Treatment with leuprorelin acetate can cause exacerbations of signs and symptoms of the disease during the first few weeks. If conditions such as vertebral metastases and/or urinary obstruction or haematuria are aggravated, neurological problems, such as weakness and/or paraesthesia of the lower limbs or worsening of urinary symptoms may occur.

4.9 Overdose

 ELIGARD 7.5 mg does not have the potential for abuse, and deliberate overdose is unlikely. There are no reports of abuse or overdose having occurred in clinical practice with leuprorelin acetate, but in the event that excessive exposure becomes a reality, observation and symptomatic supportive treatment are recommended.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

 Pharmacotherapeutic group: Gonadotropin releasing hormone analogues

ATC code: L02A E02

Leuprorelin acetate is a synthetic nonapeptide agonist of naturally occurring gonadotropin releasing hormone (GnRH) that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular steroidogenesis in males.

This effect is reversible upon discontinuation of medicinal product therapy. However, the agonist possesses greater potency than the natural hormone and the time to recovery of testosterone levels may vary between patients.

Administration of leuprorelin acetate results in an initial increase in circulating levels of luteinising hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids, testosterone and dihydrotestosterone in males. Continuous administration of leuprorelin acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to below castrate threshold ( 50 ng/dL). These decreases occur within three to five weeks after initiation of treatment. Mean testosterone levels at six months are 6.1 (± 0.4) ng/dL, comparable to levels following bilateral orchiectomy. All patients in the pivotal clinical study reached castrate levels at 6 weeks; 94 % had reached this by day 28 and 98% by day 35. In the vast majority of patients the testosterone levels seen were below 20 ng/dL although the full benefit of these low levels has not yet been established. PSA levels decreased by 94% over six months.

Long-term studies have shown that continuation of therapy maintains testosterone below the castrate level for up to seven years, and presumably indefinitely.

Tumour size was not measured directly during the clinical trial programme, but there was an indirect beneficial tumour response as shown by a 94% reduction in mean PSA for ELIGARD 7.5 mg.

5.2 Pharmacokinetic properties

 Absorption: In patients with advanced carcinoma of the prostate, mean serum leuprorelin concentrations following the initial injection rise to 25.3 ng/ml at 4-8 hr (Cmax) after injection. After the initial increase following each injection (the plateau phase from 2-28 days after each dose), serum concentrations remain relatively constant (0.28 – 1.67 ng/ml). There is no evidence of accumulation during repeated dosing.

Distribution: The mean steady-state volume of distribution of leuprorelin following intravenous bolus administration to healthy male volunteers was 27 litres. In vitro binding to human plasma proteins ranged from 43% to 49%.

Elimination: In healthy male volunteers, a 1 mg bolus of leuprorelin acetate administe