DOSAGE FORMS & STRENGTHS SECTION

3 DOSAGE FORMS AND STRENGTHS

Mycophenolic acid delayed-release tablets, USP are available as 360 mg and 180 mg tablets.

Table 1: Description of Mycophenolic Acid Delayed-Release Tablets

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CONTRAINDICATIONS SECTION

Highlight: Known hypersensitivity to mycophenolate sodium, mycophenolic acid (MPA), mycophenolate mofetil, or to any of its excipients. (4.1)

4 CONTRAINDICATIONS

4.1 Hypersensitivity Reactions

Mycophenolic acid delayed-release tablets are contraindicated in patients with a hypersensitivity to mycophenolate sodium, mycophenolic acid (MPA), mycophenolate mofetil, or to any of its excipients. Reactions like rash, pruritus, hypotension, and chest pain have been observed in clinical trials and post marketing reports [see Adverse Reactions (6)].

BOXED WARNING SECTION

WARNING: EMBRYO-FETAL TOXICITY, MALIGNANCIES, and SERIOUS INFECTIONS

See full prescribing information for complete boxed warning

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ADVERSE REACTIONS SECTION

Highlight: Most common adverse reactions (≥ 20%): anemia, leukopenia, constipation, nausea, diarrhea, vomiting, dyspepsia, urinary tract infection, CMV infection, insomnia, and postoperative pain. (6.2)

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** To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or****www.fda.gov/medwatch.**

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label.

• Embryo-Fetal Toxicity [see Boxed Warning, Warnings and Precautions (5.1)]
• Lymphomas and Other Malignancies [see Boxed Warning, Warnings and Precautions (5.3)]
• Serious Infections [see Boxed Warning, Warnings and Precautions (5.4)]
• New or Reactivated Viral Infections [see Warnings and Precautions (5.5)]
• Blood Dyscrasias, Including Pure Red Cell Aplasia [see Warnings and Precautions (5.6)]
• Serious GI Tract Complications [see Warnings and Precautions (5.7)]
• Acute Inflammatory Syndrome Associated with Mycophenolate Products [see Warnings and Precautions (5.8)]
• Rare Hereditary Deficiencies [see Warnings and Precautions (5.10)]

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below derive from two randomized, comparative, active- controlled, double-blind, double-dummy trials in prevention of acute rejection in de novo and converted stable kidney transplant patients.

In the de novo trial, patients were administered either mycophenolic acid delayed-release tablets 1.44 grams per day (N = 213) or MMF 2 grams per day (N = 210) within 48 hours post-transplant for 12 months in combination with cyclosporine, USP MODIFIED and corticosteroids. Forty-one percent of patients also received antibody therapy as induction treatment. In the conversion trial, renal transplant patients who were at least 6 months post-transplant and receiving 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 were randomized to mycophenolic acid delayed-release tablets 1.44 grams per day (N = 159) or MMF 2 grams per day (N = 163) for 12 months.

The average age of patients in both studies was 47 years and 48 years (de novo study and conversion study, respectively), ranging from 22 to 75 years. Approximately 66% of patients were male; 82% were white, 12% were black, and 6% other races. About 40% of patients were from the United States and 60% from other countries.

In the de novo trial, the overall incidence of discontinuation due to adverse reactions was 18% (39/213) and 17% (35/210) in the mycophenolic acid delayed- release tablets and MMF arms, respectively. The most common adverse reactions leading to discontinuation in the mycophenolic acid delayed-release tablets arm were graft loss (2%), diarrhea (2%), vomiting (1%), renal impairment (1%), CMV infection (1%), and leukopenia (1%). The overall incidence of patients reporting dose reduction at least once during the 0- to 12-month study period was 59% and 60% in the mycophenolic acid delayed-release tablets and MMF arms, respectively. The most frequent reasons for dose reduction in the mycophenolic acid delayed-release tablets arm were adverse reactions (44%), dose reductions according to protocol guidelines (17%), dosing errors (11%) and missing data (2%).

The most common adverse reactions (≥ 20%) associated with the administration of mycophenolic acid delayed-release tablets were anemia, leukopenia, constipation, nausea, diarrhea, vomiting, dyspepsia, urinary tract infection, CMV infection, insomnia, and postoperative pain.

The adverse reactions reported in ≥ 10% of patients in the de novo trial are presented in Table 2 below.

Table 2: Adverse Reactions (%) Reported in ≥ 10% ofde novoKidney Transplant Patients in Either Treatment Group

**The trial was not designed to support comparative claims for mycophenolic acid delayed-release tablets for the adverse reactions reported in this table.

Table 3 summarizes the incidence of opportunistic infections in de novo transplant patients.

Table 3: Viral and Fungal Infections (%) Reported Over 0 to 12 Months

Lymphoma developed in 2 de novo patients (1%), (1 diagnosed 9 days after treatment initiation) and in 2 conversion patients (1%) receiving mycophenolic acid delayed-release tablets with other immunosuppressive agents in the 12-month controlled clinical trials.

Nonmelanoma skin carcinoma occurred in 1% de novo and 12% conversion patients. Other types of malignancy occurred in 1% de novo and 1% conversion patients [see Warnings and Precautions (5.3)].

The adverse reactions reported in less than 10% of de novo or conversion patients treated with mycophenolic acid delayed-release tablets in combination with cyclosporine and corticosteroids are listed in Table 4.

Table 4: Adverse Reactions Reported in < 10% of Patients Treated with Mycophenolic Acid Delayed-Release Tablets in Combination With Cyclosporine and Corticosteroids*

*USP MODIFIED.

The following additional adverse reactions have been associated with the exposure to MPA when administered as a sodium salt or as mofetil ester:

**Gastrointestinal:**Intestinal perforation, gastrointestinal hemorrhage, gastric ulcers, duodenal ulcers [see Warnings and Precautions (5.7)], colitis (including CMV colitis), pancreatitis, esophagitis, and ileus.

Infections**:**Serious life-threatening infections, such as meningitis and infectious endocarditis, tuberculosis, and atypical mycobacterial infection [see Warnings and Precautions (5.4)].

**Respiratory:**Interstitial lung disorders, including fatal pulmonary fibrosis.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of mycophenolic acid delayed-release tablets or other MPA derivatives. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

• Congenital malformations, including ear, facial, cardiac and nervous system malformations and an increased incidence of first trimester pregnancy loss have been reported following exposure to MMF during pregnancy [see Boxed Warning, Warnings and Precautions (5.1)].
• Infections [see Warnings and Precautions (5.4, 5.5)]
  • Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal.
  • Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection, associated with serious outcomes, including deteriorating renal function and renal graft loss.
  • Viral reactivation in patients infected with HBV or HCV.
• Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressive agents [see Warnings and Precautions (5.6)].

The following additional adverse reactions have been identified during post- approval use of mycophenolic acid delayed-release tablets: agranulocytosis, asthenia, osteomyelitis, lymphadenopathy, lymphopenia, wheezing, dry mouth, gastritis, peritonitis, anorexia, alopecia, pulmonary edema, Kaposi’s sarcoma, de novo purine synthesis inhibitors-associated acute inflammatory syndrome.

CLINICAL STUDIES SECTION

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 inde novoRenal Transplant Patients (Percentage 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 delayed-release tablets patients and 4 MMF patients).

95% confidence interval of the difference in treatment failure at 6 months

(mycophenolic acid delayed-release tablets–MMF) is (-8.7%, 8.0%).

95% confidence interval of the difference in treatment failure at 12 months

(mycophenolic acid delayed-release tablets–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*

*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 delayed-release tablets patients and 12 MMF patients).

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

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

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OVERDOSAGE SECTION

10 OVERDOSAGE

Signs and Symptoms

There have been anecdotal reports of deliberate or accidental overdoses with mycophenolic acid delayed-release tablets, whereas not all patients experienced related adverse reactions.

In those overdose cases in which adverse reactions were reported, the reactions fall within the known safety profile of the class. Accordingly, an overdose of mycophenolic acid delayed-release tablets could possibly result in oversuppression of the immune system and may increase the susceptibility to infection, including opportunistic infections, fatal infections and sepsis. If blood dyscrasias occur (e.g., neutropenia with absolute neutrophil count < 1.5 x 103/mcL or anemia), it may be appropriate to interrupt or discontinue mycophenolic acid delayed-release tablets.

Possible signs and symptoms of acute overdose could include the following: hematological abnormalities, such as leukopenia and neutropenia, and gastrointestinal symptoms, such as abdominal pain, diarrhea, nausea and vomiting, and dyspepsia.

Treatment and Management

General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Although dialysis may be used to remove the inactive metabolite mycophenolic acid glucuronide (MPAG), it would not be expected to remove clinically significant amounts of the active moiety, mycophenolic acid, due to the 98% plasma protein binding of mycophenolic acid. By interfering with enterohepatic circulation of mycophenolic acid, activated charcoal or bile sequestrates, such as cholestyramine, may reduce the systemic mycophenolic acid exposure.

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INFORMATION FOR PATIENTS SECTION

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 form of birth control during the 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 Warnings 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 infection as 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)].

Immunizations

Inform patients that mycophenolic acid delayed-release tablets can interfere with the usual response to immunizations and that they should avoid live vaccines. Before seeking vaccines on their own, advise patients to discuss first with their physician [see Warnings and Precautions (5.9)].

Administration Instructions

Advise patients to swallow mycophenolic acid delayed-release tablets whole, and not to crush, chew, or cut the tablets. Inform patients to take mycophenolic acid delayed-release tablets on an empty stomach, 1 hour before or 2 hours after food intake.

Blood Donation

Advise patients not to donate blood during therapy and for at least 6 weeks following discontinuation of mycophenolic acid delayed-release tablets [see Warnings and Precautions (5.11)].

Semen Donation

Advise males of childbearing potential not to donate semen during therapy and for 90 days following discontinuation of mycophenolic acid delayed-release tablets [see Warnings and Precautions (5.12)].

Drug Interactions

Patients should be advised to report to their doctor the use of any other medications while taking mycophenolic acid delayed-release tablets. The simultaneous administration of any of the following drugs with mycophenolic acid delayed-release tablets may result in clinically significant adverse reactions:

• Antacids with magnesium and aluminum hydroxides [see Drug Interactions (7.1)], Clinical Pharmacology (12.3)]
• Azathioprine [see Drug Interactions (7.2)]
• Cholestyramine [see Drug Interactions (7.3), Clinical Pharmacology (12.3)]
• Hormonal Contraceptives (e.g., birth control pill, transdermal patch, vaginal ring, injection, and implant) [see Warnings and Precautions (5.2), Drug Interactions (7.8)]

**Dispense with Medication Guide available at: **www.aurobindousa.com/medication-guides

Distributed by:
Aurobindo Pharma USA, Inc.
****279 Princeton-Hightstown Road
East Windsor, NJ 08520

Manufactured by:
Aurobindo Pharma Limited
****Hyderabad-500 032, India

Issued: December 2023

**Dispense with Medication Guide available at: **www.aurobindousa.com/medication-guides

SPL MEDGUIDE SECTION

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Issued: December 2023

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