Mycophenolic Acid: Package Insert and Label Information (Page 4 of 6)

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 1,440 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 to 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 (Percentage of Patients) at 6 and 12 Months of Treatment when Administered in Combination With Cyclosporine* and Corticosteroids
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
*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%).

The conversion trial was conducted in 322 renal transplant patients (ages 18 to 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 (Percentage of Patients) at 6 and 12 Months of Treatment When Administered in Combination With Cyclosporine* and With or Without Corticosteroids
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)
*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%).

16 HOW SUPPLIED/STORAGE AND HANDLING

Mycophenolic Acid Delayed-Release Tablets, USP are available containing mycophenolate sodium, USP equivalent to 180 mg or 360 mg of mycophenolic acid.

360 mg tablet: Pale orange-red, oval shaped biconvex coated tablets free from physical defects, debossed with “B360” on one side and plain on other side.

Bottles of 120 tablets with child-resistant closure…………………………..NDC 70377-040-11

180 mg tablet: Lime green, round shaped beveled edged coated tablets free from physical defects, debossed with “B180” on one side and plain on other.

Bottles of 120 tablets with child-resistant closure……………………….…NDC 70377-039-11

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container (USP).

Handling

Keep out of reach and sight of children. Mycophenolic acid delayed-release tablets should not be crushed or cut in order to maintain the integrity of the enteric coating [see Dosage and Administration ( 2.3) ].

Teratogenic effects have been observed with mycophenolate sodium [see Warnings and Precautions ( 5.1) ]. If for any reason, the mycophenolic acid delayed-release tablets must be crushed, avoid inhalation of the powder, or direct contact of the powder, with skin or mucous membranes.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Embryo-Fetal Toxicity

Pregnancy loss and malformations

  • Inform pregnant women and females of reproductive potential that use of mycophenolic acid delayed-release tablets in pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations. Advise patients that they must use an acceptable form of contraception [see Warnings and Precautions (5.1), Use in Specific Populations ( 8.1, 8.3) ].
  • Encourage pregnant women to enroll in the Mycophenolate Pregnancy Registry (1-800-617-8191). This registry monitors pregnancy outcomes in women exposed to mycophenolate [see Use in Specific Populations (8.1)].

Contraception

  • Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential [see Use in Specific Populations (8.3)].
  • Females of reproductive potential must use acceptable birth control during entire mycophenolic acid delayed-release tablets therapy and for 6 weeks after stopping mycophenolic acid delayed-release tablets, unless the patient chooses to avoid heterosexual sexual intercourse completely (abstinence) Mycophenolic acid delayed-release tablets may reduce effectiveness of oral contraceptives. Use of additional barrier contraceptive methods is recommended [see Use in Specific Populations (8.3)].
  • For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryo-fetal toxicity. Risks and benefits of mycophenolic acid delayed-release tablets should be discussed with the patient [see Use in Specific Populations (8.3)].
  • Advise sexually active male patients and/or their partners to use effective contraception during the treatment of the male patient and for at least 90 days after cessation of treatment. This recommendation is based on findings of animal studies

Development of Lymphoma and Other Malignancies

  • Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. [see Warnings and Precautions (5.3)].
  • Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a broad-spectrum sunscreen with a high protection factor. [see W arnings and Precautions (5.3) ].

Increased Risk of Infection

Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infectionas explained in the Medication Guide [see Warnings and Precautions (5.4, 5.5) ].

Blood Dyscrasias

Inform patients they are at increased risk for developing blood dyscrasias (e.g., neutropenia or anemia) and to immediately contact their healthcare provider if they experience any evidence of infection, unexpected bruising, bleeding, or any other manifestation of bone marrow suppression [see Warnings and Precautions ( 5.6) ].

Gastrointestinal Tract Complications

Inform patients that mycophenolic acid delayed-release tablets can cause gastrointestinal tract complications, including bleeding, intestinal perforations, and gastric or duodenal ulcers. Advise the patient to contact their healthcare provider if they have symptoms of gastrointestinal bleeding or sudden onset or persistent abdominal pain [see Warnings and Precautions ( 5.7) ].

Acute Inflammatory Syndrome

Inform patients that acute inflammatory reactions have been reported in some patients who received mycophenolate products. Some reactions were severe, requiring hospitalization. Advise patients to contact their physician if they develop fever, joint stiffness, joint pain or muscle pains [see Warnings and Precautions (5.8) ].

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