 3.75 mg/11.25 mg therapy may be monitored by clinical parameters and by measuring serum levels of testosterone and acid phosphatase (for 3.75 mg) and prostate-specific antigen (PSA) serum levels (for 11.25 mg). Clinical studies have shown that testosterone levels increased during the first 4 days of treatment in the majority of non-orchidectomised patients. They then decreased and reached castrate levels by 2-4 weeks. Once attained, castrate levels were maintained as long as drug therapy continued. Transient increases in acid phosphatase levels sometimes occur early in the treatment period but usually return to normal or near normal values by the 4^th week of treatment.
If a patient's response appears to be sub-optimal, then it would be advisable to confirm that serum testosterone levels have reached or are remaining at castrate levels (for 11.25 mg only).
Elderly men: as for adults (for 11.25 mg only).
Treatment with Endometriosis, Uterine Fibroids and Premenopausal breast cancer: Endometriosis: Usually, for adults, 3.75 mg/11.25 mg of leuprorelin acetate (ENANTONE L.P. 3.75 mg/11.25 mg) is subcutaneously or intramuscularly administered once a month (for 3.75 mg) and ONCE EVERY THREE MONTHS (for 11.25 mg) after reconstitution. However, when the patient's weight is less than 50 kg, 1.88 mg preparation (ENANTONE L.P. 1.88 mg) may be used. Treatment should be started during the first five days of the menstrual cycle.
Monotherapy: ENANTONE L.P. 3.75 mg/11.25 mg is indicated for management of endometriosis, including pain relief and reduction of endometriosis lesions, for up to six months.
Combination therapy: In two clinical studies, 3.75 mg leuprorelin was administered monthly for a period of 12 months with concurrent hormonal replacement therapy (norethindrone acetate 5 mg daily) and calcium supplementation.
These studies demonstrated that concurrent hormonal therapy (norethindrone acetate 5 mg daily) was effective in significantly reducing the loss of bone mineral density loss that occurs with leuprorelin treatment, without comprising the efficacy of leuprorelin in relieving symptoms of endometriosis.
To flatten the endometrium before planned hysteroscopic operative interventions, an injection of ENANTONE L.P. 11.25 mg is administered s.c. or i.m. The success of treatment can be evaluated ultrasonically by measuring the endometrial thickness.
Uterine Fibroids: Usually, for adults, 1.88 mg of leuprorelin acetate (ENANTONE L.P. 1.88 mg) is subcutaneously or intramuscularly administered once a month. However, for patients with heavy weight or those with markedly enlarged uterus, 3.75 mg/11.25 mg (ENANTONE L.P. 3.75 mg/11.25 mg) is administered once a month (for 3.75 mg) and ONCE EVERY THREE MONTHS (for 11.25 mg) The administration of this drug should be initiated on the first to fifth day after the start of menstrual period.
3.75 mg: Recommended duration of therapy with ENANTONE L.P. 3.75 mg is up to 3 months. The symptoms associated with uterine fibroids will recur following discontinuation of therapy. If additional treatment with ENANTONE L.P. 3.75 mg is contemplated, bone density should be assessed prior to initiation of therapy to ensure that values are within normal limits.
11.25 mg: The duration of administration should be restricted to a period of 6 months. Repeated treatments should be carried out only after careful consideration of the risks and benefits by the treating physicians. This includes the measurement of bone density before the start of any treatment.
ENANTONE L.P. 11.25 mg concomitantly with iron therapy is indicated for the preoperative hematologic improvement of patients with anemia caused by uterine fibroids. The clinician may wish to consider a one-month trial period on iron alone in as much as some of the patients will respond to iron alone.
Premenopausal breast cancer: After reconstitution, 3.75 mg of leuprorelin acetate (ENANTONE L.P. 3.75 mg) is administered once a month as a single subcutaneous or intramuscular injection. Bone density should be assessed prior to initiation of therapy and during therapy to ensure that values are within normal limits.
Usually, for adults, 11.25 mg of Leuprorelin Acetate is subcutaneously or intramuscular administered once every 12 weeks (ONCE EVERY THREE MONTHS).
3.75 mg: Treatment with central precocious puberty: Administer 90-400 μg/kg of leuprorelin acetate subcutaneously or intramuscularly once a month. The dose may be adjusted according to the patient's response.
11.25 mg: Paediatric population: The treatment of children with leuprorelin acetate should be under the overall supervision of the paediatric endocrinologist.
The dosing scheme needs to be adapted individually.
11.25 mg of Leuprorelin Acetate is subcutaneously or intramuscularly administered once every 12 weeks (ONCE EVERY THREE MONTHS).
The duration of treatment depends on the clinical parameters at the start of treatment or during the course of treatment (final height prognosis, growth velocity, bone age and/or bone age acceleration) and is decided by the treating paediatrician together with the legal guardian and, if appropriate, the treated child. The bone age should be monitored during treatment at 6-12 month intervals.
In girls with bone maturation of older than 12 years and boys with bone maturation of older than 13 years discontinuation of treatment should be considered taking into account the clinical parameters.
In girls, pregnancy should be excluded before the start of treatment. The occurrence of pregnancy during treatment cannot be generally excluded. In such cases, medical advice should be sought.
30 mg: ENANTONE L.P. 30 MG DPS containing 30.0 mg leuprorelin acetate suspended in 1 ml sterile vehicle are administered subcutaneously or intramuscularly once every six months.
Treatment with Advanced Prostate cancer: After reconstitution, one DPS administered ONCE EVERY SIX MONTHS as a single subcutaneous or intramuscular injection. The application interval should be 168 days to maximum 182 days (24 to 26 weeks).
The injection site should be changed every six months. Injection sites may include abdominal skin, buttocks, and upper thigh.
Generally, the treatment of advanced prostate cancer with ENANTONE L.P. 30 mg is continued on a long-term basis.
Treatment with ENANTONE L.P. 30 mg should be monitored for success on a regular basis by means of clinical examinations as well as laboratory evaluations of prostate-specific antigen (PSA), and serum testosterone levels, especially in case of potential clinical signs of progression presenting despite adequate treatment.
Note: As animal experimental findings demonstrated, it is crucial to avoid accidental intra-arterial injection, in view of the potential onset of thrombosis of small vessels distal to the injection site.

3.75 mg/11.25 mg: There is no clinical experience with the effects of an acute overdosage of leuprorelin acetate. In animal studies, doses of up to 500 times the recommended human dose resulted in dyspnea, decreased activity and local irritation at the injection sites. In cases of overdosage, the patients should be monitored closely and management should be symptomatic and supportive.
30 mg: To date, no symptoms of intoxication have been reported.
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.

3.75 mg/11.25 mg: Hypersensitivity to leuprorelin, any of the excipients or other synthetic GnRH analogues or GnRH derivatives.
Undiagnosed abnormal vaginal bleeding.
In girls with central precocious puberty (for 11.25 mg only): Pregnancy and lactation; Undiagnosed vaginal bleeding.
Use in Pregnancy: Use in females who are or may become pregnant while receiving the drug as ENANTONE L.P. 3.75 mg/11.25 mg may cause fetal harm when administered to pregnant females.
Use in Lactation: Use in females who are breast feeding. Because of the lack of data regarding ENANTONE L.P 3.75 mg/11.25 mg excretion in milk and its potential effects on nursing babies, ENANTONE L.P. 3.75 mg/11.25 mg should not be used on nursing mother.
30 mg: Patients with a history of hypersensitivity to the ingredients of the preparation or synthetic LH-RH or LH-RH derivatives.

Use immediately after mixing as the suspension settle out very quickly following reconstitution.
All patients, including central precocious puberty patients: Prepare the injectable suspension at the time of use and, after reconstituting, use immediately.
Depression: There is an increased risk of depression in patients undergoing treatment with leuprorelin and patients should be monitored as appropriate.
Seizures: Postmarketing reports of seizures have been observed in patients treated with leuprorelin acetate and these events have been reported in both children and adults, and in those with or without a history of epilepsy, seizure disorders or risk factors for seizures.
Severe cutaneous adverse reactions: Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) which can be life-threatening or fatal, have been rarely reported with leuprorelin treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for delayed hypersensitivity reactions. If signs and symptoms suggestive of these reactions appear, leuprorelin should be withdrawn immediately and an alternative treatment considered (as appropriate).
Adult patients only: Metabolic changes and cardiovascular risk: Inhibition of endogenous sex hormone production, such as during androgen deprivation therapy as identified from epidemiological data or estrogen deprivation e.g. in menopausal females, is associated with metabolic changes e.g. reduction in glucose tolerance or aggravation of pre-existing diabetes as well as an increased risk for cardiovascular disease (3.75 mg & 11.25 mg).
Epidemiological data have shown that during androgen deprivation therapy changes in the metabolic condition (e.g. reduction in glucose tolerance or aggravation of pre-existing diabetes) as well as an increased risk for cardiovascular diseases may occur (30 mg).
However, prospective data did not confirm a link between treatment with GnRH analogues and an increase in cardiovascular mortality. Patients at high risk for metabolic change or syndrome, or cardiovascular diseases should be appropriately monitored.
Diabetic patients may require more frequent monitoring of blood glucose during treatment with ENANTONE L.P. 3.75 mg/30 mg.
Bone Mineral Loss: Long-term androgen deprivation either by bilateral orchiectomy or administration of GnRH analogues is associated with increased risk of bone loss which, in patients with additional risk factors, may lead to osteoporosis and increased risk of bone fracture.
However, the development of osteoporosis due to hypogonadism is secondary to an increase in cortisol levels, and is more pronounced after orchiectomy than after administration of GnRH analogues. In patients at risk, the additional administration of a bisphosphonate may represent a prophylactic measure against such bone demineralization. (For 30 mg only.)
Prostate cancer patients only: QT prolongation: 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 risks and benefits of each medicinal product, including the potential for Torsade de pointes prior to initiating leuprorelin acetate.
Effects on ability to drive and use machines: Leuprorelin acetate can influence the ability to drive and use machines due to visual disturbances and dizziness.
3.75 mg/11.25 mg: Central precocious puberty patients: Before starting treatment with leuprorelin acetate in pubescent pediatric females, pregnancy must be excluded (See Contraindications).
The treatment of children with progressive brain tumours should follow careful individual appraisal of the risks and benefits.
Bone mineral density (BMD) may decrease during GnRH analogue therapy in children with central precocious puberty. However, after cessation of treatment subsequent bone mass accrual is preserved and peak bone mass in late adolescence does not seem to be affected by treatment.
Pseudotumor cerebri/idiopathic intracranial hypertension: Pseudotumor cerebri (PTC)/idiopathic intracranial hypertension has been reported in pediatric patients receiving leuprorelin acetate. Patients should be monitored for signs and symptoms of PTC, including papilledema, headache, blurred vision, diplopia, loss of vision, pain behind the eye or pain with eye movement, tinnitus, dizziness, and nausea. If PTC is confirmed permanently discontinue use of leuprorelin acetate and treat the patient in accordance with the established treatment guidelines.
Prostate cancer patients only: Flare phenomenon: In the initial stages of therapy, a transient rise in levels of testosterone, dihydrotestosterone and acid phosphatase may occur. In some cases, this may be associated with a "flare" or exacerbation of the tumor growth resulting in temporary deterioration of the patient's condition. These symptoms usually subside on continuation of therapy.
"Flare" may manifest itself as systemic or neurological symptoms where the carcinoma has metastasized (e.g. to the spine), including bone pain, weakness of lower extremities and paresthesia in some cases. Urinary tract obstruction and hematuria may be observed as consequence of flare of the primary carcinoma.
In order to reduce the risk of flare, an anti-androgen may be administered beginning 3 days prior to leuprorelin therapy and continuing for the first two to three weeks of treatment. This has been reported to prevent the sequelae of an initial rise in serum testosterone. If an anti-androgen is used over a prolonged period, due attention should be paid to the contraindications and precautions associated with its extended use.
Patients at risk of ureteric obstruction or spinal cord compression should be considered carefully and also be closely supervised in the first few weeks of treatment. These patients should be considered for prophylactic treatment with anti-androgens. Should urological or neurological complications occur, these should be treated by appropriate specific measures.
Whilst the development of pituitary adenomas has been noted in chronic toxicity studies at high doses in some animal species, this has not been observed in long term clinical studies with leuprorelin acetate.
Endometriosis, Uterine fibroids, Breast cancer patients only: Before starting treatment with ENANTONE L.P. 3.75 mg/11.25 mg, pregnancy must be excluded (See Contraindications). During the period of the treatment, the patient should be instructed to prevent conception with the use of non-hormonal methods.
During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiological effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy.
ENANTONE L.P. 3.75 mg/11.25 mg may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix for intrauterine surgical procedures.
Prior to administration of leuprorelin acetate, undiagnosed abnormal vaginal bleeding must be investigated, diagnosis confirmed and relevant management initiated.
Bone Mineral Loss: Long-term estrogen deprivation by bilateral oophorectomy, ovarian ablation or administration of GnRH analogues is associated with increased risk of bone mineral loss which, in patients with additional risk factors, may lead to osteoporosis and increased risk of bone fracture.
The induced of hypo-estrogenic state results in a loss in bone density over the course of treatment, some of which may not be reversible. The extent of bone demineralization due to hypo-estrogenemia is proportional to time. The level of bone loss with GnRH analogues such as ENANTONE L.P. can be up to 5% after 1 year of treatment. During one e.g. six-month treatment period, this bone loss should not be significant.
In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteriod, ENANTONE L.P. 3.75 mg/11.25 mg therapy may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy with ENANTONE L.P. 3.75 mg/11.25 mg is instituted. This is particularly important in women with uterine fibroids where age related bone loss have already begun to occur.
Endometriosis patients only: As monotherapy, the duration of administration of leuprorelin acetate should be limited to 6 months, as its use is associated with an increased risk of bone mineral loss. Leuprorelin acetate can however be administered for a period of up to 12 months with concurrent hormonal replacement therapy (norethindrone acetate 5 mg daily). If it is necessary to resume administration of leuprorelin acetate, changes in bone parameters should be closely followed.
Uterine fibroid patients only: When considering the preoperative treatment of fibroids, it is mandatory to confirm the diagnosis of fibroids and exclude an ovarian mass, either visually by laparoscopy or by ultrasonography or other investigative technique, as appropriate, before ENANTONE L.P. 3.75 mg/11.25 mg therapy is instituted.
The duration of administration of leuprorelin acetate should be limited to 6 months, as its use is associated with an increased risk of bone mineral loss. If it is necessary to resume administration of leuprorelin acetate, changes in bone parameters should be closely followed.
Male: Patients with urinary obstruction and/or patients with metastatic vertebral lesions should begin ENANTONE L.P. 3.75 mg/11.25 mg therapy under close supervision for the first few weeks of treatment and may have incidences of flare up syndrome.
Female: Since menstruation should stop with effective doses of ENANTONE L.P. 3.75 mg/11.25 mg, the patients should notify her physician if regular menstruation persists.
11.25 mg: Uterine fibroid patients only: In women with submucous fibroids there have been reports of severe bleeding following the administration of ENANTONE L.P. 11.25 mg as a consequence of the acute degeneration of the fibroids. Patients should be warned of the possibility of abnormal bleeding or pain in case earlier surgical intervention is required.
Before using ENANTONE L.P. 11.25 mg for the preoperative treatment of uterine fibroids, patients with major risk factors for decreased bone mineral contents (see previous text) should have their bone density measured and where results are below the normal (5th percentile by DEXA scan) range, ENANTONE L.P. 11.25 mg therapy should not be started.
Premenopausal breast cancer: When starting treatment with ENANTONE L.P. 11.25 mg, absence/presence of hormone receptor expression should be confirmed as a rule. When hormone receptor expression is confirmed to be negative, ENANTONE L.P. 11.25 mg should not be used.
A decrease in bone mass may occur owing to estrogen reducing effect of ENANTONE L.P. 11.25 mg. 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.
In the early period after the first administration of ENANTONE L.P. 11.25 mg, a transient elevation of the serum level of estrogen may occur owing to the stimulating effect of ENANTONE L.P. 11.25 mg, as a highly active GnRH 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 L.P. 11.25 mg and any progression of the tumor is observed, the administration should be discontinued.
All children with central precocious puberty: Before starting therapy, a precise diagnosis of idiopathic and/or neurogenic central precocious puberty is necessary.
The therapy is a long-term treatment, adjusted individually. ENANTONE L.P. 11.25 mg should be administered as precisely as possible in regular 3-monthly periods. An exceptional delay of the injection date for a few days (90 ± 2 days) does not influence the results of the therapy.
Depending on the activity of the central precocious puberty, it may be necessary to increase the dosage in the presence of inadequate suppression (clinical evidence e.g. spotting or inadequate gonadotropin suppression in the LHRH test). The minimal effective 3-monthly dose to be administered should then be determined by means of the LHRH test.
In the event of a sterile abscess at the injection site (mostly reported after i.m. injection of higher than the recommended dosage) the absorption of leuprorelin acetate from the depot can be decreased. In this case the hormonal parameters (testosterone, oestradiol) should be monitored at 2-week intervals.
Sterile abscesses at the injection site often occurred when leuprorelin acetate was administered intramuscularly at higher than the recommended dosages. Therefore, in such cases, the medicinal product should be administered subcutaneously.
The occurrence of vaginal bleeding, spotting and discharge after the first injection may occur as a sign of hormone withdrawal in girls. Vaginal bleeding beyond the first/second month of treatment needs to be investigated.
Slipped femoral epiphysis can be seen after withdrawal of GnRH treatment. The suggested theory is that the low concentrations of estrogen during treatment with GnRH agonists weakens the epiphysial plate. The increase in growth velocity after stopping the treatment subsequently results in a reduction of the shearing force needed for displacement of the epiphysis.
30 mg: General: Response to treatment with ENANTONE L.P. 30 mg can be monitored by measurement of serum levels of testosterone and PSA (prostate-specific antigen).
ENANTONE L.P. 30 mg contains less than 1 mmol sodium (23 mg) per one dual chamber prefilled syringe. Presently, there is no experience available regarding treatment in children.
Whilst the development of pituitary adenomas has been noted in chronic toxicity studies at high doses in some animal species, this has not been observed in long term clinical studies with leuprorelin acetate.
In case hormone-independence of the carcinoma has been demonstrated, treatment with Enantone L.P. 30 mg is not indicated.
After surgical castration, treatment with Enantone L.P. 30 mg does not lead to further reduction of testosterone levels.
Prostate cancer: Flare phenomenon: Aggravation of the signs and symptoms of prostate cancer may occur following a transient increase in serum testosterone level in the early period after initiation of treatment, for example: bone pain, urinary tract obstruction and hematuria (as urinary symptoms), weakness of lower extremities and paresthesia (as neurologic symptoms).
Particular care should be taken of patients having spinal cord compression due to metastasis to the spine, and those with urinary tract obstruction. In administration to such patients, careful observation should be made during the first several weeks after initiation of the treatment.
The adjuvant administration of a suitable anti-androgen is to be considered in the initial phase of therapy to alleviate the symptoms potentially associated with the initial increase in testosterone levels and to attenuate the exacerbated clinical symptoms.

ENANTONE L.P. 3.75 mg should not be administered to pregnant females or nursing mothers (See Contraindications).
ENANTONE L.P. 11.25 mg should not be administered to pregnant females, females having possibilities of being pregnant or nursing mothers. [Abortion due to GnRH 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 L.P. 30 mg is not intended for the use in females 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.

The following convention is used for the classification of the frequency of an adverse drug reaction (ADR) and is based on the Council for International Organizations of Medical Sciences (CIOMS) guidelines: 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).
All Patient Populations: See Table 3.

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All Adult Populations: See Table 4.

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Adult Males: In the initial phase of therapy, a short-term increase, also known as a flare-up, of the sex hormone level occurs (flare phenomenon). Adverse events, which may occur particularly at the beginning of treatment, include urinary tract obstruction (as urinary symptoms); In patients with spinal cord compression, bone pain, weakness of lower extremities and paresthesia (as neurologic symptoms) may also occur (see Precautions). (See Table 5.)

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3.75 mg/11.25 mg: Adult Females: See Table 6.

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Additional ADRs in Breast Cancer Patients or at Differing Frequency: See Table 7.

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Additional ADRs in Endometriosis/Uterine Fibroids Patients or at Differing Frequency: See Table 8.

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Pediatric Patients: In the initial phase of therapy, a short-term increase, also known as a flare-up, of the sex hormone level occurs, followed by a decrease to values within the pre-pubertal range. Due to this pharmacological effect, adverse events may occur particularly at the beginning of treatment. (See Table 9.)

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Since androgen deprivation treatment may prolong the QT interval, the concomitant use of leuprorelin acetate 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 and antipsychotics, should be carefully evaluated (See Precautions).

Incompatibilities: No other fluid other than the sterile vehicle provided for ENANTONE L.P. 3.75 mg/11.25 mg/30 mg can be used for the reconstitution of ENANTONE L.P. 3.75 mg/11.25 mg/30 mg powder.
Special precautions for disposal and other handling: Instructions for use: ENANTONE is supplied as a dual-chamber prefilled syringe for injection.
This Instructions for Use contains information on how to reconstitute and inject ENANTONE.
Important Information: Do not use if syringe or packaging appears damaged.
Do not use the syringe if the powder appears clumped or caked.
Do not use the syringe if the powder or diluent appears discolored.
Storage Conditions: Keep the dual-chamber syringe in the outer carton in order to protect from light.
Hold the syringe upright (with the needle side up) throughout entire preparation to prevent leakage. If leaking occurs, the dose should not be administered.
Use immediately after mixing as the suspension settles out very quickly following reconstitution.
This medication may be injected intramuscularly, subcutaneously.
Parts Overview: The device may have the plunger already attached to the syringe.
Preparation: 1. Wash hands before opening the syringe package.
2. Open package and remove the syringe.
3. Check the expiration date printed on the syringe, and the powder and diluent in the syringe barrel. The powder should be white and dry, and the diluent should be clear.
4. Inspect the syringe for any damage.
a. Do not use the syringe if the powder appears clumped or caked.
b. Do not use the syringe if powder or diluent appear discolored.
c. Do not use the syringe if any part of it is damaged.
5. Gently tap the syringe to remove any lumps and release any powder stuck on the syringe walls.
6. Remove the plunger from the package.
7. Screw the plunger rod into the bottom of the syringe until the end stopper begins to rotate.
a. Do not twist or pull the plunger rod back once it has been attached.
8. Without removing the needle cap, twist the needle to the right (clockwise) to ensure it is secured tightly.
a. Do not remove needle cap until the patient is ready to inject.
9. Holding the syringe upright, release the diluents by slowly pushing the plunger until the middle stopper reaches the blue line in the middle of the syringe. See the diluent flowing into the interior chamber above the blue line.
a. Do not remove the needle cap before releasing the diluent.
b. Do not push the plunger too quickly or push past the blue line as these actions may cause leaking.
c. Do not withdraw plunger again.
10. Gently tap the syringe against the palm of the hand to mix the powder and diluent until it forms a uniform suspension. When properly mixed, the suspension should appear milky with no visible lumps.
a. If particles stick to the stopper during mixing, dislodge them by gently tapping the syringe with the finger.
b. Avoid hard tapping or shaking to prevent the generation of bubbles.
c. Use immediately after mixing as the suspension settles out very quickly following reconstitution.
11. Remove the needle cap by pulling it straight upwards.
a. Do not twist the needle cap.
12. Prime the syringe by pushing the plunger upward until all air has been expelled from the syringe.
13. The syringe is now ready for injection. Use immediately as the suspension settles out very quickly following reconstitution.
Intramuscular Administration: 1. Choose the injection site. Intramuscular injection sites include shoulder (deltoid), upper buttock (ventrogluteal), and thigh.
2. Clean the skin at the injection site with an alcohol swab and allow to air-dry.
a. Do not inject at a location where the skin is red, swollen, scarred, or damaged.
b. Do not use the same injection site for more than one injection consecutively.
3. Gently pull the skin at the injection site taut and insert needle at a 90° or 180° angle. Before inserting the needle, check the orientation of the safety device. The arrow on the safety device should be pointed towards the patient, with the round mark directed upward.
4. Once the needle has been inserted, aspirate the needle by pulling the plunger backward for 5-10 seconds. Care should be taken to avoid inadvertent injection into a blood vessel. If blood is visible in the needle barrel, stop the injection and withdraw the needle immediately.
5. Push the plunger all the way down slowly until entire contents of the syringe have been injected. Pull needle straight out at the same angle it was inserted, then use clean gauze to apply gentle pressure.
a. Do not rub the injection site.
b. Do not recap the needle after injection.
6. When injection is complete, withdraw the needle from the patient. Immediately activate the safety device by pressing upward from just below the arrow until a "CLICK" is heard or felt and the needle is fully covered.
Subcutaneous Administration: 1. Choose the injection site. Subcutaneous injection sites include stomach area (abdomen), thighs, upper arms, and buttock.
2. Clean the skin at the injection site with an alcohol swab and allow to air-dry.
a. Do not inject at a location where the skin is red, swollen, scarred, or damaged.
b. Do not use the same injection site for more than one injection consecutively.
3. Pinch a 2.5 cm section of skin between the fingers and insert needle at a 30°-90° angle. Before inserting the needle, check the orientation of the safety device. The arrow on the safety device should be pointed towards the patient, with the round mark directed upward.
4. Push the plunger all the way down slowly until the entire contents of the syringe have been injected. Pull needle straight out at the same angle it was inserted, then use clean gauze to apply gentle pressure.
a. Do not rub the injection site.
b. Do not recap the needle after injection.
5. When the injection is complete, withdraw the needle from the patient. Immediately activate the safety device by pressing upward from just below the arrow until a "CLICK" is heard or felt and the needle is fully covered.
Intramuscular and Subcutaneous Administration: 1. Choose the injection site. Intramuscular injection sites include shoulder (deltoid), upper buttock (ventrogluteal), and thigh. Subcutaneous injection sites include stomach area (abdomen), thighs, upper arms, and buttock.
2. Clean the skin at the injection site with an alcohol swab and allow to air-dry.
a. Do not inject at a location where the skin is red, swollen, scarred, or damaged.
b. Do not use the same injection site for more than one injection consecutively.
3. For intramuscular injection: a. Gently pull the skin at the injection site taut and insert needle at a 90° or 180° angle to the skin. Before inserting the needle, check the orientation of the safety device. The arrow on the safety device should be pointed towards the patient, with the round mark directed upward.
b. Once the needle has been inserted, aspirate the needle by pulling the plunger backward for 5-10 seconds. Care should be taken to avoid inadvertent injection into a blood vessel. If blood is visible in the needle barrel, stop the injection and withdraw the needle immediately.
c. Push the plunger all the way down slowly until entire contents of the syringe have been injected. Pull needle straight out at the same angle it was inserted, then use clean gauze to apply gentle pressure.
i. Do not rub the injection site.
ii. Do not recap the needle after injection.
d. When injection is complete, withdraw the needle from the patient. Immediately activate the safety device by pressing upward from just below the arrow until a "CLICK" is heard or felt and the needle is fully covered.
4. For Subcutaneous Injection: a. Pinch a 2.5 cm section of skin between the fingers and insert needle at a 30°-90° angle. Before inserting the needle, check the orientation of the safety device. The arrow on the safety device should be pointed towards the patient, with the round mark directed upward.
b. Push the plunger all the way down slowly until the entire contents of the syringe have been injected. Pull needle straight out at the same angle it was inserted, then use clean gauze to apply gentle pressure.
i. Do not rub the injection site.
ii. Do not recap the needle after injection.
c. When the injection is complete, withdraw the needle from the patient. Immediately activate the safety device by pressing upward from just below the arrow until a "CLICK" is heard or felt and the needle is fully covered.
Disposing of ENANTONE: Dispose of the used device in the appropriate sharp's container in accordance with the local standard procedure.

Special precautions for storage: Store below 30°C avoiding heat, light. Protect from freezing.

Trophic Hormones & Related Synthetic Drugs / Cancer Hormone Therapy

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

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