Mycophenolic Acid (Page 6 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week oral carcinogenicity study in rats, mycophenolate sodium was not tumorigenic at daily doses up to 9 mg per kg, the highest dose tested. This dose resulted in approximately 0.6 to 1.2 times the systemic exposure (based on plasma AUC) observed in renal transplant patients at the recommended dose of 1440 mg per day. Similar results were observed in a parallel study in rats performed with MMF. In a 104-week oral carcinogenicity study in mice, MMF was not tumorigenic at a daily dose level as high as 180 mg per kg (which corresponds to 0.6 times the recommended mycophenolate sodium therapeutic dose, based on body surface area).

The genotoxic potential of mycophenolate sodium was determined in five assays. Mycophenolate sodium was genotoxic in the mouse lymphoma/thymidine kinase assay, the micronucleus test in V79 Chinese hamster cells, and the in vivo mouse micronucleus assay. Mycophenolate sodium was not genotoxic in the bacterial mutation assay (Salmonella typhimurium TA 1535, 97a, 98, 100, and 102) or the chromosomal aberration assay in human lymphocytes.

Mycophenolate mofetil generated similar genotoxic activity. The genotoxic activity of mycophenolic acid (MPA) is probably due to the depletion of the nucleotide pool required for DNA synthesis as a result of the pharmacodynamic mode of action of MPA (inhibition of nucleotide synthesis).

Mycophenolate sodium had no effect on male rat fertility at daily oral doses as high as 18 mg per kg and exhibited no testicular or spermatogenic effects at daily oral doses of 20 mg per kg for 13 weeks (approximately 2 times the systemic exposure of MPA at the recommended therapeutic dose). No effects on female fertility were seen up to a daily dose of 20 mg per kg (approximately 3 times the systemic exposure of MPA at the recommended therapeutic dose).

14 CLINICAL STUDIES

14.1 Prophylaxis of Organ Rejection in Patients Receiving Allogeneic Renal Transplants

The safety and efficacy of mycophenolic acid delayed-release tablets in combination with cyclosporine, USP MODIFIED and corticosteroids for the prevention of organ rejection was assessed in two multicenter, randomized, double-blind, active-controlled trials in de novo and conversion renal transplant patients compared to MMF.

The de novo trial was conducted in 423 renal transplant patients (ages 18–75 years) in Austria, Canada, Germany, Hungary, Italy, Norway, Spain, UK, and USA. Eighty-four percent of randomized patients received kidneys from deceased donors. Patients were excluded if they had second or multiorgan (e.g., kidney and pancreas) transplants, or previous transplant with any other organs; kidneys from non-heart beating donors; panel reactive antibodies (PRA) of >50% at last assessment prior to transplantation, and presence of severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus. Patients were administered either mycophenolic acid delayed-release tablets 1.44 grams per day or MMF 2 grams per day within 48 hours post-transplant for 12 months in combination with cyclosporine, USP MODIFIED and corticosteroids. Forty-one percent of patients received antibody therapy as induction treatment. Treatment failure was defined as the first occurrence of biopsy proven acute rejection, graft loss, death or lost to follow-up at 6 months.

The incidence of treatment failure was similar in mycophenolic acid delayed-release tablets and MMF-treated patients at 6 and 12 months (Table 7). The cumulative incidence of graft loss, death and lost to follow-up at 12 months is also shown in Table 7.

Table 7: Treatment Failure in de novo Renal Transplant Patients (Percent of Patients) at 6 and 12 Months of Treatment when Administered in Combination with Cyclosporine* and Corticosteroids

* USP MODIFIED.

** Lost to follow-up indicates patients who were lost to follow-up without prior biopsy-proven acute rejection, graft loss or death.

*** Lost to follow-up indicates patients who were lost to follow-up without prior graft loss or death (9 mycophenolic acid patients and 4 MMF patients).

**** 95% confidence interval of the difference in treatment failure at 6 months (mycophenolic acid–MMF) is (-8.7%, 8.0%).

***** 95% confidence interval of the difference in treatment failure at 12 months (mycophenolic acid–MMF) is (-8.0%, 9.1%).

Mycophenolic Acid Delayed-Release tablets 1.44 grams per day (n=213) Mycophenolate mofetil (MMF) 2 grams per day (n=210)
6 Months n (%) n (%)
Treatment failure**** 55 (25.8) 55 (26.2)
Biopsy-proven acute rejection 46 (21.6) 48 (22.9)
Graft loss 7 (3.3) 9 (4.3)
Death 1 (0.5) 2 (1.0)
Lost to follow-up** 3 (1.4) 0
12 Months n (%) n (%)
Graft loss or death or lost to follow-up*** 20 (9.4) 18 (8.6)
Treatment failure***** 61 (28.6) 59 (28.1)
Biopsy-proven acute rejection 48 (22.5) 51 (24.3)
Graft loss 9 (4.2) 9 (4.3)
Death 2 (0.9) 5 (2.4)
Lost to follow-up** 5 (2.3) 0

The conversion trial was conducted in 322 renal transplant patients (ages 18–75 years), who were at least 6 months post-transplant and had undergone primary or secondary, deceased donor, living related, or unrelated donor kidney transplant, stable graft function (serum creatinine <2.3 mg/mL), no change in immunosuppressive regimen due to graft malfunction, and no known clinically significant physical and/or laboratory changes for at least 2 months prior to enrollment. Patients were excluded if they had 3 or more kidney transplants, multiorgan transplants (e.g., kidney and pancreas), previous organ transplants, evidence of graft rejection or who had been treated for acute rejection within 2 months prior to screening, clinically significant infections requiring continued therapy, presence of severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus.

Patients received 2 grams per day MMF in combination with cyclosporine USP MODIFIED, with or without corticosteroids for at least two weeks prior to entry in the trial. Patients were randomized to mycophenolic acid delayed-release tablets 1.44 grams per day or MMF 2 grams per day for 12 months. The trial was conducted in Austria, Belgium, Canada, Germany, Italy, Spain, and USA. Treatment failure was defined as the first occurrence of biopsy-proven acute rejection, graft loss, death, or lost to follow-up at 6 and 12 months.

The incidences of treatment failure at 6 and 12 months were similar between mycophenolic acid delayed-release tablets and MMF-treated patients (Table 8). The cumulative incidence of graft loss, death and lost to follow-up at 12 months is also shown in Table 8.

Table 8: Treatment Failure in Conversion Transplant Patients (Percent of Patients) at 6 and 12 Months of Treatment when Administered in Combination with Cyclosporine* and with or without Corticosteroids

* USP MODIFIED.

** Lost to follow-up indicates patients who were lost to follow-up without prior biopsy-proven acute rejection, graft loss, or death.

*** Lost to follow-up indicates patients who were lost to follow-up without prior graft loss or death (8 mycophenolic acid patients and 12 MMF patients).

**** 95% confidence interval of the difference in treatment failure at 6 months (mycophenolic acid–MMF) is (-7.3%, 2.7%).

***** 95% confidence interval of the difference in treatment failure at 12 months (mycophenolic acid–MMF) is (-11.2%, 1.8%).

Mycophenolic Acid Delayed-Release Tablets 1.44 grams per day (n=159) mycophenolate mofetil (MMF) 2 grams per day (n=163)
6 Months n (%) n (%)
Treatment failure**** 7 (4.4) 11 (6.7)
Biopsy-proven acute rejection 2 (1.3) 2 (1.2)
Graft loss 0 1 (0.6)
Death 0 1 (0.6)
Lost to follow-up** 5 (3.1) 7 (4.3)
12 Months n (%) n (%)
Graft loss or death or lost to follow-up*** 10 (6.3) 17 (10.4)
Treatment failure***** 12 (7.5) 20 (12.3)
Biopsy-proven acute rejection 2 (1.3) 5 (3.1)
Graft loss 0 1 (0.6)
Death 2 (1.3) 4 (2.5)
Lost to follow-up** 8 (5.0) 10 (6.1)

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