Lupron Depot leuprolide acetate Kit — NDC 0074-3346-03 (Billing 00074-3346-03)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Leuprolide acetate, a GnRH agonist, acts as an inhibitor of gonadotropin secretion. Animal studies indicate that following an initial stimulation, continuous administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect was reversible upon discontinuation of drug therapy.

Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs.

12.2Pharmacodynamics In humans, administration of leuprolide acetate results in an initial increase in circulating concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in concentrations of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased concentrations of LH and FSH. In males, testosterone is reduced to castrate concentrations.

In premenopausal females, estrogens are reduced to postmenopausal concentrations. These decreases occur within two to four weeks after initiation of treatment, and castrate concentrations of testosterone in prostatic cancer patients have been demonstrated for more than five years. Leuprolide acetate is not active when given orally.

12.3Pharmacokinetics Absorption LUPRON DEPOT 7.5 mg for 1-Month Administration Following a single injection of LUPRON DEPOT 7.5 mg for 1-month administration to patients, mean plasma measured concentrations were 20 ng/mL at 4 hours and 0.36 ng/mL at 4 weeks. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. LUPRON DEPOT 22.5 mg for 3-Month Administration Following a single injection of LUPRON DEPOT 22.5 mg for 3-month administration in patients, mean peak plasma concentrations were 48.9 ng/mL at 4 hours and then declined to 0.67 ng/mL at 12 weeks.

Leuprolide appeared to be released at a constant rate following the onset of steady-state concentrations during the third week after dosing, providing steady plasma concentrations through the 12-week dosing interval. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the monthly formulation.

LUPRON DEPOT 30 mg for 4-Month Administration Following a single injection of LUPRON DEPOT 30 mg for 4-month administration in sixteen orchiectomized prostate cancer patients, mean plasma concentrations were 59.3 ng/mL at 4 hours and then declined to 0.30 ng/mL at 16 weeks. Mean plasma concentrations from weeks 3.5 to 16 was 0.44 ± 0.20 ng/mL (range: 0.20-1.06). Leuprolide appeared to be released at a constant rate following the onset of steady-state concentrations during the fourth week after dosing, providing steady plasma concentrations throughout the 16-week dosing interval.

However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the other depot formulations. LUPRON DEPOT 45 mg for 6-Month Administration Following a single injection of LUPRON DEPOT 45 mg for 6-month administration in 26 prostate cancer patients, mean peak plasma concentration of 6.7 ng/mL was observed at 2 hours and then declined to 0.07 ng/mL at 24 weeks.

Leuprolide appeared to be released continuously following the onset of steady-state concentrations during the third week after dosing providing steady plasma concentrations through the 24-week dosing interval. The initi… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Leuprolide acetate, a GnRH agonist, acts as an inhibitor of gonadotropin secretion. Animal studies indicate that following an initial stimulation, continuous administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect was reversible upon discontinuation of drug therapy.

Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs.

12.3Pharmacokinetics Absorption LUPRON DEPOT 7.5 mg for 1-Month Administration Following a single injection of LUPRON DEPOT 7.5 mg for 1-month administration to patients, mean plasma measured concentrations were 20 ng/mL at 4 hours and 0.36 ng/mL at 4 weeks. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. LUPRON DEPOT 22.5 mg for 3-Month Administration Following a single injection of LUPRON DEPOT 22.5 mg for 3-month administration in patients, mean peak plasma concentrations were 48.9 ng/mL at 4 hours and then declined to 0.67 ng/mL at 12 weeks.

Leuprolide appeared to be released at a constant rate following the onset of steady-state concentrations during the third week after dosing, providing steady plasma concentrations through the 12-week dosing interval. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the monthly formulation.

LUPRON DEPOT 30 mg for 4-Month Administration Following a single injection of LUPRON DEPOT 30 mg for 4-month administration in sixteen orchiectomized prostate cancer patients, mean plasma concentrations were 59.3 ng/mL at 4 hours and then declined to 0.30 ng/mL at 16 weeks. Mean plasma concentrations from weeks 3.5 to 16 was 0.44 ± 0.20 ng/mL (range: 0.20-1.06). Leuprolide appeared to be released at a constant rate following the onset of steady-state concentrations during the fourth week after dosing, providing steady plasma concentrations throughout the 16-week dosing interval.

However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the other depot formulations. LUPRON DEPOT 45 mg for 6-Month Administration Following a single injection of LUPRON DEPOT 45 mg for 6-month administration in 26 prostate cancer patients, mean peak plasma concentration of 6.7 ng/mL was observed at 2 hours and then declined to 0.07 ng/mL at 24 weeks.

Leuprolide appeared to be released continuously following the onset of steady-state concentrations during the third week after dosing providing steady plasma concentrations through the 24-week dosing interval. The initial burst, followed by a decline to a steady-state concentration, was similar to the release pattern seen with the other depot formulations. In this study, mean plasma concentration-time profiles were similar after the first and second dose.

Distribution The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Elimination The mean systemic clearance of leuprolide following intravenous bolus administration to healthy male volunteers was

7.6L/h, and terminal elimination half-life was approximately 3 hours based on a two compartment model. Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.

12.2Pharmacodynamics In humans, administration of leuprolide acetate results in an initial increase in circulating concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in concentrations of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased concentrations of LH and FSH. In males, testosterone is reduced to castrate concentrations.

In premenopausal females, estrogens are reduced to postmenopausal concentrations. These decreases occur within two to four weeks after initiation of treatment, and castrate concentrations of testosterone in prostatic cancer patients have been demonstrated for more than five years. Leuprolide acetate is not active when given orally.

14 CLINICAL STUDIES Figure 8 Figure 9 Figure 10 Figure 11

14.1LUPRON DEPOT 7.5 mg for 1-Month Administration In an open-label, non-comparative, multicenter clinical study of LUPRON DEPOT 7.5 mg for 1-month administration, 56 patients with stage D 2 prostatic adenocarcinoma and no prior systemic treatment were enrolled. The objectives were to determine if a 7.5 mg depot formulation of leuprolide injected once every 4 weeks would reduce and maintain serum testosterone to castrate range (≤50 ng/dL), to evaluate objective clinical response, and to assess the safety of the formulation.

During the initial 24 weeks, serum testosterone was measured weekly, biweekly, or every four weeks and objective tumor response assessments were performed at Weeks 12 and 24. Once the patient completed the initial 24-week treatment phase, treatment continued at the investigator’s discretion. Data from the initial 24-week treatment phase are summarized in this section.

In the majority of patients, serum testosterone increased by 50% or more above baseline during the first week of treatment. Serum testosterone suppressed to the castrate range within 30 days of the initial depot injection in 94% (51/54) of patients for whom testosterone suppression was achieved (2 patients withdrew prior to onset of suppression) and within 66 days in all 54 patients. Mean serum testosterone suppressed to castrate level by Week 3.

The median dosing interval between injections was 28 days. One escape from suppression (2 consecutive testosterone values greater than 50 ng/dL after achieving castrate level) was noted at Week 18, associated with a substantial dosing delay. In this patient, serum testosterone returned to the castrate range at the next monthly measurement.

Serum testosterone was minimally above the castrate range on a single occasion for 4 other patients. No clinical significance was attributed to these rises in testosterone. Figure 8.

LUPRON DEPOT 7.5 mg for 1-Month Administration Mean Serum Testosterone Concentrations Secondary efficacy endpoints evaluated included objective tumor response, assessed by clinical evaluations of tumor burden (complete response, partial response, objectively stable, and progression), as well as changes in local disease status, assessed by digital rectal examination, and changes in prostatic acid phosphatase (PAP). These evaluations were performed at Weeks 12 and 24. The objective tumor response analysis showed a “no progression” (i.e.

Complete or partial response, or stable disease) in 77% (40/52) of patients at Week 12, and in 84% (42/50) of patients at Week 24. Local disease improved or remained stable in all (42) patients evaluated at Week 12 and in 98% (41/42) of patients elevated at Week 24. PAP normalized or decreased at Week 12 and/or 24 in the majority of patients with elevated baseline PAP.

Periodic monitoring of serum testosterone and PSA levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.

14.2LUPRON DEPOT 22.5 mg for 3-Month Administration In clinical studies, serum testosterone was suppressed to castrate within 30 days in 87 of 92 (95%) patients and within an additional two weeks in three patients. Two patients did not suppress for 15 and 28 weeks, respectively. Suppression was maintained in all of these patients with the exception of transient minimal testosterone elevations in one of them, and in another an increase in serum testosterone to above the castrate range was recorded during the 12 hour observation period after a subsequent injection.

This represents stimulation of gonadotropin secretion. Figure 9. LUPRON DEPOT 22.5 mg for 3-Month Administration Mean Serum Testosterone Concentrations An 85% rate of “no pro… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies were conducted with leuprolide acetate in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group).

In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Genotoxicity studies were conducted with leuprolide acetate using bacterial and mammalian systems.

These studies provided no evidence of mutagenic effects or chromosomal aberrations. Leuprolide may reduce male and female fertility. Administration of leuprolide acetate to male and female rats at dose of 0.024, 0.24, and 2.4 mg/kg as monthly depot formulation for up to 3 months (approximately as low as 1/30 of the human dose based on body surface area using an estimated daily dose in animals and humans) caused atrophy of the reproductive organs, and suppression of reproductive function.

These changes were reversible upon cessation of treatment.