Enantone L.P. Special Precautions

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 If signs and symptoms suggestive of these reactions appear, leuprorelin should be withdrawn immediately and an alternative treatment considered (as appropriate).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.