Sirolimus (Page 8 of 12)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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).

14 CLINICAL STUDIES

14.1 Prophylaxis 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 olution 5 mg/day, and 161 to receive azathioprine 2 to 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 (n = 284)

Sirolimus Oral Solution 5 mg/day (n = 274)

Azathioprine

2 to 3 mg/kg/day

(n = 161)

Efficacy failure at 6 months c

18.7

16.8

32.3

Components of efficacy failure

Biopsy-proven

acute rejection

16.5

11.3

29.2

Graft loss

1.1

2.9

2.5

Death

0.7

1.8

0

Lost to follow-up

0.4

0.7

0.6

Efficacy failure at 24 months

32.8

25.9

36.0

Components of efficacy failure

Biopsy-proven

acute rejection

23.6

17.5

32.3

Graft loss

3.9

4.7

3.1

Death

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 (n = 227)

Sirolimus Oral Solution

5 mg/day

(n = 219)

Placebo

(n = 130)

Efficacy failure at 6 months c

30.0

25.6

47.7

Components of efficacy failure

Biopsy-proven

acute rejection

24.7

19.2

41.5

Graft loss

3.1

3.7

3.9

Death

2.2

2.7

2.3

Lost to follow-up

0

0

0

Efficacy failure at 36 months

44.1

41.6

54.6

Components of efficacy failure

Biopsy-proven

acute rejection

32.2

27.4

43.9

Graft loss

6.2

7.3

4.6

Death

5.7

5.9

5.4

Lost 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 to 3 mg/kg/day

Placebo

Study 1

(n = 284)

(n = 274)

(n= 161)

Graft survival

Month 12

94.7

92.7

93.8

Month 24

85.2

89.1

90.1

Patient survival

Month 12

97.2

96.0

98.1

Month 24

92.6

94.9

96.3

Study 2

(n = 227)

(n =219)

(n = 130)

Graft survival

Month 12

89.9

90.9

87.7

Month 36

81.1

79.9

80.8

Patient survival

Month 12

96.5

95.0

94.6

Month 36

90.3

89.5

90.8

a: Patients received cyclosporine and corticosteroids.

b: Includes patients who prematurely discontinued treatment.

The reduction in the incidence of first biopsy-confirmed acute rejection episodes in patients treated with sirolimus compared with the control groups included a reduction in all grades of rejection.

In Study 1, which was prospectively stratified by race within center, efficacy failure was similar for sirolimus oral solution 2 mg/day and lower for sirolimus oral solution 5 mg/day compared with azathioprine in Black patients. In Study 2, which was not prospectively stratified by race, efficacy failure was similar for both sirolimus oral solution doses compared with placebo in Black patients. The decision to use the higher dose of sirolimus oral solution in Black patients must be weighed against the increased risk of dose-dependent adverse events that were observed with the sirolimus oral solution 5-mg dose [ see Adverse Reactions (6.1) ].

TABLE 11: PERCENTAGE OF EFFICACY FAILURE BY RACE AT 6 MONTHS a,b

Parameter

Sirolimus

Oral Solution

2 mg/day

Sirolimus

Oral Solution

5 mg/day

Azathioprine

2 to 3 mg/kg/day

Placebo

Study 1

Black (n = 166)

34.9 (n = 63)

18.0 (n = 61)

33.3 (n = 42)

Non-Black

(n = 553)

14.0 (n = 221)

16.4 (n = 213)

31.9 (n = 119)

Study 2

Black (n = 66)

30.8 (n = 26)

33.7 (n = 27)

38.5 (n = 13)

Non-Black

(n= 510)

29.9 (n= 201)

24.5 (n = 192)

48.7 (n = 117)

a: Patients received cyclosporine and corticosteroids.

b: Includes patients who prematurely discontinued treatment.

Mean glomerular filtration rates (GFR) post-transplant were calculated by using the Nankivell equation at 12 and 24 months for Study 1, and 12 and 36 months for Study 2. Mean GFR was lower in patients treated with cyclosporine and sirolimus oral solution compared with those treated with cyclosporine and the respective azathioprine or placebo control.

TABLE 12: OVERALL CALCULATED GLOMERULAR FILTRATION RATES (Mean ± SEM, cc/min) BY NANKIVELL EQUATION POST-TRANSPLANT a,b

Parameter

Sirolimus

Oral Solution

2 mg/day

Sirolimus

Oral Solution

5 mg/day

Azathioprine

2 to 3 mg/kg/day

Placebo

Study 1

Month 12

57.4 ± 1.3

(n = 269)

54.6 ± 1.3

(n = 248)

64.1 ± 1.6

(n= 149)

Month 24

58.4 ± 1.5

(n = 221)

52.6 ± 1.5

(n = 222)

62.4 ± 1.9

(n = 132)

Study 2

Month 12

52.4 ± 1.5

(n = 211)

51.5 ± 1.5

(n = 199)

58.0 ± 2.1

(n = 117)

Month 36

48.1 ± 1.8

(n = 183)

46.1 ± 2.0

(n = 177)

53.4 ± 2.7

(n = 102)

a: Includes patients who prematurely discontinued treatment.

b: Patients who had a graft loss were included in the analysis with GFR set to 0.

Within each treatment group in Studies 1 and 2, mean GFR at one-year post-transplant was lower in patients who experienced at least one episode of biopsy-proven acute rejection, compared with those who did not.

Renal function should be monitored, and appropriate adjustment of the immunosuppressive regimen should be considered in patients with elevated or increasing serum creatinine levels [ see Warnings and Precautions (5.8) ].

Sirolimus Tablets

The safety and efficacy of sirolimus oral solution and sirolimus tablets for the prevention of organ rejection following renal transplantation were demonstrated to be clinically equivalent in randomized, multicenter, controlled trial [see Clinical Pharmacology (12.3)].

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