Sirolimus .5 mg Tablet, Film Coated, 100-count — NDC 67877-746-01 (Billing 67877-0746-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex.

The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle.

Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats.

In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen-specific. In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.

Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells.

12.2Pharmacodynamics Orally-administered sirolimus at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of organ rejection in low-to moderate-immunologic risk renal transplant patients at 6 months following transplantation compared with either azathioprine or placebo [see Clinical Studies ( 14.1 )] . There was no demonstrable efficacy advantage of a daily maintenance dose of 5 mg with a loading dose of 15 mg over a daily maintenance dose of 2 mg with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug levels within the target-range [see Dosage and Administration ( 2.5 )].

12.3Pharmacokinetics Sirolimus pharmacokinetics activity have been determined following oral administration in healthy subjects, pediatric patients, hepatically impaired patients, and renal transplant patients. The pharmacokinetic parameters of sirolimus in low-to moderate-immunologic risk adult renal transplant patients following multiple dosing with sirolimus 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in Table 4. TABLE 4: MEAN ± SD STEADY STATE SIROLIMUS PHARMACOKINETIC PARAMETERS IN LOW-TO MODERATE-IMMUNOLOGIC RISK ADULT RENAL TRANSPLANT PATIENTS FOLLOWING SIROLIMUS TABLETS 2 MG DAILY a,b Multiple Dose (daily dose) Solution Tablets C max (ng/mL) 14.4 ± 5.3 15.0 ± 4.9 t max (hr) 2.1 ± 0.8 3.5 ±

2.4AUC (ng•h/mL) 194 ± 78 230 ± 67 C min (ng/mL)c 7.1 ± 3.5 7.6 ±

3.1CL/F(mL/h/kg) 173 ± 50 139 ± 63 a: In presence of cyclosporine administered 4 hours before sirolimus dosing. b: Based on data collected at months 1 and 3 post-transplantation. c: Average C min over 6 months. Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correl… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex.

The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle.

Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats.

In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen-specific. In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.

Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells.

12.3Pharmacokinetics Sirolimus pharmacokinetics activity have been determined following oral administration in healthy subjects, pediatric patients, hepatically impaired patients, and renal transplant patients. The pharmacokinetic parameters of sirolimus in low-to moderate-immunologic risk adult renal transplant patients following multiple dosing with sirolimus 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in Table 4. TABLE 4: MEAN ± SD STEADY STATE SIROLIMUS PHARMACOKINETIC PARAMETERS IN LOW-TO MODERATE-IMMUNOLOGIC RISK ADULT RENAL TRANSPLANT PATIENTS FOLLOWING SIROLIMUS TABLETS 2 MG DAILY a,b Multiple Dose (daily dose) Solution Tablets C max (ng/mL) 14.4 ± 5.3 15.0 ± 4.9 t max (hr) 2.1 ± 0.8 3.5 ±

2.4AUC (ng•h/mL) 194 ± 78 230 ± 67 C min (ng/mL)c 7.1 ± 3.5 7.6 ±

3.1CL/F(mL/h/kg) 173 ± 50 139 ± 63 a: In presence of cyclosporine administered 4 hours before sirolimus dosing. b: Based on data collected at months 1 and 3 post-transplantation. c: Average C min over 6 months. Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correlated with AUCτ,ss. Upon repeated, twice-daily administration without an initial loading dose in a multiple-dose study, the average trough concentration of sirolimus increases approximately 2-to 3-fold over the initial 6 days of therapy, at which time steady-state is reached.

A loading dose of 3 times the maintenance dose will provide near steady-state concentrations within 1 day in most patients [see Dosage and Administration ( 2.3 , 2.5 ), Warning and Precautions ( 5.17 )]. Absorption Following administration of sirolimus oral solution, the mean times to peak concentration (t max ) of sirolimus are approximately 1 hour and 2 hours in healthy subjects and renal transplant patients, respectively. The systemic availability of sirolimus is low, and was estimated to be approximately 14% after the administration of sirolimus oral solution.

In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of sirolimus oral solution to stable renal transplant patients, are dose-proportional between 3 and 12 mg/m 2 .

Food Effects To minimize variability in sirolimus concentrations, both sirolimus oral solution and tablets should be taken consistently with or without food [see Dosage and Administration ( 2 )]. In healthy subjects, a high-fat meal (861.8 kcal, 54.9% kcal from fat) increased the mean total exposure (AUC) of sirolimus by 23 to 35%, compared with fasting. The effect of food on the mean sirolimus C max was inconsistent depending on the sirolimus dosage form evaluated.

Distribution The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (V ss /F) of sirolimus is 12 ± 8 L/kg. Sirolimus is extensively bound (approximately 92%) to human plasma proteins, mainly serum albumin (97%), α1-acid glycoprotein, and lipoproteins.

Metabolism Sirolimus is a substrate for both CYP3A4 and P-gp. Sirolimus is extensively metabolized in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations.

Inducers of CYP3A4 and P-gp decrease sirolimus concentrations [see Warnings and Precautions ( 5.20 ) and Drug Interactions ( 7 )] . Sirolimus is extensively metabolized by O-demethylation and/or hydroxylation. Seven (7) major metabolites, including hydroxy, demethyl, and hydroxydemethyl, are identifiable in whole blood.

Some of these metabolites are also detectable in plasma, fecal, and… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Orally-administered sirolimus at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of organ rejection in low-to moderate-immunologic risk renal transplant patients at 6 months following transplantation compared with either azathioprine or placebo [see Clinical Studies ( 14.1 )] . There was no demonstrable efficacy advantage of a daily maintenance dose of 5 mg with a loading dose of 15 mg over a daily maintenance dose of 2 mg with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug levels within the target-range [see Dosage and Administration ( 2.5 )].

14 CLINICAL STUDIES

14.1Prophylaxis of Organ Rejection in Renal Transplant Patients Sirolimus Oral Solution The safety and efficacy of sirolimus oral solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials. These studies compared two dose levels of sirolimus oral solution (2 mg and 5 mg, once daily) with azathioprine (Study 1) or placebo (Study 2) when administered in combination with cyclosporine and corticosteroids. Study 1 was conducted in the United States at 38 sites.

Seven hundred nineteen (719) patients were enrolled in this trial and randomized following transplantation; 284 were randomized to receive sirolimus oral solution 2 mg/day; 274 were randomized to receive sirolimus oral solution 5 mg/day, and 161 to receive azathioprine 2-3 mg/kg/day. Study 2 was conducted in Australia, Canada, Europe, and the United States, at a total of 34 sites. Five hundred seventy-six (576) patients were enrolled in this trial and randomized before transplantation; 227 were randomized to receive sirolimus oral solution 2 mg/day; 219 were randomized to receive sirolimus oral solution 5 mg/day, and 130 to receive placebo.

In both studies, the use of antilymphocyte antibody induction therapy was prohibited. In both studies, the primary efficacy endpoint was the rate of efficacy failure in the first 6 months after transplantation. Efficacy failure was defined as the first occurrence of an acute rejection episode (confirmed by biopsy), graft loss, or death.

The tables below summarize the results of the primary efficacy analyses from these trials. Sirolimus oral solution, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of efficacy failure (statistically significant at the < 0.025 level; nominal significance level adjusted for multiple [2] dose comparisons) at 6 months following transplantation compared with both azathioprine and placebo. TABLE 8: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 24 MONTHS FOR STUDY 1 a,b Parameter Sirolimus oral solution 2 mg/day Sirolimus oral solution 5 mg/day Azathioprine 2-3 mg/kg/day (n=284) (n=274) (n=161) Efficacy failure at 6 monthsc 18.7 16.8

32.3Components of efficacy failure Biopsy-proven acute rejection 16.5 11.3

29.2Graft loss 1.1 2.9

2.5Death 0.7 1.8 0 Lost to follow-up 0.4 0.7

0.6Efficacy failure at 24 months 32.8 25.9

36.0Components of efficacy failure Biopsy-proven acute rejection 23.6 17.5

32.3Graft loss 3.9 4.7

3.1Death 4.2 3.3 0 Lost to follow-up 1.1 0.4 0.6 a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued treatment. c: Primary endpoint. TABLE 9: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 36 MONTHS FOR STUDY 2 a,b Parameter Sirolimus oral solution 2 mg/day Sirolimus oral solution 5 mg/day Placebo (n=227) (n=219) (n=130) Efficacy failure at 6 monthsc 30.0 25.6

47.7Components of efficacy failure Biopsy-proven acute rejection 24.7 19.2

41.5Graft loss 3.1 3.7

3.9Death 2.2 2.7

2.3Lost to follow-up 0 0 0 Efficacy failure at 36 months 44.1 41.6

54.6Components of efficacy failure Biopsy-proven acute rejection 32.2 27.4

43.9Graft loss 6.2 7.3

4.6Death 5.7 5.9

5.4Lost to follow-up 0 0.9 0.8 a: Patients received cyclosporine and corticosteroids. b: Includes patients who prematurely discontinued treatment. c: Primary endpoint. Patient and graft survival at 1 year were co-primary endpoints. The following table shows graft and patient survival at 1 and 2 years in Study 1, and 1 and 3 years in Study 2.

The graft and patient survival rates were similar in patients treated with sirolimus and comparator-treated patients. TABLE 10: GRAFT AND PATIENT SURVIVAL (%) FOR STUDY 1 (12 AND 24 MONTHS) AND STUDY 2 (12 AND 36 MONTHS) a,b Parameter Sirolimus oral solution 2 mg/day Sirolimus oral solution 5 mg/day Azathioprine 2-3 mg/kg/day Placebo Study 1 (n=284) (n=274) (n=161) Graft survival Month 12 94.7 92.7

93.8Month 24 85.2 89.1… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2 mg daily clinical dose (adjusted for body surface area), there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. In a second mouse study at dosages that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), hepatocellular adenoma and carcinoma in males were considered sirolimus-related.

In the 104-week rat study at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for body surface area), there were no significant findings. Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay. When female rats were treated by oral gavage with sirolimus and mated to untreated males, female fertility was decreased at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg, on a body surface area basis) due to decreased implantation.

In addition, reduced ovary and uterus weight were observed. The NOAEL for female rat fertility was 0.1 mg/kg (0.5-fold the clinical dose of 2 mg). When male rats were treated by oral gavage with sirolimus and mated to untreated females, male fertility was decreased at 2 mg/kg (9.7-fold the clinical dose of 2 mg, on a body surface area basis).

Atrophy of testes, epididymides, prostate, seminiferous tubules, and reduced sperm counts were observed. The NOAEL for male rat fertility was 0.5 mg/kg (2.5-fold the clinical dose of 2 mg). Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at 0.1 mg/kg (1-fold the clinical dose of 2 mg, on a body surface area basis).