Mycophenolate Mofetil (Page 7 of 10)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week oral carcinogenicity study in mice, mycophenolate mofetil in daily doses up to 180 mg/kg was not tumorigenic. The highest dose tested was 0.4 times the recommended clinical dose (2 grams/day) in renal transplant patients and 0.3 times the recommended clinical dose (3 grams/day) in cardiac transplant patients when corrected for differences in body surface area (BSA). In a 104-week oral carcinogenicity study in rats, mycophenolate mofetil in daily doses up to 15 mg/kg was not tumorigenic. The highest dose was 0.07 times the recommended clinical dose in kidney transplant patients and 0.05 times the recommended clinical dose in heart transplant patients when corrected for BSA. While these animal doses were lower than those given to patients, they were maximal in those species and were considered adequate to evaluate the potential for human risk [see Warnings and Precautions (5.2)].

The genotoxic potential of mycophenolate mofetil was determined in five assays. Mycophenolate mofetil was genotoxic in the mouse lymphoma/thymidine kinase assay and the in vivo mouse micronucleus assay. Mycophenolate mofetil was not genotoxic in the bacterial mutation assay, the yeast mitotic gene conversion assay or the Chinese hamster ovary cell chromosomal aberration assay.

Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. This dose represents 0.1 times the recommended clinical dose in renal transplant patients and 0.06 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (principally of the head and eyes) in the first generation offspring in the absence of maternal toxicity. This dose was 0.02 times the recommended clinical dose in renal transplant patients and 0.01 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.

14 CLINICAL STUDIES

14.1 Kidney Transplantation

Adults

The three de novo kidney transplantation studies compared two dose levels of oral mycophenolate mofetil (1 gram twice daily and 1.5 grams twice daily) with azathioprine (2 studies) or placebo (1 study) to prevent acute rejection episodes. One of the two studies with azathioprine (AZA) control arm also included anti-thymocyte globulin (ATGAM®) induction therapy. The geographic location of the investigational sites of these studies are included in Table 11.

In all three de novo kidney transplantation studies, the primary efficacy endpoint was the proportion of patients in each treatment group who experienced treatment failure within the first 6 months after transplantation. Treatment failure was defined as biopsy-proven acute rejection on treatment or the occurrence of death, graft loss or early termination from the study for any reason without prior biopsy-proven rejection.

Mycophenolate mofetil, in combination with corticosteroids and cyclosporine, reduced (statistically significant at 0.05 level) the incidence of treatment failure within the first 6 months following transplantation (Table 11). Patients who prematurely discontinued treatment were followed for the occurrence of death or graft loss, and the cumulative incidence of graft loss and patient death combined are summarized in Table 12. Patients who prematurely discontinued treatment were not followed for the occurrence of acute rejection after termination.

Table 11: Treatment Failure in De Novo Kidney Transplantation Studies

USA Study

(N=499 patients)

Mycophenolate

Mofetil

2 grams/day

(n=167 patients)

Mycophenolate

Mofetil

3 grams/day

(n=166 patients)

AZA

1 to 2 mg/kg/day

(n=166 patients)

All 3 groups received anti-thymocyte globulin induction, cyclosporine and corticosteroids

All treatment failures

31.1%

31.3%

47.6%

Early termination without prior acute rejection

9.6%

12.7%

6.0%

Biopsy-proven rejection episode on treatment

19.8%

17.5%

38.0%

Europe/Canada/ Australia Study (N=503 patients)

Mycophenolate

Mofetil

2 grams/day

(n=173 patients)

Mycophenolate

Mofetil

3 grams/day

(n=164 patients)

AZA

100 to 150 mg/day

(n=166 patients)

No induction treatment administered; all 3 groups received cyclosporine and corticosteroids.

All treatment failures

38.2%

34.8%

50.0%

Early termination without prior acute rejection

13.9%

15.2%

10.2%

Biopsy-proven rejection

episode on treatment

19.7%

15.9%

35.5%

Europe Study

(N=491 patients)

Mycophenolate

Mofetil

2 grams/day

(n=165 patients)

Mycophenolate

Mofetil

3 grams/day

(n=160 patients)

Placebo

(n=166 patients)

No induction treatment administered; all 3 groups received cyclosporine and corticosteroids.

All treatment failures

30.3%

38.8%

56.0%

Early termination without prior acute rejection

11.5%

22.5%

7.2%

Biopsy-proven rejection

episode on treatment

17.0%

13.8%

46.4%

*Does not include death and graft loss as reason for early termination.

No advantage of mycophenolate mofetil at 12 months with respect to graft loss or patient death (combined) was established (Table 12). Numerically, patients receiving mycophenolate mofetil 2 grams/day and 3 grams/day experienced a better outcome than controls in all three studies; patients receiving mycophenolate mofetil 2 grams/day experienced a better outcome than mycophenolate mofetil 3 grams/day in two of the three studies. Patients in all treatment groups who terminated treatment early were found to have a poor outcome with respect to graft loss or patient death at 1 year.

Table 12: De Novo Kidney Transplantation Studies Cumulative Incidence of Combined Graft Loss or Patient Death at 12 Months

Study

Mycophenolate

Mofetil

2 grams/day

Mycophenolate

Mofetil

3 grams/day

Control

(AZA or Placebo)

USA

8.5%

11.5%

12.2%

Europe/Canada/Australia

11.7%

11.0%

13.6%

Europe

8.5%

10.0%

11.5%

Pediatrics- De Novo Kidney transplantation PK Study with Long Term Follow-Up

One open-label, safety and pharmacokinetic study of mycophenolate mofetil for oral suspension 600 mg/m2 twice daily (up to 1 gram twice daily) in combination with cyclosporine and corticosteroids was performed at centers in the United States (9), Europe (5) and Australia (1) in 100 pediatric patients (3 months to 18 years of age) for the prevention of renal allograft rejection. Mycophenolate mofetil was well tolerated in pediatric patients [see Adverse Reactions (6.1)] , and the pharmacokinetics profile was similar to that seen in adult patients dosed with 1 gram twice daily mycophenolate mofetil capsules [see Clinical Pharmacology (12.3)]. The rate of biopsy-proven rejection was similar across the age groups (3 months to <6 years, 6 years to <12 years, 12 years to 18 years). The overall biopsy-proven rejection rate at 6 months was comparable to adults. The combined incidence of graft loss (5%) and patient death (2%) at 12 months post-transplant was similar to that observed in adult kidney transplant patients.

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