Lucrin Depot 11,25 Mg Suspension

Prostate Cancer

LUCRIN DEPOT 11,25 MG PDS is indicated in the palliative treatment of advanced prostatic cancer. It offers an alternative treatment of prostatic cancer when orchidectomy or oestrogen administration is either not indicated or unacceptable to the patient.

Endometriosis

LUCRIN DEPOT 11,25 mg PDS is indicated in the treatment of endometriosis for a period of six months. It can be used as sole therapy or as an adjunct to surgery.

Uterine Fibroids

LUCRIN DEPOT 11,25 mg PDS is indicated in the treatment of leiomyoma uteri (uterine fibroids) for a period up to six months. Therapy may be preoperative prior to myomectomy or hysterectomy, or it may provide symptomatic relief for the perimenopausal woman who does not desire surgery.

Breast Cancer

LUCRIN DEPOT 11,25 mg PDS is indicated as adjuvant therapy to surgery in breast carcinomas.

General

LUCRIN DEPOT 11,25 mg PDS must be administered under the supervision of a medical practitioner.

Prostate Cancer

The recommended dose of LUCRIN DEPOT 11,25 mg PDS in the palliative treatment of advanced prostatic carcinoma is 11,25 mg administered as a single subcutaneous or intramuscular injection every 3 months. In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of castration-resistant prostate cancer. Reference should be made to relevant guidelines.

Endometriosis/Uterine Fibroids

The recommended dose of LUCRIN DEPOT 11,25 mg PDS in the treatment of endometriosis and uterine fibroids is 11,25 mg administered as a single subcutaneous or intramuscular injection every 3 months.

Breast Cancer

The recommended dose of LUCRIN DEPOT 11,25 mg PDS as adjuvant therapy to surgery in breast carcinoma is 11,25 mg administered as a single subcutaneous or intramuscular injection every 3 months.

LUCRIN DEPOT 11,25 mg PDS is contraindicated in patients with known hypersensitivity to leuprolide acetate or similar nonapeptides or any of the excipients. (see section 6.1) LUCRIN DEPOT 11,25 mg PDS is contraindicated in women who are, or may become pregnant while receiving the medicine. LUCRIN DEPOT 11,25 mg PDS should not be administered to women who are breastfeeding. LUCRIN DEPOT 11,25 mg PDS should not be administered to patients with undiagnosed vaginal bleeding. LUCRIN DEPOT should not be administered to patients who have had an anaphylactic reaction to leuprolide acetate (see section 4.4).

All Populations

During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of LUCRIN DEPOT 11,25 mg PDS. Therefore, an increase in clinical signs and symptoms may be observed. Worsening of pre-existing signs and symptoms during the first weeks of treatment may occur. Worsening of symptoms may contribute to paralysis with or without fatal complications.

Isolated cases of anaphylaxis have been reported with the monthly depot formulation (LUCRIN DEPOT 3,75 mg PDS) of leuprolide acetate. Convulsions have been observed in patients on LUCRIN DEPOT 11,25 mg PDS therapy. These included patients in the female and paediatric populations, patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and in patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above.

Men

Prostate Cancer

Flare effect: Worsening of signs and symptoms of prostate cancer have been reported during the first week of treatment with LUCRIN DEPOT 11,25 mg PDS. Patients may experience a temporary increase in bone pain, which may be managed symptomatically. Cases of ureteral obstruction and spinal cord compression have been observed, which may cause paralysis with or without fatal complications. For patients at risk, the medical practitioner may consider initiating therapy with daily injections of a GnRH agonist for the first two weeks to facilitate withdrawal of treatment if that is considered necessary. Hyperglycaemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists such as LUCRIN DEPOT 11,25. Hyperglycaemia may represent development of diabetes mellitus or worsening of glycaemic control in patients with diabetes. Monitor blood glucose and/or glycosylated haemoglobin (HbA1c) periodically in patients receiving LUCRIN DEPOT 11,25, and manage with current practice for treatment of hyperglycaemia or diabetes. Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists such as LUCRIN DEPOT 11,25 in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving LUCRIN DEPOT 11,25 should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice. Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy. Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction or haematuria which, if aggravated, may lead to temporary weakness, paralysis or paresthesia of the lower limbs or worsening of urinary symptoms.

Effect on QT/QTc Interval: In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicines that might prolong the QT interval medical practitioners should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating LUCRIN DEPOT 11,25 mg PDS. Since androgen deprivation treatment may prolong the QT interval, the concomitant use of LUCRIN DEPOT 11,25 mg PDS with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de points such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated.

Women

Endometriosis/Uterine Fibroids: During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiological effect of the medicine. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy at adequate doses. However, reports of heavy vaginal bleeding requiring medical or surgical intervention with continued therapy have been reported in the treatment of submucous leiomyoma uteri. LUCRIN DEPOT 11,25 mg PDS is not a contraceptive. If contraception is required, a non-hormonal method of contraception should be used.

Changes in Bone Density: In endometriosis patients, vertebral bone density as measured by dual energy x-ray absorptiometry (DEXA) decreased by an average of 3,9 % at six months compared with the pre-treatment value. For those patients who were tested at six or twelve months after discontinuation of therapy, mean bone density returned to within 2 % of pre-treatment. When LUCRIN DEPOT 11,25 mg PDS was administered for three months in uterine fibroid patients, vertebral trabecular bone mineral density as assessed by quantitative digital radiography (QDR) revealed a mean decrease of 2,7 % compared with baseline. Six months after discontinuation of therapy, a trend toward recovery was observed.

Changes in Laboratory Values During Treatment:

• Liver Enzymes: Three percent of uterine fibroid patients treated with LUCRIN DEPOT 11,25 mg PDS, experienced transaminase values that were at least twice the baseline value and above the upper limit of the normal range. None of the laboratory increases were associated with clinical symptoms.
• Lipids: Triglycerides were increased above the upper limit of normal in 32 % of the endometriosis patients who received LUCRIN DEPOT 11,25 mg PDS. Of those endometriosis and uterine fibroid patients whose pre-treatment cholesterol values were in the normal range, mean change following therapy was +16 mg/dL to +17 mg/dL in endometriosis patients and +11 mg/dL to +29 mg/dL in uterine fibroid patients. In the endometriosis treated patients, increases from the pre-treatment values were statistically significant (p<0,03).

Impairment of fertility: Studies in adults with LUCRIN DEPOT 11,25 mg PDS have shown full reversibility of fertility suppression when the medicine is discontinued after continuous administration for periods of up to 24 weeks.

Medicine interactions: Pharmacokinetic-based medicine-medicine interaction studies have not been conducted with LUCRIN DEPOT 11,25 mg PDS. However, due to leuprolide acetate being a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and due to this compound being only 46 % bound to plasma proteins, medicine interactions are not expected to occur.

Prostate Cancer: See section 4.4.

Laboratory Tests: Response to LUCRIN DEPOT 11,25 mg PDS used in the palliative treatment of advanced prostatic cancer, should be monitored by measuring serum levels of testosterone and acid phosphatase. In the majority of patients, testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week. Castrate levels were reached within two to four weeks and once achieved was maintained for as long as the patients received their injections.

Medicine/Laboratory Test Interactions: Administration of LUCRIN DEPOT 11,25 mg PDS in women results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after LUCRIN DEPOT 11,25 mg PDS treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and for up to three months after discontinuation of LUCRIN DEPOT 11,25 mg PDS may be misleading.

Pregnancy: The safety of LUCRIN DEPOT 11,25 mg PDS in pregnancy has not been established.

Breastfeeding: It is not known whether LUCRIN DEPOT 11,25 mg PDS is excreted in human milk. Therefore LUCRIN DEPOT 11,25 mg PDS should not be administered to women breastfeeding their infants.

LUCRIN DEPOT 11, 25 mg PDS may cause convulsion, blurred vision and dizziness which may affect the ability to drive and use machines (see section 4.8).

Prostate Cancer: The following adverse events are associated with the pharmacological actions of LUCRIN on the steroidogenesis:

SYSTEM ORGAN CLASS ADVERSE EVENTS

Neoplasm benign, malignant and unspecified (including cysts and polyps) Prostate tumour flare, aggravation of prostate cancer

Metabolism and nutrition disorders Weight gain, weight loss

Psychiatric disorders Loss or decreased libido, increased libido

Nervous system disorders Headache, muscular weakness

Vascular disorders Vasodilatation, hot flushes, hypotension, orthostatic hypotension

Skin and subcutaneous tissue disorders Dry skin, hyperhydrosis, rash, urticaria, hair growth abnormal, hair disorder, night sweats, hypotrichosis, pigmentation disorder, cold sweat, hirsutism

Reproductive system and breast disorders Gynaecomastia, breast tenderness, erectile dysfunction, testicular pain, breast enlargement, breast pain, prostate pain, penile swelling, penis disorder, testis atrophy

General disorders and administration site conditions Mucosal dryness

Investigations PSA increased, bone density decreased

Long exposure (6 to 12 months) Diabetes mellitus, glucose tolerance impaired, total cholesterol increased, LDL increased, triglycerides increased, osteoporosis

Men: In the majority of patients testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week treatment.

Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction or hematuria which, if aggravated, may lead to neurological problems such as temporary weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms (see section 4.4).

See section 4.4 and section 4.8. In cases of overdosage, the patients should be monitored closely and treatment should be symptomatic and supportive.