ELIGARD Leuprolide Acetate Kit — NDC 62935-453-45 (Billing 62935-0453-45)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Leuprolide acetate, a gonadotropin releasing hormone (GnRH) agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Animal and human studies indicate that after an initial stimulation, chronic administration of leuprolide acetate results in suppression of testicular and ovarian steroidogenesis. This effect is reversible upon discontinuation of drug therapy.

In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels 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 levels of LH and FSH. In males, testosterone is reduced to below castrate threshold (≤50 ng/dL).

These decreases occur within two to four weeks after initiation of treatment. Long-term studies have shown that continuation of therapy with leuprolide acetate maintains testosterone below the castrate level for up to seven years.

12.2Pharmacodynamics Following the first dose of ELIGARD ® , mean serum testosterone concentrations transiently increased, then fell to below castrate threshold (≤ 50 ng/dL) within three weeks for all ELIGARD ® concentrations. Continued monthly treatment with ELIGARD ® 7.5 mg maintained castrate testosterone suppression throughout the study. No breakthrough of testosterone concentrations above castrate threshold (> 50 ng/dL) occurred at any time during the study once castrate suppression was achieved (Figure 1).

One patient received less than a full dose of ELIGARD ® 22.5 mg at baseline, never suppressed and withdrew from the study at Day 73. Of the 116 patients remaining in the study, 115 (99%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 35, 116 (100%) had serum testosterone levels below the castrate threshold.

Once testosterone suppression was achieved, one patient (< 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) following the initial injection; that patient remained below the castrate threshold following the second injection (Figure 2). One patient withdrew from the ELIGARD ® 30 mg study at Day 14. Of the 89 patients remaining in the study, 85 (96%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28).

By Day 42, 89 (100%) of patients attained castrate testosterone suppression. Once castrate testosterone suppression was achieved, three patients (3%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (Figure 3). One patient at Day 1 and another patient at Day 29 were withdrawn from the ELIGARD ® 45 mg study.

Of the 109 patients remaining in the study, 108 (99.1%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). One patient did not achieve castrate suppression and was withdrawn from the study at Day 85. Once castrate testosterone suppression was achieved, one patient (< 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (Figure 4).

Leuprolide acetate is not active when given orally.

12.3Pharmacokinetics Absorption ELIGARD ® 7.5 mg The pharmacokinetics/pharmacodynamics observed during three once-monthly injections in 20 patients with advanced prostate cancer is shown in Figure 1. Mean serum leuprolide concentrations following the initial injection rose to 25.3 ng/mL (C max ) at approximately 5 hours after injection. After the initial increase following each injection, serum concentrations remained relatively constant (0.28 – 2.00 ng/mL).

Figure 1. Pharmacokinetic/Pharmacodynamic Response (N=20) to ELIGARD ® 7.5 mg – Patients Dosed Initially and at Months 1 and 2 A reduced number of sampling time points resulted in the apparent dec… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Leuprolide acetate, a gonadotropin releasing hormone (GnRH) agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Animal and human studies indicate that after an initial stimulation, chronic administration of leuprolide acetate results in suppression of testicular and ovarian steroidogenesis. This effect is reversible upon discontinuation of drug therapy.

In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels 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 levels of LH and FSH. In males, testosterone is reduced to below castrate threshold (≤50 ng/dL).

These decreases occur within two to four weeks after initiation of treatment. Long-term studies have shown that continuation of therapy with leuprolide acetate maintains testosterone below the castrate level for up to seven years.

12.2Pharmacodynamics Following the first dose of ELIGARD ® , mean serum testosterone concentrations transiently increased, then fell to below castrate threshold (≤ 50 ng/dL) within three weeks for all ELIGARD ® concentrations. Continued monthly treatment with ELIGARD ® 7.5 mg maintained castrate testosterone suppression throughout the study. No breakthrough of testosterone concentrations above castrate threshold (> 50 ng/dL) occurred at any time during the study once castrate suppression was achieved (Figure 1).

One patient received less than a full dose of ELIGARD ® 22.5 mg at baseline, never suppressed and withdrew from the study at Day 73. Of the 116 patients remaining in the study, 115 (99%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 35, 116 (100%) had serum testosterone levels below the castrate threshold.

Once testosterone suppression was achieved, one patient (< 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) following the initial injection; that patient remained below the castrate threshold following the second injection (Figure 2). One patient withdrew from the ELIGARD ® 30 mg study at Day 14. Of the 89 patients remaining in the study, 85 (96%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28).

By Day 42, 89 (100%) of patients attained castrate testosterone suppression. Once castrate testosterone suppression was achieved, three patients (3%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (Figure 3). One patient at Day 1 and another patient at Day 29 were withdrawn from the ELIGARD ® 45 mg study.

Of the 109 patients remaining in the study, 108 (99.1%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). One patient did not achieve castrate suppression and was withdrawn from the study at Day 85. Once castrate testosterone suppression was achieved, one patient (< 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (Figure 4).

Leuprolide acetate is not active when given orally.

14 CLINICAL STUDIES One open-label, multicenter study was conducted with each ELIGARD ® formulation (7.5 mg, 22.5 mg, 30 mg, and 45 mg) in patients with Jewett stage A though D prostate cancer who were treated with at least a single injection of study drug (Table 8). These studies evaluated the achievement and maintenance of castrate serum testosterone suppression over the duration of therapy (Figures 5-8). During the AGL9904 study using ELIGARD ® 7.5 mg, once testosterone suppression was achieved, no patients (0%) demonstrated breakthrough (concentration > 50 ng/dL) at any time in the study.

During the AGL9909 study using ELIGARD ® 22.5 mg, once testosterone suppression was achieved, only one patient (< 1%) demonstrated breakthrough following the initial injection; that patient remained below the castrate threshold following the second injection. During the AGL0001 study using ELIGARD ® 30 mg, once testosterone suppression was achieved, three patients (3%) demonstrated breakthrough. In the first of these patients, a single serum testosterone concentration of 53 ng/dL was reported on the day after the second injection.

In this patient, castrate suppression was reported for all other time points. In the second patient, a serum testosterone concentration of 66 ng/dL was reported immediately prior to the second injection. This rose to a maximum concentration of 147 ng/dL on the second day after the second injection.

In this patient, castrate suppression was again reached on the seventh day after the second injection and was maintained thereafter. In the final patient, serum testosterone concentrations > 50 ng/dL were reported at 2 and at 8 hours after the second injection. Serum testosterone concentration rose to a maximum of 110 ng/dL on the third day after the second injection.

In this patient, castrate suppression was again reached eighteen days after the second injection and was maintained until the final day of the study, when a single serum testosterone concentration of 55 ng/dL was reported. During the AGL0205 study using ELIGARD ® 45 mg, once testosterone suppression was achieved, one patient (<1%) demonstrated breakthrough. This patient reached castrate suppression at Day 21 and remained suppressed until Day 308 when his testosterone level rose to 112 ng/dL.

At Month 12 (Day 336), his testosterone was 210 ng/dL. Table 8. Summary of ELIGARD ® Clinical Studies ELIGARD ® 7.5 mg 22.5 mg 30 mg 45 mg Study number AGL9904 AGL9909 AGL0001 AGL0205 Total number of patients 120 (117 completed) 117 2 (111 completed 3 ) 90 (82 completed 4 ) 111 (103 completed 5 ) Jewett stages Stage A ‑ 2 2 5 Stage B ‑ 19 38 43 Stage C 89 60 16 19 Stage D 31 36 34 44 Treatment 6 monthly injections 1 injection (4 patients) 1 injection (5 patients) 1 injection (5 patients) 2 injections, one every three months (113 patients) 2 injections, one every four months (85 patients) 2 injections, one every six months (106 patients) Duration of therapy 6 months 6 months 8 months 12 months Mean testosterone concentration (ng/dL) Baseline 361.3 367.1 385.5 367.7 Day 2 574.6 (Day 3) 588.0 610.0 588.6 Day 14 Below Baseline (Day 10) Below Baseline Below Baseline Below Baseline Day 28 21.8 27.7 (Day 21) 17.2

16.7Conclusion 6.1 10.1 12.4

12.6Number of patients below castrate threshold ( ≤ 50 ng/dL) Day 28 112 of 119 (94.1%) 115 of 116 (99%) 85 of 89 (96%) 108 of 109 (99.1%) Day 35 ‑ 116 (100%) ‑ ‑ Day 42 119 (100%) ‑ 89 (100%) ‑ Conclusion 117 1 (100%) 111 (100%) 81 (99%) 102 (99%) Two patients withdrew for reasons unrelated to drug. One patient received less than a full dose at Baseline, never suppressed, and was withdrawn at Day 73 and given an alternate treatment. All non-evaluable patients who attained castration by Day 28 maintained castration at each time point up to and including the time of withdrawal.

One patient withdrew on Day 14. All 7 non-evaluable patients who had achieved castration by Day 28 maintained castration at each time point, up to and including… [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 high 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. No carcinogenicity studies have been conducted with ELIGARD ® .

Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems and with ELIGARD ® 7.5 mg in bacterial systems. These studies provided no evidence of a mutagenic potential.