LUCRIN Depot Solution for injection Ref.[50336] Active ingredients: Leuprorelin

All Populations

During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of LUCRIN DEPOT 3,75. 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.

Bone Mineral Density

Decreased bone mineral density can occur in women and in men. There is no data in men regarding reversibility after withdrawal of LUCRIN DEPOT 3,75. In women, bone mineral density loss may or may not be reversible after withdrawal of LUCRIN DEPOT 3,75 (see section 4.8).

Convulsions

Postmarketing reports of convulsions have been observed in patients on LUCRIN DEPOT 3,75 therapy. These included patients in the female and paediatric populations, patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumours, and in patients on concomitant medicines 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.

Women

Endometriosis

LUCRIN DEPOT 3,75 should not be administered to patients with undiagnosed abnormal vaginal bleeding.

Pregnancy must be excluded before starting with treatment. LUCRIN DEPOT 3,75 is contraindicated in pregnancy. When used monthly at the recommended dose, LUCRIN DEPOT 3,75 usually inhibits ovulation and stops menstruation.

However, taking LUCRIN DEPOT 3,75 does not ensure contraception. Therefore, patients should use non-hormonal methods of contraception. Patients should be advised to see their doctor if they believe they may be pregnant.

If a patient becomes pregnant during treatment, LUCRIN DEPOT 3,75 must be discontinued and the patient must be apprised of the potential risk of the foetus.

During the early phase of therapy in endometriosis, sex steroids temporarily rise above baseline because of the physiologic effect of LUCRIN DEPOT 3,75. Therefore, an increase in the clinical signs and symptoms may be observed during the initial days of therapy, but these dissipate with continued therapy at adequate doses.

Men

Prostate Cancer

Worsening of signs and symptoms during the first weeks of treatment of prostate cancer may occur with LUCRIN DEPOT 3,75. Patients may experience a temporary increase in bone pain, which should be managed symptomatically. Cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. For patients at risk, the medical practitioner may consider initiating therapy with daily (short-acting) LUCRIN injections 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 3,75. 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 3,75, 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 3,75 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 3,75 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 who may develop paraesthesia or paralysis and/or urinary obstruction or haematuria which, if aggravated, may lead to urological problems such as temporary weakness and/or paraesthesia of the lower limbs or worsening of urinary symptoms.

Effect on QT/QTc Interval

LUCRIN DEPOT 3,75 deprivation treatment may prolong the QT interval in patients with a history of, or risk factors for, QT prolongation. Torsade de pointes has been reported in association with LUCRIN DEPOT 3,75.

The concomitant use of LUCRIN DEPOT 3,75 with medicines known to prolong the QT interval or able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antidysrhythmic medicines, methadone, macrolide antibiotics, moxifloxacin, antipsychotics, etc. should be carefully evaluated.

Changes in Laboratory values during treatment

Response to leuprolide acetate, should be monitored by measuring serum levels of testosterone as well as prostate-specific antigen and prostatic 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 were maintained for as long as the patients received their injections. Transient increases in acid phosphatase levels have occurred early in treatment. However, by the fourth week, the elevated levels usually decrease to values at or near baseline.

During clinical trials isolated elevations of SGOT (ALT) were observed. In clinical trials LUCRIN DEPOT 3,75 was associated with elevation of total cholesterol, triglycerides, lactate dehydrogenase (LDH) and phosphorous and decreases in high-density lipoprotein (HDL) and white blood cell (WBC) counts.

Children

Central Precocious Puberty

Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with rapidly advancing ventral precocious puberty.

Laboratory tests

Response to LUCRIN DEPOT 3,75 should be monitored one to two months after the start of therapy, with a GnRH stimulation test and sex steroid levels. Measurement of bone age for advancement should be done every 6 to 12 months.

Information for parents

Prior to starting therapy with LUCRIN DEPOT 3,75, the parent(s) or guardian(s) must be made aware of the importance of continuous therapy. Adherence to four-week medicine administration schedules must be complied with if therapy is to be successful.

Noncompliance with LUCRIN DEPOT 3,75 regimen or inadequate dosing may result in inadequate control of the pubertal process. The consequences of poor control include the return of pubertal signs such as menses, breast development, and testicular growth. The long-term consequences of inadequate control of gonadal steroid secretion are unknown, but may include a further compromise of adult stature.

Bone Mineral Density

Bone mineral density (BMD) may decrease during GnRH 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.

• During the first two months of therapy, a female may experience menses or spotting. If bleeding continues beyond the second month, notify the medical practitioner.
• Any irritation at the injection site should be reported to the medical practitioner immediately. Page 11 of 48 CCDS03671017 & CCDS03671119
• Any unusual signs or symptoms should be reported to the medical practitioner.

Impairment of fertility

Studies in adults with LUCRIN DEPOT 3,75 have shown reversibility of fertility suppression when the medicine was discontinued after continuous administration for period of up to 24-weeks.

Pharmacokinetic-based interaction studies have not been conducted with LUCRIN DEPOT 3,75. However, due to LUCRIN DEPOT 3,75 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.

Medicine / Laboratory Test Interactions

Diagnostic tests of pituitary gonadotropic and gonadal function conducted during treatment and up to 4 to 8 weeks after discontinuation of LUCRIN DEPOT 3,75 therapy may be misleading, as therapeutic doses of LUCRIN DEPOT 3,75 result in suppression of the pituitary-gonadal system.

Pregnancy

LUCRIN DEPOT 3,75 is contraindicated during pregnancy or lactation (see section 4.3). The safety of leuprolide acetate in pregnancy has not been established.

Breastfeeding

Mothers on LUCRIN DEPOT 3,75 should not breastfeed their infants.

LUCRIN DEPOT 3,75 may cause convulsions, blurred vision or dizziness that may impair the patient’s ability to drive or to use machinery.

Women

The most common adverse events in women are associated with the pharmacological
actions of LUCRIN on the steroidogenesis:

Changes in Bone Density

In controlled clinical studies, patents with endometriosis (six months of therapy) or uterine fibroids (three months of therapy) were treated with LUCRIN DEPOT 3, 75. 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 pretreatment 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 3,75 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.

Table 1 presents ADRs and frequencies (very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); unknown (unable to estimate frequency based upon available data) from endometriosis and breast cancer clinical studies. Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischaemic attack. Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH agonist and these events.

TABLE 1. ADVERSE EVENTS REPORTED IN ENDOMETRIOSIS AND BREAST CANCER CLINICAL STUDIES:

Prostate Cancer

The most common adverse events in men are associated with the pharmacological actions
of LUCRIN on the steroidogenesis:

Men

In the majority of patients testosterone levels increase above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of 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 paraesthesia of the lower limbs or worsening of urinary symptoms (see section 4.4).

Table 2 presents all adverse drug reactions (ADR) and frequencies (very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100) not known (unable to estimate frequency based upon available data) from prostate cancer clinical studies.

TABLE 2. ADVERSE EVENTS REPORTED IN PROSTATE CANCER CLINICAL STUDIES:

Central Precocious Puberty

The most common adverse events are associated with the pharmacological actions of LUCRIN on the steroidogenesis:

Table 3 presents ADRs and frequencies (very common (≥1/10); common (≥1/100 to <1/10);
uncommon (≥1/1,000 to <1/100); unknown (unable to estimate frequency based upon
available data) from CPP clinical studies.

TABLE 3. ADVERSE EVENTS REPORTED IN CENTRAL PRECOCIOUS PUBERTY
CLINICAL STUDIES:

Table 4. Post-marketing Experience Adverse Events seen in Prostate Cancer,
Endometriosis, Breast Cancer and Central Precocious Puberty:

^a Depression and mood swing are commonly observed adverse reactions with long term use of GnRH agonists.
^b Only in men/prostate cancer population
^c Only in women/Endo and breast cancer populations
^d Only in children/CPP population

Psychiatric Events

Psychiatric events have been reported in patients taking GnRH agonists, including LUCRIN DEPOT 3,75. Postmarketing reports with this class of medicines include symptoms of emotional lability, such as crying, irritability, impatience, anger and aggression. A definitive cause and effect relationship between the treatment with GnRH agonists and the occurrence of these events has not been established. Monitoring for development or worsening of psychiatric symptoms during treatment with LUCRIN DEPOT 3,75 is recommended.

Reporting of side effects

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8 You can also report side effects to AbbVie (Pty) Ltd via this e-mail address: MEAPV@abbvie.co

No other fluid should be used for reconstitution of LUCRIN DEPOT 3,75 mg.