Enantone L.P.

Enantone L.P.

leuprorelin

Manufacturer:

Takeda

Distributor:

DKSH
Full Prescribing Info
Contents
Leuprorelin acetate.
Description
Enantone L.P. 1.88 mg/Enantone L.P. 3.75 mg is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone.
Enantone L.P. 11.25 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 3 month depot injection.
For Dual Chamber Pre-filled Syringe (DPS) with a needle (25 G in 1.88 mg and 3.75 mg; 23 G in 11.25 mg): Each DPS contains 1.88-, 3.75- and 11.25 mg leuprorelin acetate, respectively and 1ml sterile vehicle. The DPS is a dual chamber syringe with white powder in the front chamber and clear, colorless fluid in the rear chamber.
Action
Pharmacology: Pharmacodynamics: Enantone L.P. 11.25 mg: Enantone L.P 11.25 mg contains leuprorelin acetate is 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.
Enantone L.P. 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 prepubertal levels; Suppression of prematurely increased sexual hormone levels to prepubertal 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.
Clinical Studies: Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg: 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 3.75mg 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 LHRH analogues compared with patients treated with orchidectomy.
In another randomised, open-label, multi-centre comparative trial, 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 (7.5mg/month) which is therapeutically equivalent to the European licensed dose.
The use of a LHRH 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.
Enantone L.P. 11.25 mg: Premenopausal breast cancer: Table 1 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.)

Click on icon to see table/diagram/image

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 above 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.)

Click on icon to see table/diagram/image

Pharmacokinetics: Enantone L.P. 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. injection 11.25 mg, 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 1st injection in the majority of patients.
The metabolism, distribution and excretion of leuprorelin acetate in humans have not been fully determined.
In children: Figure 1 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 1.)

Click on icon to see table/diagram/image

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 below. The blood concentrations fluctuated mostly at 0.1 ng/mL from 16 weeks after administration, when it reached the steady state, to 24 weeks after administration. (See Figure 2.)

Click on icon to see table/diagram/image

Toxicology: Enantone 11.25 mg: Preclinical Safety Data: Animal studies have shown that leuprorelin acetate has 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 fetal mortality and decreased fetal weights reflecting the pharmacological effects of this LHRH antagonist.
Indications/Uses
Enantone L.P. 1.88 mg: Endometriosis; decrease of myoma volume and/or amelioration of symptoms in uterine myoma with hypermenorrhea, hypogastralgia, low back pain, anemia, etc.
Enantone L.P. 3.75 mg: Prostate cancer: (for metastatic prostate cancer; locally advanced-prostate cancer, as an alternative to surgical castration for locally-advanced prostate cancer; 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 stages 1-4).
Uterine leiomyomata (fibroids);
Central precocious puberty;
Premenopausal breast cancer.
Enantone L.P. 11.25 mg: Prostate cancer: Metastatic prostate cancer; locally advanced prostate cancer; as an alternative to surgical castration for locally-advanced prostate cancer; 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 extra-genital localization (from stage I to stage IV): (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 Leiomyomata (Fibroids), when suppression of ovarian hormone production is indicated, as a preoperative measure for the volume reduction of individual myomas in myoma nucleation or hysterectomy.
Premenopausal breast cancer.
Treatment of central precocious puberty (girls under 9 years of age, boys under 10 years of age).
Dosage/Direction for Use
The lyophilized microcapsules of Enantone L.P. 1.88 mg/Enantone L.P. 3.75 mg/Ennatone L.P. 11.25 mg are to be reconstituted and administration with the following directions:
For vial and ampule: Using a syringe with a 23-gauge needle, withdraw 2 ml of vehicle from ampule, and inject it into the vial.
Shake well to thoroughly disperse particles to obtain a uniform suspension. The suspension will appear milky.
Withdraw the entire content of the vial into the syringe and inject it at the time of reconstitution as single subcutaneous or intramuscular injection once a month (1.88 mg), at the time of reconstitution (3.75 mg), once every three months (11.25 mg).
For Dual Chamber Pre-filled Syringe (DPS) with a needle: Powder and fluid must be mixed before use.
To prepare for an injection, screw the white plunger firmly into the syringe.
Ensure that the needle is properly fastened to the syringe.
NOTE: Never pull back the plunger rod during the following process.
Tap gently on the syringe to ensure that there are no large quantities of powder remaining on the chamber wall.
Hold the syringe upright with the tip of the needle upwards. Push the plunger in slowly (approximately 6-8 seconds) until the rubber stopper reaches the blue line in the middle of the syringe and the fluid starts to mix with the powder.
NOTE: Pushing the plunger rod quickly or over the blue line makes the leakage of the suspension from the needle.
Hold the syringe upright. Mix the powder and fluid thoroughly by shaking gently or rolling the syringe between the palms to ensure a uniform suspension. The suspension has a milky appearance.
If powder sticks to the rubber stopper, tap the syringe gently with the finger.
NOTE: Avoid hard tapping to prevent of generating the bubble.
Hold the syringe upright. With the other hand, pull the needle cap upwards without twisting.
Hold the syringe upright. Push the plunger forwards to expel all air from the syringe.
Inject the entire contents of the syringe subcutaneously (e.g. into abdomen, thigh or gluteal region) or intramuscularly immediately after preparation. Make sure the injection is not given into a blood vessel. As the suspension settles very quickly following preparation, Enantone L.P. 11.25 mg DPS must be mixed and used immediately.
The patient must be instructed not to massage the injection site.
Although the suspension has been shown to be stable for 24 hours following reconstitution, since the product does not contain a preservative, the suspension should be discarded if not used immediately.
As with other drugs administered regularly by injection, the injection site should be varied periodically.
Enantone L.P. 1.88 mg: Treatment with Endometriosis: Usually, for adults, 3.75 mg of leuprorelin acetate is subcutaneously and intramuscularly administered once a month. However, when the patient's weight is less than 50 kg, 1.88 mg preparation may be used.
The administration of this drug should be initiated on the first to fifth day after the start of menstrual period.
Treatment with Uterine myoma: Usually, for adults, 1.88 mg of leuprorelin acetate is subcutaneously and intramuscularly administered once a month.
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.
Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg: Treatment with Prostate Cancer: After reconstitution, one vial administered once every three months as a single subcutaneous or intramuscular injection.
The majority of patients will respond to 3.75 mg and 11.25 mg dose. Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg therapy should not be discontinued when remission or improvement occurs.
Response to Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg therapy should be monitored by clinical parameters and by measuring serum levels of testosterone and acid phosphatase (3.75 mg only), or prostate-specific antigen (PSA) serum levels (11.25 mg only). 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. 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 (11.25 mg only). Transient increased in acid phosphatase levels sometimes occur early in the treatment period but usually return to normal or near normal values by the 4th week of treatment.
Elderly men: As for adults (11.25 mg only).
Treatment with Endometriosis and Uterine Leiomyomata (Fibroids) and Premenopausal breast cancer: Endometriosis: Usually, for adults, 3.75 mg and 11.25 mg of leuprorelin acetate (Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg) is subcutaneously or intramuscularly administered once a month (3.75 mg only) or once every three months after reconstitution (11.25 mg only). 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.
Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg is indicated for management of endometriosis, including pain relief and reduction of endometriosis lesions, for 6 months. Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg can be safely and effectively administered for a period of 12 months with concurrent hormonal replacement therapy (norethindrone acetate 5 mg daily).
Enantone L.P. 11.25 mg: 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 Leiomyomata (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 (Enantone L.P. 3.75 mg) is administered and 11.25 mg (Enantone L.P. 11.25 mg) is administered once every three months. The administration of this drug should be initiated on the first to fifth day after the start of menstrual period.
Enantone L.P. 3.75 mg: Recommended duration of therapy with Enantone L.P. 3.75 mg is up to 3 months. The symptoms associated with uterine leiomyomata will recur following discontinuation of therapy. If additional treatment with Enantone L.P. 3.75 mg is contemplates, bone density should be assessed prior to initiation of therapy to ensure that values are within normal limits.
Enantone L.P. 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 risk-to benefit ratio 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 leiomyomata. 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: Enantone L.P. 3.75 mg: After reconstitution, one vial of Enantone L.P. 3.75 mg administered once a month as a single subcutaneous or intramuscular injection. Treatment should be started during the first five days of the menstrual cycle. Recommended duration of therapy with Enantone L.P. 3.75 mg is six months. The symptoms associated with premenopausal breast cancer will recur following discontinuation of therapy. If additional treatment with Enantone L.P. 3.75 mg is contemplates, bone density should be assessed prior to initiation of therapy to ensure that values are within normal limits.
Enantone L.P. 11.25 mg: Treatment with Premenopausal breast cancer: Usually, for adults, 11.25 mg of Leuprorelin Acetate is subcutaneously or intramuscular administered once every 12 weeks (once every three months).
Enantone L.P. 3.75 mg: Treatment with central precocious puberty: Administer 90-400 μ/kg of leuprorelin acetate subcutaneously or intramuscularly once a month. The dose may be adjusted according to the patient's response.
Enantone L.P. 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.
Overdosage
Enantone L.P. 3.75 mg/Enantone L.P. 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.
Contraindications
Hypersensitivity to GnRH or GnRH analogues or any of the excipients in Enantone L.P.
Undiagnosed abnormal vaginal bleeding.
In girls with central precocious puberty & undiagnosed vaginal bleeding (Enantone L.P. 11.25 mg only).
Use in Pregnancy & Lactation: Use in women who are or may become pregnant while receiving Enantone L.P. may cause fetal harm when administered to a pregnant woman. Because of the lack of data regarding Enantone L.P. excretion in milk and its potential effects on nursing babies, Enantone L.P. should not be used on nursing mothers.
Special Precautions
Enantone L.P. 1.88 mg: General: Since Enantone L.P. 1.88 mg is a sustained-release preparation with its action lasting for 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 leuprorelin acetate, resulting in a transient aggravation of the clinical condition. Therefore, the method of administering once a month should be observed.
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 in Dosage & Administration.
Uterine Myoma and Endometriosis: It should be noted that the treatment of uterine myoma with Enantone L.P. 1.88 mg 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.
Careful Administration: Enantone L.P. 1.88 mg should be administered with care in the following patients.
Patients with submucous myoma [Bleeding symptom may be aggravated.]
In administration of Enantone L.P. 1.88 mg, care should be taken to differentiate a similar disease (malignant tumor, etc.) from endometriosis and uterine myoma. If, during administration of Enantone L.P. 1.88 mg, any growing phyma is found or no improvement is seen in the clinical symptom, the administration should be discontinued.
Before starting treatment with this drug, pregnancy must be excluded (see Contraindications). It is imperative the administration is initiated on the first to fifth day after the start of menstrual period. During the period of the treatment, the patient should be instructed to prevent conception with the use of non-hormonal methods.
In the early period after the first administration of Enantone L.P. 1.88 mg, a transient elevation of the serum level of estrogen may occur owing to the stimulating effect of Enantone L.P. 1.88 mg, 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.
Long-term gonadotropin deprivation either by bilateral oophorectomy 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. Therefore, the duration of administration of this drug should be limited to 6 months. When it is necessary to resume administration of this drug, the bone mass should be examined as far as possible.
Since a depressed state like climacteric disturbance may occur, the patient's condition should be closely observed.
There is an increased risk of depression in patients undergoing treatment with leuprorelin and patients should be monitored as appropriate.
Severe vaginal bleeding may be observed during treatment with this drug. Therefore, close observation should be made, and if any abnormality is observed, appropriate measures should be taken.
In administration of Enantone L.P. 1.88 mg 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.
Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg: General: Diabetic patients may require more frequent monitoring of blood glucose during treatment with Enantone L.P 3.75 mg and 11.25 mg.
Prepare the injectable suspension at the time of use and, after reconstituting, use immediately.
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.
Prostate cancer: 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 including bone pain, urinary tract obstruction, hematuria, weakness of lower extremities and paresthesia in some cases. 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.
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.
Metabolic Changes and Cardiovascular Risk: 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. However, prospective data did not confirm the link between treatment with GnRH analogues and an increase in cardiovascular mortality. Patients at high risk for metabolic or cardiovascular diseases should be appropriately monitored.
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 benefit risk ratio including the potential for Torsade de pointes prior to initiating leuprorelin acetate.
Endometriosis, Uterine myoma, Breast cancer (3.75 mg): Before starting treatment with Enantone L.P. 3.75 mg/Enantone L.P. 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.
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/Enantone L.P. 11.25 mg therapy is instituted.
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.
The induced of hypo-estrogenic state results in a small 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 and, consequently, is the adverse event responsible for limiting the duration of therapy to 6 months. The generally accepted level of bone loss with LHRH analogues such as Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg is 5%. During one six-month treatment period, this bone loss should not be important. 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/Enantone L.P. 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/Enantone L.P. 11.25 mg is instituted. This is particularly important in women with uterine fibroids where age related bone loss have already begun to occur. Therefore, before using Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg for the preoperative treatment of uterine fibroids, patients with major risk factors for decreased bone mineral contents (see above) should have their bone density measured and where results are below the normal (5th percentile by DEXA scan) range, Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg therapy should not be started.
In women with submucous fibroids there have been reports of severe bleeding following the administration of Enantone L.P. 3.75 mg/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. Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix for intrauterine surgical procedures.
Undiagnosed abnormal vaginal bleeding.
Bone Mineral Loss: Long-term gonadotropin deprivation either by bilateral oophorectomy 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. Therefore, the duration of administration of this drug should be limited to 6 months.* When it is necessary to resume administration of this drug, the bone mass should be examined as far as possible. (*for Endometriosis and/or Uterine Myoma.)
Depression: There is an increased risk of depression in patients undergoing treatment with leuprorelin and patients should be monitored as appropriate.
Precaution: Male: Patients with urinary obstruction and/or patients with metastatic vertebral lesions should begin Enantone L.P. 3.75 mg/Enantone L.P. 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/Enantone L.P. 11.25 mg, the patients should notify her physician if regular menstruation persists.
Enantone L.P. 3.75 mg: Central precocious puberty: The treatment of children with progressive brain tumours should follow careful individual appraisal of the risks and benefits.
Enantone L.P. 11.25 mg: 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.
Before starting treatment, it should be confirmed that the patient is not pregnant. During the period of treatment with Enantone L.P. 11.25 mg, 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 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.
Patients with submucous myoma (Bleeding symptom may be aggravated).
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 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 L.P. 11.25 mg 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.
In girls with central precocious puberty: Before starting the 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 treatment of children with progressive brain tumours should follow a careful individual appraisal of the risks and benefits.
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.
Bone mineral density (BMD) may decrease during GnRH therapy for 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.
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.
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.
Use In Pregnancy & Lactation
It 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.]
Use in women who are or may become pregnant while receiving Enantone L.P. may cause fetal harm when administered to a pregnant woman. Because of the lack of data regarding Enantone L.P. excretion in milk and its potential effects on nursing babies, Enantone L.P. should not be used on nursing mothers.
Adverse Reactions
Enantone L.P. 1.88 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 3.)

Click on icon to see table/diagram/image

The adverse reactions listed below have been observed in the above investigations, spontaneous reports, etc.
Clinically significant adverse reactions: 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 anaphylactoid symptoms may occur (< 0.1%), careful inquiry should be made, and close observation should be made after the administration of Enantone L.P. 1.88 mg. 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.
As with other agents in this class, very rare cases of pituitary apoplexy have been reported following initial administration in patients with pituitary adenoma. Therefore, if headache, vision impairment, visual field disorder, etc. are observed immediately after the first dose of Enantone L.P. 1.88 mg appropriate measures, such as surgical treatment, should be taken after conducting examination.
Other adverse reactions: See Table 4.

Click on icon to see table/diagram/image

Immune system disorders: Hypersensitivity including Anaphylactic reaction, Rash and Pruritus.
Metabolism and nutrition disorders: Weight fluctuation, Decreased appetite.
Psychiatric disorders: Libido decreased, Affect lability, Depression, Sleep disorder.
Nervous system disorders: Headache, Dizziness, Paresthesia, Pituitary Haemorrhage, Seizure.
Eye disorders: Visual impairment.
Vascular disorders:
Hot flush.
Gastrointestinal disorders: Nausea, Vomiting.
Hepatobiliary disorders: Liver function test abnormal, usually transient.
Skin and subcutaneous tissue disorders: Alopecia, Hyperhydrosis.
Musculoskeletal and connective tissue disorders: Arthralgia, Myalgia.
Reproductive system and breast disorders: Breast atrophy, Vulvovaginal dryness, Vulvovaginitis.
General disorders and administration site conditions: Injection site reaction, Oedema.
Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg: General (all indications):
As with other agents in this class, very rare cases of pituitary apoplexy have been reported following initial administration in patients with pituitary adenoma.
Prostate cancer: Flare phenomenon: Bone pain, Urinary tract obstruction (as urinary symptoms), Weakness of lower extremity, Paresthesia (as neurologic symptoms).
Immune system disorders: Hypersensitivity including Anaphylactic reaction, Rash and Pruritus.
Metabolism and nutrition disorders: Decreased appetite.
Psychiatric disorders: Decreased libido, depression.
Nervous system disorders: Paresthesia, Dizziness, Headache, Pituitary Haemorrhage, Seizure.
Cardiac disorders: QT prolongation (see Precautions and Interactions).
Vascular disorders: Hot flush.
Gastrointestinal disorders: Nausea, Vomiting, Diarrhea.
Hepatobiliary disorders: Abnormal liver function test, usually transient.
Skin and subcutaneous tissue disorders: Hyperhydrosis.
Musculoskeletal and connective tissue disorders: Bone pain, decreased bone density, Muscular weakness.
Renal and urinary disorders: Urinary tract obstruction.
Reproductive system and breast disorders: Erectile dysfunction, Testicular atrophy, Gynaecomastia.
General disorders and administration site conditions: Injection site reaction, Oedema.
Endometriosis, Uterine myoma, Breast cancer/Premenopausal breast cancer: Immune system disorders: Hypersensitivity, including Anaphylactic reaction, Rash and Pruritus.
Metabolism and nutrition disorders: Weight fluctuation, Decreased appetite.
Psychiatric disorders: Decreased libido, Affect lability, Depression, Sleep disorder.
Nervous system disorders: Headache, Dizziness, Paresthesia, Pituitary Haemorrhage, Seizure.
Eye disorders: Visual impairment.
Vascular disorders: Hot flush.
Gastrointestinal disorders: Nausea, Vomiting.
Hepatobiliary disorders: Liver function test abnormal, usually transient.
Skin and subcutaneous tissue disorders: Alopecia, Hyperhydrosis.
Musculoskeletal and connective tissue disorders: Arthralgia, Myalgia.
Reproductive system and breast disorders: Breast atrophy, Vulvovaginal dryness, Vulvovaginitis.
General disorders and administration site conditions: Injection site reaction, Oedema.
Enantone L.P. 3.75 mg: Central precocious puberty: In the initial phase of therapy, a short-term increase as 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.
The following convention is used (where available) 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).
Immune system disorders: Very rare: Hypersensitivity, Anaphylactic reaction.
Psychiatric disorders: Common: Affect lability.
Nervous system disorders: Common: Headache. Very rare: Pituitary haemorrhage. Frequency not known: Seizure.
Gastrointestinal disorders: Common: Abdominal pain, Nausea, Vomiting.
Skin and subcutaneous tissue disorders: Common: Acne.
Reproductive system and breast disorders: Common: Vaginal haemorrhage, Vaginal Discharge.
Note: In general, the occurrence of vaginal spotting with continued treatment (subsequent to possible withdrawal bleeding in the first month of treatment) should be assessed as a sign of potential under-dosage. The pituitary suppression should then be determined by an LHRH test.
General disorders and administration site conditions: Common: Injection site reaction.
Enantone L.P. 11.25 mg: Premenopausal breast cancer: Adverse reactions, including abnormalities in laboratory data, were observed in 90 (96.8%) of 93 patients that were evaluated for the safety in the clinical studies conducted in Japan. As for the subjective and objective adverse reactions, symptoms resulting from decreased estrogen, disorder in the administration site, etc. were mainly investigated. Major adverse reactions were feeling of warmth/ hot flashes /feeling of hot flashes/ in 72 patients, headache/dull headache in 45 patients, diaphoresis/night sweats in 18 patients, disorder in the administration site in 42 patients (mainly mild induration), and nausea/vomiting in 21 patients. Administration of Enantone L.P. was discontinued because of feeling of warmth/dull headache/nausea in 1 patient and because of administration site induration/pain in 1 patient.
Also major abnormalities in laboratory data were increased γ-GTP in 16 patients, increased ALT (GPT) in 14 patients, and increased AST (GOT) in 11 patients, etc.
Adverse reactions, including abnormalities in laboratory data, were observed in 280 (95.2%) of 294 patients that were evaluated for the safety in the clinical studies conducted abroad. Major adverse reactions were hot flushes in 245 patients, weight increase in 234 patients, and excessive sweating in 228 patients, etc.
Adverse reactions, including abnormalities in laboratory data, were observed in 121 (19.1%) of 635 patients in the post-marketing investigation of the results of drug use (as of the end of the reexamination period). Major adverse reactions were disorder in the injection site (injection site induration in 40 patients, injection site pain in 17 patients, injection site erythema in 15 patients, injection site swelling in 10 patients), and hot flushes in 35 patients, etc.
Since a depressed state like climacteric disturbance resulting from estrogen reducing effect of Enantone L.P. may occur (0.1% -< 5%), the patient's condition should be closely observed.
Other adverse ractions: See Table 5.

Click on icon to see table/diagram/image

In Children: In the initial phase of therapy, a short-term increase as 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.
Immune system disorders: Very rare: General allergic reactions (fever, rash, e.g. itching, anaphylactic reactions).
Psychiatric disorders: Common: Emotional lability.
Nervous system disorders: Common: Headache.
As with other medicinal products of this class, very rare cases of pituitary apoplexy have been reported following initial administration in patients with pituitary adenoma.
Gastrointestinal disorders: Common: Abdominal pain / abdominal cramps, nausea, vomiting.
Skin and subcutaneous tissue disorders: Common: Acne.
Reproductive system and breast disorders: Common: Vaginal bleeding, spotting, discharge.
Note: In general, the occurrence of vaginal spotting with continued treatment (subsequent to possible withdrawal bleeding in the first month of treatment) should be assessed as a sign of potential under dosage. The pituitary suppression should then be determined by an LHRH test.
General disorders and administration site conditions: Common: Injection site reactions.
Drug Interactions
Enantone L.P. 1.88 mg: It should be administered with care when co-administered with the following drugs. (See Table 6).

Click on icon to see table/diagram/image

Enantone L.P. 3.75 mg/Enantone L.P. 11.25 mg: Prostate cancer: 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, antipsychotics, should be carefully evaluated (see Precautions).
Caution For Usage
Incompatibilities: No other fluid other than the sterile vehicle provided for ENANTONE L.P. 1.88 mg/11.25 mg can be used for the reconstitution of Enantone L.P. 1.88 mg/11.25 mg powder.
Storage
Store below 25°C, avoiding heat and light. Protect from freezing.
Enantone L.P. 1.88 mg: Shelf-Life: 3 years unopened. Once reconstituted with sterile vehicle, the suspension should be administered immediately.
ATC Classification
L02AE02 - leuprorelin ; Belongs to the class of gonadotropin releasing hormone analogues. Used in endocrine therapy.
Presentation/Packing
Powd for inj [dual chamber pre-filled syringe (DPS)] 1.88 mg x 1's. 3.75 mg x 1's. 11.25 mg x 1's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in