NDC 68254-5000 Mycophenolate Mofetil

Mycophenolate Mofetil

NDC Product Code 68254-5000

NDC Code: 68254-5000

Proprietary Name: Mycophenolate Mofetil What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Mycophenolate Mofetil What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
BLUE (C48333)
BROWN (C48332)
Shape: CAPSULE (C48336)
Size(s):
19 MM
Imprint(s):
C3;250
Score: 1

NDC Code Structure

NDC 68254-5000-1

Package Description: 100 CAPSULE in 1 BOTTLE

NDC 68254-5000-2

Package Description: 500 CAPSULE in 1 BOTTLE

NDC Product Information

Mycophenolate Mofetil with NDC 68254-5000 is a a human prescription drug product labeled by Concord Biotech Limited. The generic name of Mycophenolate Mofetil is mycophenolate mofetil. The product's dosage form is capsule and is administered via oral form.

Labeler Name: Concord Biotech Limited

Dosage Form: Capsule - A solid oral dosage form consisting of a shell and a filling. The shell is composed of a single sealed enclosure, or two halves that fit together and which are sometimes sealed with a band. Capsule shells may be made from gelatin, starch, or cellulose, or other suitable materials, may be soft or hard, and are filled with solid or liquid ingredients that can be poured or squeezed.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Mycophenolate Mofetil Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • MYCOPHENOLATE MOFETIL 250 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • POVIDONE K90 (UNII: RDH86HJV5Z)
  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • TALC (UNII: 7SEV7J4R1U)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • GELATIN (UNII: 2G86QN327L)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • WATER (UNII: 059QF0KO0R)
  • SHELLAC (UNII: 46N107B71O)
  • ALCOHOL (UNII: 3K9958V90M)
  • ISOPROPYL ALCOHOL (UNII: ND2M416302)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • AMMONIA (UNII: 5138Q19F1X)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)
  • HYDROXYPROPYL CELLULOSE (110000 WAMW) (UNII: 5Y0974F5PW)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Antimetabolite Immunosuppressant - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Concord Biotech Limited
Labeler Code: 68254
FDA Application Number: ANDA210181 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 10-01-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Mycophenolate Mofetil Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Other

  • Use during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations. Avoid if safer treatment options are available. Females of reproductive potential must be counseled regarding pregnancy prevention and planning [see Warnings and Precautions (5.1), Use in Special Populations (8.1, 8.3)] .  Increased risk of development of lymphoma and other malignancies, particularly of the skin [see Warnings and Precautions (5.2)].  Increased susceptibility to bacterial, viral, fungal and protozoal infections, including opportunistic infections and viral reactivation of hepatitis B and C, which may lead to hospitalizations and fatal outcomes [see Warnings and Precautions (5.3)].

Mycophenolate mofetil capsules are indicated for the prophylaxis of organ rejection, in recipients of allogeneic kidney [see Clinical Studies (14.1)], heart [see Clinical Studies (14.2)] or liver transplants [see Clinical Studies (14.3)], in combination with other immunosuppressant.

  • The following adverse reactions are discussed in greater detail in other sections of the label:Embryofetal Toxicity [see Warnings and Precautions (5.1)]Lymphomas and Other Malignancies [see Warnings and Precautions 5.2)]Serious Infections [see Warnings and Precautions (5.3)]Blood Dyscrasias: Neutropenia, Pure Red Cell Aplasia [see Warnings and Precautions (5.4)]Gastrointestinal Complications [see Warnings and Precautions (5.5)]

2.1 Important Administration Instructions

Mycophenolate mofetil capsulesMycophenolate mofetil capsules should not be used interchangeably with mycophenolic acid delayed-release tablets without supervision of a physician with experience in immunosuppressive therapy because the rates of absorption following the administration of Mycophenolate mofetil capsules and mycophenolic acid delayed-release tablets are not equivalent.Mycophenolate mofetil capsules should not be opened or crushed. Patients should avoid inhalation or contact of the skin or mucous membranes with the powder contained in Mycophenolate mofetil capsules. If such contact occurs, they must wash the area of contact thoroughly with soap and water. In case of ocular contact, rinse eyes with plain water.The initial oral dose of Mycophenolate mofetil capsules should be given as soon as possible following kidney, heart or liver transplant. It is recommended that Mycophenolate mofetil capsules be administered on an empty stomach. In stable transplant patients, however Mycophenolate mofetil capsules may be administered with food if necessary [see Clinical Pharmacology (12.3)]. Patients should be instructed to take a missed dose as soon as they remember, except if it is closer than 2 hours to the next scheduled dose; in this case, they should continue to take Mycophenolate mofetil capsules at the usual times.

2.2 Dosing For Kidney Transplant Patients: Adults And Pediatrics

AdultsThe recommended dose for adult kidney transplant patients is 1 g orally, twice daily (daily dose of 2 g).Pediatrics (3 months and older)Pediatric dosing is based on body surface area (BSA). Pediatric patients with BSA ≥1.25 m2  may be dosed with capsules as follows: Table 1. Pediatric Dosing Using Capsules for Pediatric Kidney Transplant Body Surface Area Dosing 1.25 m2  to  <1.5 m2 Mycophenolate mofetil capsule 750 mg twice daily (1.5 g daily dose) ≥ 1.5 m2 Mycophenolate mofetil capsules 1 g twice daily (2 g daily dose)

2.3 Dosing For Heart Transplant Patients: Adults

The recommended dose of Mycophenolate mofetil capsules for adult heart transplant patients is 1.5 g orally administered twice daily (daily dose of 3 g).

2.4 Dosing For Liver Transplant Patients: Adults

The recommended dose of Mycophenolate mofetil capsules for adult liver transplant patients is 1.5 g administered orally twice daily (daily dose of 3 g).

2.5 Dosing Adjustments: Patients With Renal Impairment, Neutropenia

Renal ImpairmentNo dose adjustments are needed in kidney transplant patients with delayed graft function postoperatively [see Clinical Pharmacology (12.3)]. In kidney transplant patients with severe chronic impairment of the graft (GFR <25 mL/min/1.73 m2), do not administer doses of Mycophenolate mofetil capsules greater than 1 g twice a day. These patients should be carefully monitored [see Clinical Pharmacology (12.3)].  NeutropeniaIf neutropenia develops (ANC <1.3 × 103/µL), dosing with Mycophenolate mofetil capsules should be interrupted or reduced, appropriate diagnostic tests performed, and the patient managed appropriately [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

3 Dosage Forms And Strengths

Mycophenolate mofetil is available in the following dosage form and strength: Capsules 250 mg mycophenolate mofetil, White to off white granular powder filled in size '1' hard gelatin capsule with opaque blue cap imprinted "C3 250" and opaque brown body.

4 Contraindications

Allergic reactions to Mycophenolate mofetil capsules have been observed; therefore, Mycophenolate mofetil capsules are contraindicated in patients with a hypersensitivity to mycophenolate mofetil (MMF), mycophenolic acid (MPA) or any component of the drug product.

5.1 Embryofetal Toxicity

Use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney and nervous system. Females of reproductive potential must be made aware of these risks and must be counseled regarding pregnancy prevention and planning. Avoid use of MMF during pregnancy if safer treatment options are available [see Use in Specific Populations (8.1, 8.3)].

5.2 Lymphoma And Other Malignancies

Patients receiving immunosuppressant, including Mycophenolate mofetil capsules, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Adverse Reactions (6.1)]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. For patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.Post-transplant lymphoproliferative disorder (PTLD) developed in 0.4% to 1% of patients receiving Mycophenolate mofetil capsules (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of kidney, heart, and liver transplant patients [see Adverse Reactions (6.1)]. In pediatric patients, no other malignancies besides PTLD were observed in clinical trials [see Adverse Reactions (6.1)].

5.3 Serious Infections

  • Patients receiving immunosuppressants, including Mycophenolate mofetil capsules, are at increased risk of developing bacterial, fungal, protozoal and new or reactivated viral infections, including opportunistic infections. The risk increases with the total immunosuppressive load. These infections may lead to serious outcomes, including hospitalizations and death [see Adverse Reactions (6.1), (6.2)].Serious viral infections reported include:  Polyomavirus-associated nephropathy (PVAN), especially due to BK virus infection  JC virus-associated progressive multifocal leukoencephalopathy (PML), and  Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease.  Viral reactivation in patients infected with Hepatitis B and CConsider reducing immunosuppression in patients who develop new infections or reactivate viral infections, weighing the risk that reduced immunosuppression represents to the functioning allograft.PVAN, especially due to BK virus infection, is associated with serious outcomes, including deteriorating renal function and renal graft loss [see Adverse Reactions (6.2)]. Patient monitoring may help detect patients at risk for PVAN.PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia [see Adverse Reactions (6.2)]. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms.The risk of CMV viremia and CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receives a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease.Viral reactivation has been reported in patients infected with HBV or HCV. Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended.

5.4 Blood Dyscrasias: Neutropenia And Pure Red Cell Aplasia (Prca)

Severe neutropenia [absolute neutrophil count (ANC) <0.5 × 103/µL] developed in transplant patients receiving Mycophenolate mofetil 3 g daily [see Adverse Reactions (6.1)]. Patients receiving Mycophenolate mofetil should be monitored for neutropenia. Neutropenia has been observed most frequently in the period from 31 to 180 days post-transplant in patients treated for prevention of kidney, heart and liver rejection. The development of neutropenia may be related to Mycophenolate mofetil itself, concomitant medications, viral infections, or a combination of these causes. If neutropenia develops (ANC <1.3 × 103/µL), dosing with Mycophenolate mofetil capsules should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately [see Dosage and Administration (2.5)].Patients receiving Mycophenolate mofetil capsules should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.Consider monitoring with complete blood counts weekly for the first month, twice monthly for the second and third months and, monthly for the remainder of the first year.Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Mycophenolate mofetil in combination with other immunosuppressive agents. In some cases, PRCA was found to be reversible with dose reduction or cessation of Mycophenolate mofetil therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk.

5.5 Gastrointestinal Complications

Gastrointestinal bleeding requiring hospitalization, ulceration and perforations were observed in clinical trials. Physicians should be aware of these serious adverse effects particularly when administering Mycophenolate mofetil capsules to patients with a gastrointestinal disease.

5.6 Patients With Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency (Hgprt)

Mycophenolate mofetil is an inosine monophosphate dehydrogenase (IMPDH) inhibitor; therefore it should be avoided in patients with hereditary deficiencies of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndromes because it may cause an exacerbation of disease symptoms characterized by the overproduction and accumulation of uric acid leading to symptoms associated with gout such as acute arthritis, tophi, nephrolithiasis or urolithiasis and renal disease including renal failure.

5.7 Immunizations

During treatment with Mycophenolate mofetil capsules, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Advise patients to discuss with the physician before seeking any immunizations.

5.10 Blood Donation

Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of Mycophenolate mofetil capsules because their blood or blood products might be administered to a female of reproductive potential or a pregnant woman.

5.11 Semen Donation

Based on animal data, men should not donate semen during therapy and for 90 days following discontinuation of Mycophenolate mofetil capsules [see Use in Specific Populations (8.3)].

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 primarily derive from five randomized, active-controlled double-blind 12-month trials of Mycophenolate mofetil in de novo kidney (3) heart (1) and liver (1) transplant patients [see Clinical Studies (14.1, 14.2 and 14.3)].Mycophenolate mofetil OralThe incidence of adverse reactions for Mycophenolate mofetil was determined in five randomized, comparative, double-blind trials in the prevention of rejection in kidney, heart and liver transplant patients (two-active and one placebo-controlled trials, one active-controlled trial, and one active-controlled trial, respectively) [see Clinical Studies (14.1, 14.2 and 14.3)].The three de novo kidney studies with 12-month duration compared two dose levels of oral Mycophenolate mofetil (1 g twice daily and 1.5 g twice daily) with azathioprine (2 studies) or placebo (1 study) when  administered in combination with cyclosporine (Sandimmune®) and corticosteroids to prevent acute rejection episodes. One study also included anti-thymocyte globulin (ATGAM®) induction therapy.In the de novo heart transplantation study with 12-month duration, patients received Mycophenolate mofetil 1.5 g twice daily (n=289) or azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine (Sandimmune® or Neoral®) and corticosteroids as maintenance immunosuppressive therapy.In the de novo liver transplantation study with 12-month duration, patients received Mycophenolate mofetil 1 g twice daily intravenously for up to 14 days followed by Mycophenolate mofetil 1.5 g twice daily orally or azathioprine 1 to 2 mg/kg/day intravenously followed by azathioprine 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The total number of patients enrolled was 565.Approximately 53% of the kidney transplant patients, 65% of the heart transplant patients, and 48% of the liver transplant patients were treated for more than 1 year. Adverse reactions reported in ≥ 20% of patients in the Mycophenolate mofetil treatment groups are presented below. The safety data of three kidney transplantation studies are pooled together. Table 3. Adverse Reactions in Controlled Studies of De Novo Kidney, Heart or Liver Transplantation (Reported in ≥20% of Patients in the Mycophenolate mofetil Group) Kidney Studies Heart Study Liver Study Mycophenolate mofetil  2 g/day Mycophenolate mofetil 3 g/day Azathioprine 1 to 2 mg/kg/day or 100 to 150 mg/day Mycophenolate mofetil 3 g/day Azathioprine 1.5 to 3 mg/kg/ day Mycophenolate mofetil  3 g/day Azathioprine 1 to 2 mg/kg/day (n=336) (n=330) (n=326) (n=289) (n=289) (n=277) (n=287) % % % % % % % Body as a Whole   Infection 18.2 20.9 19.9 25.6 19.4 27.1 25.1   Sepsis – – – – – 27.4 26.5   Ascites – – – – – 24.2 22.6 Hematologic and Lymphatic   Anemia 25.6 25.8 23.6 42.9 43.9 43.0 53.0   Leukopenia 23.2 34.5 24.8 30.4 39.1 45.8 39.0   Thrombocytopenia – – – 23.5 27.0 38.3 42.2   Leukocytosis – – – 40.5 35.6 22.4 21.3 Urogenital   Urinary tract infection 37.2 37.0 33.7 – – – – Cardiovascular   Hypertension 32.4 28.2 32.2 77.5 72.3 62.1 59.6   Hypotension – – – 32.5 36.0 – –   Tachycardia – – – 20.1 18.0 22.0 15.7 Metabolic and Nutritional   Peripheral edema 28.6 27.0 28.2 64.0 53.3 48.4 47.7   Hyper- cholesterolemia – – – 41.2 38.4 – –   Edema – – – 26.6 25.6 28.2 28.2   Hypokalemia – – – 31.8 25.6 37.2 41.1   Hyperkalemia – – – – – 22.0 23.7   Hyperglycemia – – – 46.7 52.6 43.7 48.8   Creatinine increased – – – 39.4 36.0 – –   BUN increased – – – 34.6 32.5 – –   Lactic dehydrogenase increased – – – 23.2 17.0 – –    Hypomagnesemia – – – – – 39.0 37.6    Hypocalcemia – – – – – 30.0 30.0 Digestive    Diarrhea 31.0 36.1 20.9 45.3 34.3 51.3 49.8    Constipation 22.9 18.5 22.4 41.2 37.7 37.9 38.3    Nausea 19.9 23.6 24.5 54.0 54.3 54.5 51.2    Dyspepsia – – – – – 22.4 20.9    Vomiting – – – 33.9 28.4 32.9 33.4    Anorexia – – – – – 25.3 17.1    Liver function tests abnormal – – – – – 24.9 19.2 Respiratory    Infection 22.0 23.9 19.6 37.0 35.3 – –    Dyspnea – – – 36.7 36.3 31.0 30.3    Cough increased – – – 31.1 25.6 – –    Sinusitis – – – 26.0 19.0 – –    Pleural effusion – – – – – 34.3 35.9 Skin and Appendages    Rash – – – 22.1 18.0 – – Nervous System    Tremor – – – 24.2 23.9 33.9 35.5    Insomnia – – – 40.8 37.7 52.3 47.0    Dizziness – – – 28.7 27.7 – –    Anxiety – – – 28.4 23.9 – –    Paresthesia – – – 20.8 18.0 – –In the three de novo kidney studies, patients receiving 2 g/day of Mycophenolate mofetil had an overall better safety profile than did patients receiving 3 g/day of Mycophenolate mofetil.Post-transplant lymphoproliferative disease (PTLD) developed in 0.4% to 1% of patients receiving Mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressive agents in controlled clinical trials of kidney, heart and liver transplant patients followed for at least 1 year [see Warnings and Precautions (5.2)]. Non-melanoma skin carcinomas occurred in 1.6% to 4.2% of patients, other types of malignancy  in 0.7% to 2.1% of patients. Three-year safety data in kidney and heart transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. In pediatric patients, PTLD was observed in 1.35% (2/148) by 12 months post-transplant.Severe neutropenia (ANC <0.5 × 103/µL) developed in up to 2.0% of kidney transplant patients, up to 2.8% of heart transplant patients and up to 3.6% of liver transplant patients receiving Mycophenolate mofetil 3 g daily [see Warnings and Precautions (5.4) and Dosage and Administration (2.5)].Table 4 shows the incidence of opportunistic infections that occurred in the kidney, heart, and liver transplant populations in the azathioprine-controlled prevention trials: Table 4. Opportunistic Viral and Fungal Infections in Controlled Studies of De Novo Kidney, Heart or Liver Transplantation Kidney Studies Heart Study Liver Study Mycophenolate mofetil 2 g/day Mycophenolate mofetil 3 g/day Azathioprine 1 to 2 mg/kg/day or 100 to 150 mg/day Mycophenolate mofetil 3 g/day Azathioprine 1.5 to 3 mg/kg/ day Mycophenolate mofetil 3 g/day Azathioprine  1 to 2 mg/kg/ day (n=336) (n=330) (n=326) (n=289) (n=289) (n=277) (n=287) % % % % % % % Herpes simplex 16.7 20.0 19.0 20.8 14.5 10.1 5.9 Cytomegalovirus – Viremia/syndrome 13.4 12.4 13.8 12.1 10.0 14.1 12.2 – Tissue invasive disease 8.3 11.5 6.1 11.4 8.7 5.8 8.0 Herpes zoster 6.0 7.6 5.8 10.7 5.9 4.3 4.9 – Cutaneous disease 6.0 7.3 5.5 10.0 5.5 4.3 4.9 Candida 17.0 17.3 18.1 18.7 17.6 22.4 24.4 – Mucocutaneous 15.5 16.4 15.3 18.0 17.3 18.4 17.4The following other opportunistic infections occurred with an incidence of less than 4% in Mycophenolate mofetil patients in the above azathioprine-controlled studies: Herpes zoster visceral disease; Candida urinary tract infection, fungemia/disseminated disease and tissue invasive disease; Cryptococcosis; Aspergillus/Mucor; Pneumocystis jirovecii.In patients receiving Mycophenolate mofetil (2 g or 3 g) in controlled studies for prevention of kidney, heart or liver rejection, fatal infection/sepsis occurred in approximately 2% of kidney and heart patients and in 5% of liver patients [see Warnings and Precautions  (5.3)].The following adverse reactions were reported with 3% to <20% incidence in kidney, heart, and liver transplant patients treated with Mycophenolate mofetil, in combination with cyclosporine and corticosteroids. Table 5. Adverse Reactions Reported in 3% to <20% of Patients Treated With Mycophenolate mofetil in Combination with Cyclosporine and Corticosteroids Body System Adverse Reactions Body as a Whole Abscess, cellulitis, chills occurring with fever, malaise, peritonitis Hematologic and Lymphatic coagulation disorder, ecchymosis, pancytopenia, petechia, polycythemia, prothrombin time increased, thromboplastin time increased Urogenital acute kidney failure, albuminuria, dysuria, hematuria, kidney failure, kidney tubular necrosis, pain, pyelonephritis, scrotal edema Cardiovascular angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, congestive heart failure, extrasystole, heart failure, hypotension, palpitation, pericardial effusion, pulmonary hypertension, supraventricular tachycardia, supraventricular extrasystoles, syncope, tachycardia, ventricular  extrasystole, ventricular tachycardia Metabolic and Nutritional acidosis,  hypercholesteremia, hyperlipemia Digestive anorexia, esophagitis, flatulence, gastritis, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, gum hyperplasia, hepatitis, ileus, jaundice,  melena, mouth ulceration, nausea and vomiting, oral moniliasis, stomach ulcer, stomatitis Respiratory bronchitis, epistaxis, hemoptysis, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory moniliasis, rhinitis, sinusitis Skin and Appendages acne, fungal dermatitis, hemorrhage, hirsutism, pruritus, rash, skin benign neoplasm, skin carcinoma, vesiculobullous  rashPediatric StudyThe type and frequency of adverse events in a clinical study for prevention of kidney allograft rejection in 100 pediatric patients 3 months  to  18 years of age dosed with Mycophenolate mofetil oral suspension 600   mg/m2  twice daily (up to 1 g twice daily) were generally similar to  those observed in adult patients  dosed with Mycophenolate mofetil capsules at a dose of 1 g twice daily with the exception of abdominal pain, fever, infection, pain, sepsis, diarrhea, vomiting, pharyngitis, respiratory tract infection, hypertension, leukopenia, and anemia, which were observed in a higher proportion in pediatric   patients.GeriatricsElderly patients (≥65 years), particularly those who are receiving Mycophenolate mofetil as part of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus [CMV] tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema,  compared to  younger individuals [see Warnings and Precautions (5.3) and Adverse Reactions  (6.1)].Mycophenolate mofetil IntravenousThe safety profile of Mycophenolate mofetil Intravenous was determined from a single, double-blind, controlled comparative study of the safety of 2 g/day of intravenous and oral Mycophenolate mofetil in kidney transplant patients in the immediate post-transplant period (administered for the first 5 days). The potential venous irritation of Mycophenolate mofetil Intravenous was evaluated by comparing the adverse reactions attributable to peripheral venous infusion of Mycophenolate mofetil Intravenous with those observed in the intravenous placebo group; patients in the placebo group received active medication by the oral route.Adverse reactions attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4% in patients treated with Mycophenolate mofetil Intravenous.

6.2 Postmarketing Experience

  • The following adverse reactions have been identified during post-approval use of Mycophenolate mofetil. 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:Embryo-Fetal Toxicity: Congenital malformations, and spontaneous abortions, mainly in the first trimester, have been reported following exposure to mycophenolate mofetil (MMF) in combination with other immunosuppressants during pregnancy [see Warnings and Precautions (5.1), and Use in Specific Populations (8.1), (8.3)]. Congenital malformations include:Facial malformations: cleft lip, cleft palate, micrognathia, hypertelorism of the orbitsAbnormalities of the ear and eye: abnormally formed or absent external/middle ear, coloboma, microphthalmosMalformations  of the  fingers: polydactyly, syndactyly, brachydactylyCardiac  abnormalities: atrial and ventricular septal  defectsEsophageal  malformations: esophageal atresiaNervous system malformations: such as spina bifida.Digestive: colitis, pancreatitis, isolated cases of intestinal villous atrophy.Hematologic and Lymphatic: Cases of pure red cell aplasia (PRCA) and hypogammaglobulinemia have been reported in patients treated with Mycophenolate mofetil in combination with other immunosuppressive agents [see Warnings and Precautions (5.4)] .Infections : Meningitis, infectious endocarditis, tuberculosis, atypical mycobacterial infection, progressive multifocal leukoencephalopathy, BK virus infection, viral reactivation of hepatitis B and hepatitis C [see Warnings and Precautions (5.3)] .Respiratory : Interstitial lung disorders, fatal pulmonary fibrosis, have been reported rarely and should be considered in the differential diagnosis of pulmonary symptoms ranging from dyspnea to respiratory failure in post-transplant patients receiving Mycophenolate mofetil.

7.1 Effect Of Other Drugs On Mycophenolate Mofetil

Table 6. Drug Interactions with Mycophenolate mofetil that Affect Mycophenolic Acid (MPA) Exposure Antacids with Magnesium or Aluminum HydroxideClinical Impact Concomitant use with an antacid containing magnesium or aluminum hydroxide decreases MPA systemic exposure [see Clinical Pharmacology (12.3)] , which may reduce Mycophenolate mofetil efficacy.Prevention or Management Administer magnesium or aluminum hydroxide containing antacids at least 2h after Mycophenolate mofetil administration. Proton Pump Inhibitors (PPIs)Clinical Impact Concomitant use with PPIs decreases MPA systemic exposure [see Clinical Pharmacology (12.3)] , which may reduce Mycophenolate mofetil   efficacy.Prevention or Management Monitor patients for alterations in efficacy when PPIs are co-administered with Mycophenolate mofetil.Examples Lansoprazole, pantoprazole Drugs  that Interfere  with Enterohepatic RecirculationClinical Impact Concomitant use with drugs that directly interfere with enterohepatic recirculation, or indirectly interfere with enterohepatic recirculation by altering the gastrointestinal flora, can decrease MPA systemic exposure [see Clinical Pharmacology (12.3)] , which may reduce Mycophenolate mofetil efficacy.Prevention or Management Monitor patients for alterations in efficacy or Mycophenolate mofetil related adverse reactions when these drugs are co-administered with   Mycophenolate mofetil.Examples Trimethoprim/sulfamethoxazole, bile acid sequestrants (cholestyramine), rifampin as well as aminoglycoside, cephalosporin, fluoroquinolone and penicillin classes of antimicrobials Drugs Modulating GlucuronidationClinical Impact Concomitant use with drugs inducing glucuronidation decreases MPA systemic exposure, potentially reducing Mycophenolate mofetil efficacy, while use with drugs inhibiting glucuronidation increases MPA systemic exposure [see Clinical Pharmacology (12.3)] , which may increase the risk of Mycophenolate mofetil related adverse reactions.Prevention or Management Monitor patients for alterations in efficacy or Mycophenolate mofetil related adverse reactions when these drugs are co-administered with   Mycophenolate mofetil.Examples Telmisartan (induces glucuronidation); isavuconazole (inhibits glucuronidation). Calcium  Free  Phosphate BindersClinical Impact Concomitant use with calcium free phosphate binders decrease MPA systemic exposure [see Clinical Pharmacology (12.3)] , which may reduce Mycophenolate mofetil efficacy.Prevention or Management Administer calcium free phosphate binders at least 2 hours after Mycophenolate mofetil.Examples Sevelamer

7.2 Effect Of Mycophenolate Mofetil On Other Drugs

Table 7. Drug Interactions with Mycophenolate mofetil that Affect Other Drugs Drugs that Undergo Renal Tubular SecretionClinical Impact When concomitantly used with Mycophenolate mofetil, its metabolite MPAG, may compete with drugs eliminated by renal tubular secretion which may increase plasma concentrations and/or adverse reactions associated with these drugs.Prevention or Management Monitor for drug-related adverse reactions in patients with renal impairment.Examples Acyclovir, ganciclovir, probenecid, valacyclovir, valganciclovir Combination  Oral ContraceptivesClinical Impact Concomitant use with Mycophenolate mofetil decreased the systemic exposure to levonorgestrel, but did not affect the systemic exposure to ethinylestradiol [see Clinical Pharmacology (12.3)] , which may result in reduced combination oral contraceptive effectiveness.Prevention or Management Use additional barrier contraceptive methods.

8.1 Pregnancy

Pregnancy Exposure RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to mycophenolate during pregnancy and those becoming pregnant within 6 weeks of discontinuing Mycophenolate mofetil treatment. To report a pregnancy or obtain information about the registry, visit www.mycophenolateREMS.com or call 1-800-617-8191.Risk SummaryUse of mycophenolate mofetil (MMF) during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of multiple congenital malformations in multiple organ systems [see Human Data]. Oral administration of mycophenolate to rats and rabbits during the period of organogenesis produced congenital malformations and pregnancy loss at doses less than the recommended clinical dose (0.02 to 0.1 times the recommended clinical doses in kidney and heart transplant patients) [see Animal Data].Consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of Mycophenolate mofetil capsules should be discussed with the pregnant woman.The estimated background risk of pregnancy loss and congenital malformations in organ transplant populations is not clear. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.DataHuman DataA spectrum of congenital malformations (including multiple malformations in individual newborns) has been reported in 23 to 27% of live births in MMF exposed pregnancies, based on published data from pregnancy registries. Malformations that have been documented include external ear, eye, and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney, and nervous system.Based on published data from pregnancy registries, the risk of first trimester pregnancy loss has been reported at 45 to 49% following MMF exposure.Animal DataIn animal reproductive toxicology studies, there were increased rates of fetal resorptions and malformations in the absence of maternal toxicity. Oral administration of MMF to pregnant rats from Gestational Day 7 to Day 16 produced increased embryofetal lethality and fetal malformations including anophthalmia, agnathia, and hydrocephaly at doses equivalent to 0.03 and 0.02 times the recommended human doses for renal and cardiac transplant patients, respectively, when corrected for BSA. Oral administration of MMF to pregnant rabbits from Gestational Day 7 to Day 19 produced increased embryofetal lethality and fetal malformations included ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia at dose equivalents as low as 0.1 and 0.06 times the recommended human doses for renal and cardiac transplant patients, respectively, when corrected for BSA.

8.2 Lactation

Risk SummaryThere are no data on the presence of mycophenolate in human milk, or the effects on milk production. There are limited data in the National Transplantation Pregnancy Registry on the effects of mycophenolate on a breastfed child [see Data]. Studies in rats treated with MMF have shown mycophenolic acid (MPA) to be present in milk. Because available data are limited, it is not possible to exclude potential risks to a breastfeeding infant.The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Mycophenolate mofetil and any potential adverse effects on the breastfed infant from Mycophenolate mofetil or from the underlying maternal condition.DataLimited information is available from the National Transplantation Pregnancy Registry. Of seven infants reported by the National Transplantation Pregnancy Registry to have been breastfed while the mother was taking mycophenolate, all were born at 34-40 weeks gestation, and breastfed for up to 14 months. No adverse events were reported.

8.3 Females And Males Of Reproductive Potential

  • Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning.Pregnancy PlanningFor patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity whenever possible. Risks and benefits of Mycophenolate mofetil capsules should be discussed with the patient.Pregnancy TestingTo prevent unplanned exposure during pregnancy, all females of reproductive potential should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL immediately before starting Mycophenolate mofetil capsules. Another pregnancy test with the same sensitivity should be done 8 to 10 days later. Repeat pregnancy tests should be performed during routine follow-up visits. Results of all pregnancy tests should be discussed with the patient. In the event of a positive pregnancy test, consider alternative immunosuppressants with less potential for embryofetal toxicity whenever possible.ContraceptionFemale PatientsFemales of reproductive potential taking Mycophenolate mofetil capsules must receive contraceptive counseling and use acceptable contraception (see Table 8 for acceptable contraception methods). Patients must use acceptable birth control during the entire Mycophenolate mofetil capsules therapy, and for 6 weeks after stopping Mycophenolate mofetil capsules, unless the patient chooses abstinence.Patients should be aware that Mycophenolate mofetil capsules reduces blood levels of the hormones from the oral contraceptive pill and could theoretically reduce its effectiveness [see Drug Interactions (7.2)]. Table 8. Acceptable Contraception Methods for Females of Reproductive Potential Pick from the following birth control options: Option 1 Methods to Use AloneIntrauterine devices (IUDs)Tubal sterilizationPatient's partner vasectomy OR Option 2 Hormone Methods choose 1 Barrier Methods choose 1 Choose One Hormone Method AND One Barrier Method Estrogen and ProgesteroneOral Contraceptive PillTransdermal patchVaginal ring Progesterone-onlyInjectionImplant ANDDiaphragm with spermicideCervical cap with spermicideContraceptive spongeMale condomFemale condom OR Option 3 Barrier Methods choose 1 Barrier Methods choose 1 Choose One Barrier Method from each column (must choose two methods)Diaphragm with spermicideCervical cap with spermicideContraceptive sponge ANDMale condomFemale condomMale PatientsGenotoxic effects have been observed in animal studies at exposures exceeding the human therapeutic exposures by approximately 2.5 times. Thus, the risk of genotoxic effects on sperm cells cannot be excluded. Based on this potential risk, sexually active male patients and/or their female partners are recommended to use effective contraception during treatment of the male patient and for at least 90 days after cessation of treatment. Also, based on the potential risk of genotoxic effects, male patients should not donate sperm during treatment with Mycophenolate mofetil capsules and for at least 90 days after cessation of treatment [see Use in Special Populations (8.1), Nonclinical Toxicology (13.1), Patient Counseling Information (17.9)].

8.4 Pediatric Use

Safety and effectiveness of Mycophenolate mofetil have been established in pediatric patients 3 months and older for the prophylaxis of kidney rejection after allogeneic kidney transplant. Use of Mycophenolate mofetil in this population is supported by evidence from adequate and well-controlled studies of Mycophenolate mofetil in adults with additional data from one open-label, pharmacokinetic and safety study of Mycophenolate mofetil in pediatric patients after receiving allogeneic kidney transplant [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)].Safety and effectiveness in pediatric patients receiving allogeneic heart or liver transplants have not been established.

8.5 Geriatric Use

Clinical studies of Mycophenolate mofetil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should take into consideration the presence of decreased hepatic, renal or cardiac function and of concomitant drug therapies. [see Adverse Reactions (6.1), Drug Interactions (7)].

8.6 Patients With Renal Impairment

Patients with Kidney TransplantNo dose adjustments are needed in kidney transplant patients experiencing delayed graft function postoperatively but patients should be carefully monitored [see Clinical Pharmacology (12.3)].In kidney transplant patients with severe chronic impairment of the graft (GFR <25 mL/min/1.73 m2), no dose adjustment is necessary; however, doses greater than 1 g administered twice a day should be avoided.Patients with Heart and Liver TransplantNo data are available for heart or liver transplant patients with severe chronic renal impairment. Mycophenolate mofetil capsules may be used for heart or liver transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.

8.7 Patients With Hepatic Impairment

Patients with Kidney TransplantNo dose adjustments are recommended for kidney transplant patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies [see Clinical Pharmacology (12.3)].Patients with Heart TransplantNo data are available for heart transplant patients with severe hepatic parenchymal disease.

10 Overdosage

Possible signs and symptoms of acute overdose include hematological abnormalities such as leukopenia and neutropenia, and gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, vomiting, and dyspepsia.The experience with overdose of Mycophenolate mofetil capsules in humans is limited. The reported effects associated with overdose fall within the known safety profile of the drug. The highest dose administered to kidney transplant patients in clinical trials has been 4 g/day. In limited experience with heart and liver transplant patients in clinical trials, the highest doses used were 4 g/day or 5 g/day. At doses of 4 g/day or 5 g/day, there appears to be a higher rate, compared to the use of 3 g/day or less, of gastrointestinal intolerance (nausea, vomiting, and/or diarrhea), and occasional hematologic abnormalities, particularly neutropenia [see Warnings and Precautions (5.4)].Treatment and ManagementMPA and the phenolic glucuronide metabolite of MPA (MPAG) are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 µg/mL), small amounts of MPAG are removed. By increasing excretion of the drug, MPA can be removed by bile acid sequestrants, such as cholestyramine [see Clinical Pharmacology (12.3)].

11 Description

Mycophenolate mofetil is an antimetabolite immunosuppressant. It is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate  dehydrogenase  (IMPDH) inhibitor.The chemical name for mycophenolate mofetil (MMF) is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has an empirical formula of C23H31NO7, a molecular weight of 433.50, and the following structural formula: MMF is a white to off-white crystalline powder. It is slightly soluble in water (43 µg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for MMF are 5.6 for the morpholino group and 8.5 for the phenolic group.MMF hydrochloride has a solubility of 65.8 mg/mL in 5% Dextrose Injection USP (D5W). The pH of the reconstituted solution is 2.4 to 4.1.Mycophenolate mofetil is available for oral administration as capsules containing 250 mg of MMF.Inactive ingredients in Mycophenolate mofetil capsules 250 mg include microcrystalline cellulose, hydroxypropyl cellulose, povidone (K-90), croscarmellose sodium, talc and magnesium stearate. The capsule shells contain FD&C blue #2, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. The imprinting ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, iron oxide black and potassium hydroxide.Mycophenolate Mofetil Capsules meets USP Dissolution Test 2.

12.1 Mechanism Of Action

Mycophenolate mofetil (MMF) is absorbed following oral administration and hydrolyzed to mycophenolic acid (MPA), the active metabolite. MPA is a selective, uncompetitive, and reversible inhibitor of inosine  monophosphate  dehydrogenase  (IMPDH), and  therefore  inhibits  the  de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B- lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation. Addition of guanosine or deoxyguanosine reverses the  cytostatic effects of MPA on lymphocytes. MPA also suppresses antibody formation by B-lymphocytes. MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection. MMF did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of these events to DNA synthesis and proliferation.

12.2 Pharmacodynamics

There is a lack of information regarding the pharmacodynamic effects of MMF.

12.3 Pharmacokinetics

  • AbsorptionFollowing oral and intravenous administration, MMF undergoes complete conversion to MPA, the active metabolite. In 12 healthy volunteers, the mean absolute bioavailability of oral MMF relative to intravenous MMF was 94%. Two 500 mg Mycophenolate mofetil tablets have been shown to be bioequivalent to four 250 mg Mycophenolate mofetil capsules. Five mL of the 200 mg/mL constituted Mycophenolate mofetil oral suspension have been shown to be bioequivalent to four 250 mg capsules.The mean (± SD) pharmacokinetic parameters estimates for MPA following the administration of MMF given as single doses to healthy volunteers, and multiple doses to kidney, heart, and liver transplant patients are show in Table 9.The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in kidney transplant patients receiving multiple oral doses of MMF up to a daily dose of 3 g (1.5 g twice daily) (see Table 9). Table 9. Pharmacokinetic Parameters for MPA [mean (±SD)] Following Administration of MMF to Healthy Volunteers (Single Dose), and Kidney, Heart, and Liver Transplant Patients (Multiple Doses) Healthy Volunteers Dose/Route Tmax   (h) Cmax   (mcg/mL) Total AUC (mcg· h/mL) Single dose 1 g/oral 0.80 (±0.36) (n=129) 24.5 (±9.5) (n=129) 63.9 (±16.2) (n=117) Kidney Transplant Patients (twice daily dosing) Time After Transplantation Dose/Route T max   (h) C max (mcg/mL) Interdosing Interval AUC (0-12h)(mcg·h/mL) 5 days 1 g/iv 1.58 (±0.46) (n=31) 12.0 (±3.82) (n=31) 40.8 (±11.4) (n=31) 6 days 1 g/oral 1.33 (±1.05) (n=31) 10.7 (±4.83) (n=31) 32.9 (±15.0) (n=31) Early (Less than 40 days) 1 g/oral 1.31 (±0.76) (n=25) 8.16 (±4.50) (n=25) 27.3 (±10.9) (n=25) Early (Less than 40 days) 1.5 g/oral 1.21 (±0.81) (n=27) 13.5 (±8.18) (n=27) 38.4 (±15.4) (n=27) Late (Greater than 3 months) 1.5 g/oral 0.90 (±0.24) (n=23) 24.1 (±12.1) (n=23) 65.3 (±35.4) (n=23) Heart transplant Patients (twice daily dosing) Time After Transplantation Dose/Route T max (h) C max (mcg/mL) Interdosing Interval AUC (0-12h)(mcg·h/mL) Early (Day before discharge) 1.5 g/oral 1.8 (±1.3) (n=11) 11.5 (±6.8) (n=11) 43.3 (±20.8) (n=9) Late (Greater than 6 months) 1.5 g/oral 1.1 (±0.7) (n=52) 20.0 (±9.4) (n=52) 54.1AUC(0-12h) values  quoted are extrapolated from data  from samples collected over 4 hours. (±20.4) (n=49) Liver transplant Patients (twice daily dosing) Time After Transplantation Dose/Route T max (h) C max (mcg/mL) Interdosing Interval AUC (0-12h)(mcg·h/mL) 4 to 9 days 1 g/iv 1.50 (±0.517) (n=22) 17.0 (±12.7) (n=22) 34.0 (±17.4) (n=22) Early (5 to 8 days) 1.5 g/oral 1.15 (±0.432) (n=20) 13.1 (±6.76) (n=20) 29.2 (±11.9) (n=20) Late (Greater than 6 months) 1.5 g/oral 1.54 (±0.51) (n=6) 19.3 (±11.7) (n=6) 49.3 (±14.8) (n=6)In the early post-transplant period (less than 40 days post-transplant), kidney, heart, and liver transplant patients had mean MPA AUCs approximately 20% to 41% lower and mean Cmax approximately 32% to 44% lower compared to the late transplant period (i.e., 3 to 6 months post-transplant) (non-stationarity in MPA  pharmacokinetics).Mean MPA AUC values following administration of 1 g twice daily intravenous Mycophenolate mofetil over 2 hours to kidney transplant patients for 5 days were about 24% higher than those observed after oral administration of a similar dose in the immediate post-transplant phase.In liver transplant patients, administration of 1 g twice daily intravenous Mycophenolate mofetil followed by 1.5 g twice daily oral Mycophenolate mofetil resulted in mean MPA AUC estimates similar to those found in kidney transplant patients administered 1 g Mycophenolate mofetil twice daily.Effect of FoodFood (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of MMF when administered at doses of 1.5 g twice daily to kidney transplant patients. However, MPA Cmax was decreased by 40% in the presence of food [see Dosage and Administration (2.1)].DistributionThe mean (±SD) apparent volume of distribution of MPA in 12 healthy volunteers is approximately 3.6 (±1.5) L/kg. At clinically relevant concentrations, MPA is 97% bound to plasma albumin. The phenolic glucuronide metabolite of MPA (MPAG) is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable kidney transplant patients; however, at higher MPAG concentrations (observed in patients with kidney impairment or delayed kidney graft function), the binding of MPA may be reduced as a result of competition between MPAG and MPA for protein binding. Mean blood to plasma ratio of radioactivity concentrations was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into the cellular fractions of blood.In vitro studies to evaluate the effect of other agents on the binding of MPA to human serum albumin (HSA) or plasma proteins showed that salicylate (at 25 mg/dL with human serum albumin) and MPAG (at ≥460 mcg/mL with plasma proteins) increased the free fraction of MPA. MPA at concentrations as high as 100 mcg/mL had little effect on the binding of warfarin, digoxin or propranolol, but decreased the binding of theophylline from 53% to 45% and phenytoin from 90% to 87%.EliminationMean (±SD) apparent half-life and plasma clearance of MPA are 17.9 (±6.5) hours and 193 (±48) mL/min following oral administration and 16.6 (±5.8) hours and 177 (±31) mL/min following intravenous administration, respectively.MetabolismThe parent drug, MMF, can be measured systemically during the intravenous infusion; however, approximately 5 minutes after the infusion is stopped or after oral administration, MMF concentrations are below the limit of quantitation (0.4 mcg/mL).Metabolism to MPA occurs pre-systemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form MPAG, which is not pharmacologically active. In vivo, MPAG is converted to MPA during enterohepatic recirculation. The following metabolites of the 2- hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of MMF to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.Due to the enterohepatic recirculation of MPAG/MPA, secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to 12 hours post-dose. Bile sequestrants, such as cholestyramine, reduce MPA AUC by interfering with this enterohepatic recirculation of the drug [see Overdose (10) and Drug Interaction Studies].ExcretionNegligible amount of drug is excreted as MPA (less than 1% of dose) in the urine. Orally administered radiolabeled MMF resulted in complete recovery of the administered dose, with 93% of the   administered dose recovered in the urine and 6% recovered in feces. Most (about 87%) of the administered dose is excreted in the urine as MPAG. At clinically encountered concentrations, MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 mcg/mL), small amounts of MPAG are removed.Increased plasma concentrations of MMF metabolites (MPA 50% increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal insufficiency [see Specific Populations]Specific PopulationsPatients with Renal ImpairmentThe mean (±SD) pharmacokinetic parameters for MPA following the administration of oral MMF given as single doses to non-transplant subjects with renal impairment are presented in Table 10.In a single-dose study, MMF was administered as a capsule or as an intravenous infusion over 40 minutes. Plasma MPA AUC observed after oral dosing to volunteers with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) was about 75% higher relative to that observed in healthy volunteers (GFR >80 mL/min/1.73 m2). In addition, the single-dose plasma MPAG AUC was 3-fold to 6-fold higher in volunteers with severe renal impairment than in volunteers with mild renal impairment or healthy volunteers, consistent with the known renal elimination of MPAG. No data are available on the safety of long-term exposure to this level of MPAG.Plasma MPA AUC observed after single-dose (1 g) intravenous dosing to volunteers (n=4) with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) was 62.4 mcg·h/mL (±19.3). Multiple dosing of MMF in patients with severe chronic renal impairment has not been studied.Patients with Delayed Graft Function or NonfunctionIn patients with delayed renal graft function post-transplant, mean MPA AUC(0-12h) was comparable to that seen in post-transplant patients without delayed renal graft function. There is a potential for a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. However, dose adjustment does not appear to be necessary in patients with delayed renal graft function. Mean plasma MPAG AUC(0-12h) was 2-fold to 3-fold higher than in post-transplant patients without delayed renal graft function [see Dosage and Administration (2.5)].In eight patients with primary graft non-function following kidney transplantation, plasma concentrations of MPAG accumulated about 6-fold to 8-fold after multiple dosing for 28 days. Accumulation of MPA was about 1-fold to 2-fold.The pharmacokinetics of MMF are not altered by hemodialysis. Hemodialysis usually does not remove MPA or MPAG. At high concentrations of MPAG (>100 mcg/mL), hemodialysis removes only small amounts of MPAG.Patients with Hepatic ImpairmentThe mean (±SD) pharmacokinetic parameters for MPA following the administration of oral MMF given as single doses to non-transplant subjects with hepatic impairment is presented in Table 10.In a single-dose (1 g oral) study of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers,  hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this study were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this study had about a 50% lower AUC as compared to healthy volunteers in other studies, thus making comparisons between volunteers with alcoholic cirrhosis and healthy volunteers difficult. In a single-dose (1 g intravenous) study of 6 volunteers with severe hepatic impairment (aminopyrine breath test less than 0.2% of dose) due to alcoholic cirrhosis, MMF was rapidly converted to MPA. MPA AUC was 44.1 mcg·h/mL (±15.5). Table10. Pharmacokinetic Parameters for MPA [mean (±SD)] Following Single Doses of MMF Capsules in Chronic Renal and Hepatic Impairment Pharmacokinetic Parameters for Renal Impairment Dose Tmax (h) Cmax (mcg/mL) AUC(0-96h) (mcg·h/mL) Healthy Volunteers GFR greater than 80 mL/min/1.73 m2 (n=6) 1 g 0.75 (±0.27) 25.3 (±7.99) 45.0 (±22.6) Mild Renal Impairment GFR 50 to 80 mL/min/1.73 m2 (n=6) 1 g 0.75 (±0.27) 26.0 (±3.82) 59.9 (±12.9) Moderate  Renal Impairment GFR 25 to 49 mL/min/1.73 m2 (n=6) 1 g 0.75 (±0.27) 19.0 (±13.2) 52.9 (±25.5) Severe Renal Impairment GFR less than 25 mL/min/1.73 m2 (n=7) 1 g 1.00 (±0.41) 16.3 (±10.8) 78.6 (±46.4) Pharmacokinetic Parameters for Hepatic Impairment Dose Tmax (h) Cmax (mcg/mL) AUC(0-48h) (mcg·h/mL) Healthy Volunteers (n=6) 1 g 0.63 (±0.14) 24.3 (±5.73) 29.0 (±5.78) Alcoholic Cirrhosis (n=18) 1 g 0.85 (±0.58) 22.4 (±10.1) 29.8 (±10.7)Pediatric PatientsThe pharmacokinetic parameters of MPA and MPAG have been evaluated in 55 pediatric patients (ranging from 1 year to 18 years of age) receiving Mycophenolate mofetil oral suspension at a dose of 600 mg/m2 twice daily (up to a maximum of 1 g twice daily) after allogeneic kidney transplantation. The pharmacokinetic data for MPA is provided in Table 11. Table 11. Mean (±SD) Computed Pharmacokinetic Parameters for MPA by Age and Time after Allogeneic Renal Transplantation Age Group (n) Time Tmax (h) Dose Adjusted  adjusted to a dose of 600 mg/m2  Cmax (mcg/mL) Dose Adjusted  AUC0-12 (mcg·h/mL) 1 to less than 2 yr (6) a subset of 1 to  <6  yr 1 to less than 6 yr (17) 6 to less than 12 yr (16) 12 to 18 yr (21) Early (Day 7) 3.03 (4.70) 1.63 (2.85) 0.940 (0.546) 1.16 (0.830) 10.3 (5.80) 13.2 (7.16) 13.1 (6.30) 11.7 (10.7) 22.5 (6.66) 27.4 (9.54) 33.2 (12.1) 26.3 (9.14) n=20 1 to less than 2 yr (4) 1 to less than 6 yr (15) 6 to less than 12 yr (14) 12 to 18 yr (17) Late (Month 3) 0.725 (0.276) 0.989 (0.511) 1.21 (0.532) 0.978 (0.484) 23.8 (13.4) 22.7 (10.1) 27.8 (14.3) 17.9 (9.57) 47.4 (14.7) 49.7 (18.2) 61.9 (19.6) 53.6 (20.3) n=16 1 to less than 2 yr (4) 1 to less than 6 yr (12) 6 to less than 12 yr (11) 12 to 18 yr (14) Late (Month 9) 0.604 (0.208) 0.869 (0.479) 1.12 (0.462) 1.09 (0.518) 25.6 (4.25) 30.4 (9.16) 29.2 (12.6) 18.1 (7.29) 55.8 (11.6) 61.0 (10.7) 66.8 (21.2) 56.7 (14.0)The Mycophenolate mofetil oral suspension dose of 600 mg/m2 twice daily (up to a maximum of 1 g twice daily) achieved mean MPA AUC values in pediatric patients similar to those seen in adult kidney transplant patients receiving Mycophenolate mofetil capsules at a dose of 1 g twice daily in the early post-transplant period. There was wide variability in the data. As observed in adults, early post-transplant MPA AUC values were approximately 45% to 53% lower than those observed in the later post-transplant period (>3 months). MPA AUC values were similar in the early and late post-transplant period across the 1 to 18- year age range.Male and Female PatientsData obtained from several studies were pooled to look at any gender-related differences in the pharmacokinetics of MPA (data were adjusted to 1 g oral dose). Mean (±SD) MPA AUC(0-12h) for males (n=79) was 32.0 (±14.5) and for females (n=41) was 36.5 (±18.8) mcg·h/mL while mean (±SD) MPA Cmax was 9.96 (±6.19) in the males and 10.6 (±5.64) mcg/mL in the females. These differences are not of clinical significance.Geriatric PatientsThe pharmacokinetics of mycophenolate mofetil and its metabolites have not been found to be altered in elderly transplant patients when compared to younger transplant patients.Drug Interactions StudiesAcyclovirCoadministration of MMF (1 g) and acyclovir (800 mg) to 12 healthy volunteers resulted in no significant change in MPA AUC and Cmax. However, MPAG and acyclovir plasma AUCs were increased 10.6% and 21.9%, respectively.  Antacids with Magnesium and Aluminum HydroxidesAbsorption of a single dose of MMF (2 g) was decreased when administered to 10 rheumatoid arthritis patients also taking Maalox® TC (10 mL qid). The Cmax and AUC(0-24h) for MPA were 33% and 17% lower, respectively, than when MMF was administered alone  under fasting  conditions.Proton Pump Inhibitors (PPIs)Coadministration of PPIs (e.g., lansoprazole, pantoprazole) in single doses to healthy volunteers and multiple doses to transplant patients receiving Mycophenolate mofetil has been reported to reduce the exposure to MPA. An approximate reduction of 30 to 70% in the Cmax and 25% to 35% in the AUC of MPA has  been observed, possibly due to a decrease in MPA solubility at an increased gastric pH.CholestyramineFollowing single-dose administration of 1.5 g MMF to 12 healthy volunteers pretreated with 4 g three times a day of cholestyramine for 4 days, MPA AUC decreased approximately 40%. This decrease is consistent with interruption of enterohepatic recirculation which may be due to binding of recirculating MPAG with cholestyramine in the intestine.CyclosporineCyclosporine (Sandimmune®) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 g twice daily of MMF in 10 stable kidney transplant patients. The mean (±SD) AUC(0-12h) and Cmax of cyclosporine after 14 days of multiple doses of MMF were 3290 (±822) ng·h/mL and 753 (±161) ng/mL, respectively, compared to 3245 (±1088) ng·h/mL and 700 (±246) ng/mL, respectively, 1 week before administration of  MMF.Cyclosporine A interferes with MPA enterohepatic recirculation. In kidney transplant patients, mean MPA exposure (AUC(0-12h)) was approximately 30-50% greater when MMF was administered without cyclosporine compared with when MMF is coadministered with cyclosporine. This interaction is due to cyclosporine inhibition of multidrug-resistance-associated protein 2 (MRP-2) transporter in the biliary tract, thereby preventing the excretion of MPAG into the bile that would lead to enterohepatic recirculation of MPA. This information should be taken into consideration when MMF is used without cyclosporine.Drugs Affecting GlucuronidationConcomitant administration of drugs inhibiting glucuronidation of MPA may increase MPA exposure (e.g., increase of MPA AUC(0-∞) by 35% was observed with concomitant administration of isavuconazole).Concomitant administration of telmisartan and Mycophenolate mofetil resulted in an approximately 30% decrease in MPA concentrations. Telmisartan changes MPA's elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results in an enhanced UGT1A9 expression and glucuronidation activity.GanciclovirFollowing single-dose administration to 12 stable kidney transplant patients, no pharmacokinetic interaction was observed between MMF (1.5 g) and intravenous ganciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and Cmax (n=10) were 54.3 (±19.0) mcg·h/mL and 11.5 (±1.8) mcg/mL, respectively, after coadministration of the two drugs, compared to 51.0 (±17.0) mcg·h/mL and 10.6 (±2.0) mcg/mL, respectively, after administration of intravenous ganciclovir alone. The mean (±SD) AUC and Cmax of MPA (n=12) after coadministration were 80.9 (±21.6) mcg·h/mL and 27.8 (±13.9) mcg/mL, respectively, compared to values of 80.3 (±16.4) µg·h/mL and 30.9 (±11.2) mcg/mL, respectively, after administration of MMF alone.Oral ContraceptivesA study of coadministration of Mycophenolate mofetil capsules (1 g twice daily) and combined oral contraceptives  containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) was conducted in 18 women with psoriasis over 3 consecutive menstrual cycles. Mean serum levels of LH, FSH and progesterone were not significantly affected. Mean AUC(0-24h) was similar for ethinylestradiol and 3-keto desogestrel; however, mean levonorgestrel AUC(0-24h) significantly decreased by about 15%. There was large inter-patient variability (%CV in the range of 60% to 70%) in the data, especially for ethinylestradiol.SevelamerConcomitant administration of sevelamer and MMF in adult and pediatric patients decreased the mean MPA Cmax and AUC(0-12h) by 36% and 26% respectively.AntimicrobialsAntimicrobials eliminating beta-glucuronidase-producing bacteria in the intestine (e.g. aminoglycoside, cephalosporin, fluoroquinolone, and penicillin classes of antimicrobials) may interfere with the MPAG/MPA enterohepatic recirculation thus leading to reduced systemic MPA exposure. Information concerning antibiotics is as follows:  Trimethoprim/Sulfamethoxazole: Following single-dose administration of MMF (1.5 g) to 12 healthy male volunteers on day 8 of a 10-day course of trimethoprim 160 mg/sulfamethoxazole 800 mg administered twice daily, no effect on the bioavailability of MPA was observed. The mean (±SD) AUC and Cmaxof MPA after concomitant administration were 75.2 (±19.8) mcg·h/mL and 34.0 (±6.6) µg/mL, respectively, compared to 79.2 (±27.9) mcg·h/mL and 34.2 (±10.7) mcg/mL, respectively, after administration of MMF alone.  Norfloxacin and Metronidazole: Following single-dose administration of MMF (1 g) to 11 healthy volunteers on day 4 of a 5-day course of a combination of norfloxacin and metronidazole, the mean MPA AUC(0-48h) was significantly reduced by 33% compared to the administration of MMF alone (p<0.05). The mean (±SD) MPA AUC(0-48h) after coadministration of MMF with norfloxacin or metronidazole separately was 48.3 (±24) mcg·h/mL and 42.7 (±23) mcg·h/mL, respectively, compared with 56.2 (±24) mcg·h/mL after administration of MMF alone.  Ciprofloxacin and Amoxicillin Plus Clavulanic Acid: A total of 64 Mycophenolate mofetil capsules-treated kidney transplant recipients received either oral ciprofloxacin 500 mg twice daily or amoxicillin plus clavulanic acid 375 mg three time daily for 7 or at least 14 days, respectively. Approximately 50% reductions in median trough MPA concentrations (pre-dose) from baseline (Mycophenolate mofetil capsules alone) were observed in 3 days following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. These reductions in trough MPA concentrations tended to diminish within 14 days of antimicrobial therapy and ceased within 3 days of discontinuation of antibiotics.  Rifampin: In a single heart-lung transplant patient, after correction for dose, a 67% decrease in MPA exposure (AUC(0-12h)) has  been observed with concomitant administration of MMF and rifampin.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a 104-week oral carcinogenicity study in mice, MMF in daily doses up to 180 mg/kg was not tumorigenic. The highest dose tested was 0.4 times the recommended clinical dose (2 g/day) in renal transplant patients and 0.3 times the recommended clinical dose (3 g/day) in cardiac transplant patients when corrected for differences in body surface area (BSA). In a 104-week oral carcinogenicity study in rats, MMF 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 MMF was determined in five assays. MMF was genotoxic in the mouse lymphoma/thymidine kinase assay and the in vivo mouse micronucleus assay. MMF was not genotoxic in the bacterial mutation assay, the yeast mitotic gene conversion assay or the Chinese hamster ovary cell chromosomal aberration assay.MMF 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.

14.1 Kidney Transplantation

AdultsThe three de novo kidney transplantation studies compared two dose levels of oral Mycophenolate mofetil (1 g twice daily and 1.5 g 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 12.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 capsules, 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 12). 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 13. Patients who prematurely discontinued treatment were not followed for the occurrence of acute rejection after termination. Table 12. Treatment Failure in De Novo Kidney Transplantation Studies USA Study (N=499 patients) Mycophenolate mofetil 2 g/day (n=167 patients) Mycophenolate mofetil 3 g/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 rejectionDoes not include death and graft loss as reason for early termination. 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 g/day (n=173 patients) Mycophenolate mofetil 3 g/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 g/day (n=165 patients) Mycophenolate mofetil 3 g/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%No advantage of Mycophenolate mofetil at 12 months with respect to graft loss or patient death (combined) was established (Table 13). Numerically, patients receiving Mycophenolate mofetil 2 g/day and 3 g/day experienced a better outcome than controls in all three studies; patients receiving Mycophenolate mofetil  2 g/day experienced a better outcome than Mycophenolate mofetil 3 g/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 13. De Novo Kidney Transplantation Studies Cumulative Incidence of Combined Graft Loss or Patient Death at 12 Months Study Mycophenolate mofetil 2 g/day Mycophenolate mofetil 3 g/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-UpOne open-label, safety and pharmacokinetic study of Mycophenolate mofetil oral suspension 600 mg/m2 twice daily (up to 1 g 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 g 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 renal transplant patients.

14.2 Heart Transplantation

  • A double-blind, randomized, comparative, parallel-group, multicenter study in primary de novo heart transplant recipients was performed at centers in the United States (20), in Canada (1), in Europe (5) and in Australia (2). The total number of patients enrolled (ITT population) was 650; 72 never received study drug and 578 received study drug (Safety Population). Patients received Mycophenolate mofetil 1.5 g twice daily (n=289) or AZA 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine (Sandimmune® or Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The two primary efficacy endpoints were: (1) the proportion of patients who, after transplantation, had at least one endomyocardial biopsy-proven rejection with hemodynamic compromise, or were re-transplanted or died, within the first 6 months, and (2) the proportion of patients who died or were re-transplanted during the first 12 months following transplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection for up to 6 months and for the occurrence of death for 1 year.The analyses of the endpoints showed:  Rejection: No difference was established between Mycophenolate mofetil and AZA with respect to biopsy-proven rejection with hemodynamic compromise.  Survival: Mycophenolate mofetil was shown to be at least as effective as AZA in preventing death or re-transplantation at 1 year (see Table 14 ). Table 14. De Novo Heart Transplantation Study Rejection at 6 Months/Death or Re-transplantation at 1 Year All Patients (ITT) Treated Patients AZA N = 323 Mycophenolate mofetil N = 327 AZA  N = 289 Mycophenolate mofetil  N = 289 Biopsy-proven rejection with hemodynamic compromise at 6 monthsHemodynamic compromise occurred if any of the following criteria were met: pulmonary capillary wedge pressure ≥20 mm or a 25% increase; cardiac index <2.0 L/min/m2 or a 25% decrease; ejection fraction ≤30%; pulmonary artery oxygen saturation ≤60% or a 25% decrease; presence of new S3 gallop; fractional shortening was ≤20% or a 25% decrease; inotropic support required to manage the clinical condition. 121 (38%) 120 (37%) 100 (35%) 92 (32%) Death or re-transplantation at 1 year 49 (15.2%) 42 (12.8%) 33 (11.4%) 18 (6.2%)

14.3 Liver Transplantation

A double-blind, randomized, comparative, parallel-group, multicenter study in primary hepatic transplant recipients was performed at centers in the United States (16), in Canada (2), in Europe (4) and in Australia (1). The total number of patients enrolled was 565. Per protocol, patients received Mycophenolate mofetil 1 g twice daily intravenously for up to 14 days followed by Mycophenolate mofetil 1.5 g twice daily orally or AZA 1 to 2 mg/kg/day intravenously followed by AZA 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The actual median oral dose of AZA on study was 1.5 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) initially and 1.26 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) at 12 months. The two primary endpoints were: (1) the proportion of patients who experienced, in the first 6 months post-transplantation, one or more episodes  of biopsy-proven and treated rejection or death or re-transplantation, and (2) the proportion of patients who experienced graft loss (death or re-transplantation) during the first 12 months post-transplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection and for the occurrence of graft loss (death or re-transplantation) for 1 year.In combination with corticosteroids and cyclosporine, Mycophenolate mofetil demonstrated a lower rate of acute rejection at 6 months and a similar rate of death or re-transplantation at 1 year compared to AZA (Table 15). Table 15 De Novo Liver Transplantation Study Rejection at 6 Months/Death or Re-transplantation at 1 Year AZA N = 287 Mycophenolate mofetil N = 278 Biopsy-proven, treated rejection at 6 months (includes death or re-transplantation) 137 (47.7%) 107 (38.5%) Death or re-transplantation at 1 year 42 (14.6%) 41 (14.7%)

15 References

1. "OSHA Hazardous Drugs." OSHA.  http://www.osha.gov/SLTC/hazardousdrugs/index.html

16.1 Handling And Disposal

Mycophenolate mofetil (MMF) has demonstrated teratogenic effects in humans [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Mycophenolate mofetil capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in Mycophenolate mofetil capsules. Follow applicable special handling and disposable procedures1.

16.2 Mycophenolate Mofetil Capsules 250 Mg

Capsules: White to off white granular powder filled in size '1' hard gelatin capsule with opaque blue cap imprinted "C3 250" and opaque brown body. Sizes Bottle of 100                                                                             NDC 68254-5000-1 Bottle of 500                                                                             NDC 68254-5000-2 Storage: Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F)

17 Patient Counseling Information

Information for PatientsSee FDA-approved patient labeling (Medication Guide).

17.1 Embryofetal Toxicity

  • Pregnancy loss and malformations  Inform females of reproductive potential and pregnant women that use of Mycophenolate mofetil capsules during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations. Advise 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 Pregnancy Exposure Registry. 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 an acceptable form of birth control during the entire Mycophenolate mofetil capsules therapy and for 6 weeks after stopping Mycophenolate mofetil capsules, unless the patient chooses abstinence. Mycophenolate mofetil capsules 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 embryofetal toxicity. Risks and benefits of Mycophenolate mofetil capsules should be discussed with the patient.  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 [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)] .

17.2 Development Of Lymphoma And Other Malignancies

  • Inform patients that they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression [see Warnings and Precautions (5.2)] .  Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use of sunscreen with high protection factor.

17.3 Increased Risk Of Serious Infections

Inform patients that they are at increased risk of developing a variety of infections due to immunosuppression. Instruct them to contact their physician if they develop any of the signs and symptoms of infection explained in the Medication Guide.

17.4 Blood Dyscrasias

Inform patients that they are at increased risk for developing blood adverse effects such as anemia or low white blood cells. Advise patients to immediately contact their healthcare provider if they experience any evidence of infection, unexpected bruising, or bleeding, or any other manifestation of bone marrow suppression [see Warnings and Precautions (5.4)].

17.5 Gastrointestinal Tract Complications

Inform patients that Mycophenolate mofetil capsules 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 (5.5)].

17.6 Immunizations

Inform patients that Mycophenolate mofetil capsules can interfere with the usual response to immunizations. Before seeking vaccines on their own, advise patients to discuss first with their physician. [see Warnings and Precautions (5.7)].

17.7 Administration Instructions

  • Advise patients not to open Mycophenolate mofetil capsules.  Advise patients to avoid inhalation or contact of the skin or mucous membranes with the powder contained in Mycophenolate mofetil capsules. If such contact occurs, they must wash the area of contact thoroughly with soap and water. In case of ocular contact, rinse eyes with plain water.  Advise patients to take a missed dose as soon as they remember, except if it is closer than 2 hours to the next scheduled dose; in this case they should continue to  take  Mycophenolate mofetil capsules at the usual times.

17.8 Blood Donation

Advise patients not to donate blood during therapy and for at least 6 weeks following discontinuation of Mycophenolate mofetil capsules.

17.9 Semen Donation

Advise males of childbearing potential not to donate semen during therapy and for 90 days following discontinuation of Mycophenolate mofetil capsules.Manufactured By:Concord Biotech Limited,297-298/2P, At Valthera Ta. Dholka,Ahmedabad – 382225, Gujarat, India.

Medication Guide

  • Mycophenolate mofetil capsules, USP 250 mg (MYE koe FEN oh late MOE fe til)Read the Medication Guide that comes with Mycophenolate mofetil capsules before you start taking it and each time you refill your prescription. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about Mycophenolate mofetil capsules?Mycophenolate mofetil capsules can cause serious side effects, including:Increased risk of loss of a pregnancy (miscarriage) and higher risk of birth defects. Females who take Mycophenolate mofetil during pregnancy have a higher risk of miscarriage during the first 3 months (first trimester), and a higher risk that their baby will be born with birth defects.  If you are a female who can become pregnant , your doctor must talk with you about acceptable birth control methods (contraceptive counseling) to use while taking Mycophenolate mofetil capsules. You should have 1 pregnancy test immediately before starting Mycophenolate mofetil capsules and another pregnancy test 8 to 10 days later. Pregnancy tests should be repeated during routine follow-up visits with your doctor. Talk to your doctor about the results of all of your pregnancy tests.You must use acceptable birth control during your entire Mycophenolate mofetil treatment and for 6 weeks after stopping Mycophenolate mofetil, unless at any time you choose to avoid sexual intercourse (abstinence) with a man completely. Mycophenolate mofetil decreases blood levels of the hormones in birth control pills that you take by mouth. Birth control pills may not work as well while you take Mycophenolate mofetil capsules, and you could become pregnant. If you take birth control pills while using Mycophenolate mofetil capsules you must also use another form of birth control. Talk to your doctor about other birth control methods that you can use while taking Mycophenolate mofetil capsules.If you are sexually active male whose female partner can become pregnant while you are taking Mycophenolate mofetil capsules, use effective contraception during treatment and for at least 90 days after stopping Mycophenolate mofetil capsules.If you plan to become pregnant , talk with your doctor. Your doctor will decide if other medicines to prevent rejection may be right for you.If you become pregnant while taking Mycophenolate mofetil capsules, do not stop taking Mycophenolate mofetil. Call your doctor right away. you and your doctor may decide that other medicines to prevent rejection may be right for you. You and your doctor should report your pregnancy to the Mycophenolate Pregnancy Registry either:By phone  at 1-800-617-8191 orBy visiting the  REMS website at www.mycophenolateREMS.comThe purpose of this registry is to gather information about the health of you and your baby.Increased risk of getting certain cancers. People who take Mycophenolate mofetil have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Tell your doctor if you have:unexplained fever,  prolonged tiredness, weight loss or lymph node swellinga change in the size and color of  a molea brown or black skin lesion with uneven borders, or one part of the lesion does not look like the othera new skin lesion or bumpany other changes to your healthIncreased risk of getting serious infections. Mycophenolate mofetil weakens the body's immune system and affects your ability to fight infections. Serious infections can happen with Mycophenolate mofetil capsules and can lead to hospitalizations and death. These serious infections can include:Viral infections. Certain viruses can live in your body and cause active infections when your immune system is weak. Viral infections that can happen with Mycophenolate mofetil include:Shingles, other herpes infections, and cytomegalovirus (CMV). CMV can cause serious tissue and blood infections.BK virus. BK virus can affect how your kidney works and cause your transplanted kidney to fail.Hepatitis B and C viruses. Hepatitis viruses can affect how your liver works. Talk to your doctor about how hepatitis viruses may affect you.A brain infection called Progressive Multifocal Leukoencephalopathy (PML). In some patients, Mycophenolate mofetil may cause an infection of the brain that may cause death. You are at risk for this brain infection because you have a weakened immune system. Call your doctor right away if you have any  of the following symptoms:Weakness on one side of the bodyYou are confused or have  problems thinkingYou do not care about things that  you usually care about (apathy)You cannot control your musclesFungal infections. Yeasts and other types of fungal infections can happen with Mycophenolate mofetil and can cause serious tissue and blood infections (See "What are the possible side effects of Mycophenolate mofetil capsules?" ).Call your doctor right away if you have any of the following signs and symptoms of infection:temperature of 100.5°F or greaterpain during urinationcold symptoms, such as a runny nose or sore throatwhite patches in the mouth  or throatunexpected bruising  or bleedingflu symptoms, such as an upset stomach, stomach pain, vomiting or diarrheacuts, scrapes or incisions that are red,  warm and oozing pusearache or headacheSee "What are the possible side effects of Mycophenolate mofetil capsules?" for information about other serious side effects. What is Mycophenolate mofetil capsules?  Mycophenolate mofetil capsules is a prescription medicine to prevent rejection (antirejection medicine) in people who have received a kidney, heart or liver transplant. Rejection is when the body's immune system perceives the new organ as a "foreign" threat and attacks it.  Mycophenolate mofetil capsules is used with other medicines containing cyclosporine and corticosteroids.Who should not take Mycophenolate mofetil capsules?Do not take Mycophenolate mofetil capsules if you are allergic to mycophenolate mofetil or any of the ingredients in Mycophenolate mofetil capsules. See the end of this Medication Guide for a complete list of ingredients in Mycophenolate mofetil capsules. What should I tell my doctor before taking Mycophenolate mofetil capsules?Tell your doctor about all of your medical conditions, including if you:  have any digestive problems, such as  ulcers.  have Lesch-Nyhan or Kelley-Seegmiller syndrome or another rare inherited deficiency hypoxanthine-guanine phosphoribosyl-transferase (HGPRT). You should not take Mycophenolate mofetil capsules if you have one of these disorders.  plan to receive any vaccines. People taking Mycophenolate mofetil capsules should not receive live vaccines. Some vaccines may not work as well during treatment with Mycophenolate mofetil capsules.  are pregnant or plan to become pregnant. See "What is the most important information I should know about Mycophenolate mofetil capsules?"  are breastfeeding or plan to breastfeed. It is not known if Mycophenolate mofetil passes into breast milk. You and your doctor will decide if you will take Mycophenolate mofetil capsules or breastfeed.Tell your healthcare provider about all of the medicines you take, including prescription and over- the-counter medicines, vitamins and herbal supplements. Some medicines may affect the way Mycophenolate mofetil works, and Mycophenolate mofetil may affect how some medicines work.Especially tell your doctor if you take:  birth control pills (oral contraceptives). See "What is the most important information I should know about Mycophenolate mofetil capsules?"  sevelamer (Renagel®, RenvelaTM). These products should be taken at least 2 hours after taking Mycophenolate mofetil capsules.  Acyclovir (Zovirax®), valacyclovir (Valtrex®), ganciclovir (CYTOVENE®-IV, Vitrasert®), valganciclovir (VALCYTE®).  rifampin (Rifater®, Rifamate®, Rimactane®, Rifadin®).  antacids that contain magnesium and aluminum (Mycophenolate mofetil capsules and the antacid should not be taken at the same time).  proton pump inhibitors (PPIs) (Prevacid®, Protonix®).  sulfamethoxazole/trimethoprim (BACTRIMTM,  BACTRIM DSTM).  norfloxacin (Noroxin®) and metronidazole (Flagyl®, Flagyl®ER, Flagyl®IV, Metro IV, Helidac®, PyleraTM).  ciprofloxacin (Cipro®, Cipro®XR, Ciloxan®, Proquin®XR) and amoxicillin plus clavulanic acid (Augmentin®, Augmentin XRTM).  azathioprine (Azasan®, Imuran®).  cholestyramine  (Questran Light®, Questran®, Locholest Light, Locholest, Prevalite®).Know the medicines you take. Keep a list of them to show to your doctor or nurse and pharmacist when you get a new medicine. Do not take any new medicine without talking with your doctor. How should I take Mycophenolate mofetil capsules?Take Mycophenolate mofetil capsules exactly as prescribed.Do not stop taking Mycophenolate mofetil capsules or change the dose unless your doctor tells you to.If you miss a dose of Mycophenolate mofetil capsules, or you are not sure when you took your last dose, take your prescribed dose of Mycophenolate mofetil capsules as soon as you remember. If your next dose is less than 2 hours away, skip the missed dose and take your next dose at your normal scheduled time. Do not take 2 doses at the same time. Call your doctor if you are not sure what to do.Take Mycophenolate mofetil capsules on an empty stomach, unless your doctor tells you otherwise.Do not open or crush Mycophenolate mofetil capsules.If you are not able to swallow Mycophenolate mofetil capsules, your doctor may prescribe Mycophenolate mofetil Oral Suspension. This is a liquid form of Mycophenolate mofetil. Your pharmacist will mix the medicine before you pick it up from a pharmacy.Do not breathe in (inhale) or let Mycophenolate mofetil powder come in contact with your skin or mucous membranes.If you accidentally get the powder on the skin, wash the area well with soap and water.If you accidentally get the powder in your eyes or other mucous membranes, flush with plain water.If you take too much Mycophenolate mofetil capsules, call your doctor or the poison control center right away.What should I avoid while taking Mycophenolate mofetil capsules?Avoid becoming pregnant. See"What is the most important information I should know about Mycophenolate mofetil capsules?"Limit the amount of time you spend in sunlight. Avoid using tanning beds or sunlamps. People who take Mycophenolate mofetil capsules have a higher risk of getting skin cancer. (See "What is the most important information I should know about Mycophenolate mofetil capsules?" ) Wear protective clothing when you are in the sun and use a sunscreen with a high protection factor. This is especially important if your skin is very fair or if you have a family history of skin cancer.You should not donate blood while taking Mycophenolate mofetil capsules and for at least 6 weeks after stopping Mycophenolate mofetil capsules.You should not donate sperm while taking Mycophenolate mofetil capsules and for 90 days after stopping Mycophenolate mofetil capsules.Mycophenolate mofetil capsules may influence your ability to drive and use machines (See "What are the possible side effects of Mycophenolate mofetil capsules?"). If you experience drowsiness, confusion, dizziness, tremor, or low blood pressure during treatment with Mycophenolate mofetil capsules, you should be cautious about driving or using heavy machines. What are the possible side effects of Mycophenolate mofetil capsules?Mycophenolate mofetil capsules can cause serious side effects, including:See "What is the most important information I should know about Mycophenolate mofetil capsules?"Low blood cell counts. People taking high doses of Mycophenolate mofetil capsules each day may have a decrease in blood counts, including:white blood cells, especially Neutrophils. Neutrophils fight against bacterial infections. You have a higher chance of getting an infection when your white blood cell count is low. This is most common from 1 month to 6 months after your transplant.red blood cells. Red blood cells carry oxygen to your body tissues. You have a higher chance of getting severe anemia when your red blood cell count is low.platelets . Platelets help with blood clotting.Your doctor will do blood tests before you start taking Mycophenolate mofetil capsules and during treatment with Mycophenolate mofetil capsules to check your blood cell counts. Tell your doctor right away if you have any signs of infection (see "What is the most important information I should know about Mycophenolate mofetil capsules?"), including any unexpected bruising or bleeding. Also, tell your doctor if you have unusual tiredness, lack of energy, dizziness or fainting. Stomach problems. Stomach problems including problems including intestinal bleeding, a tear in your intestinal wall (perforation) or stomach ulcers can happen in people who take Mycophenolate mofetil capsules. Bleeding can be severe and you may have to be hospitalized for treatment. Call your doctor right away if you have sudden or severe stomach-area pain or stomach-area pain that does not go away, or if you have diarrhea.The most common side effects of Mycophenolate mofetil capsules include:  diarrhea  changes in laboratory blood levels, including high levels of blood sugar (hyperglycemia)  blood problems including low white and red blood cell counts  stomach problems  including diarrhea, constipation, nausea and vomiting  infections  blood pressure problems  rash  fast heart beat  swelling of the lower legs, ankles and feet  nervous system problems such as headache, dizziness and tremorSide effects that can happen more often in children than in adults taking Mycophenolate mofetil capsules include:  stomach area pain  vomiting  fever  sore throat  infection  colds (respiratory tract infections)  pain  high blood pressure  blood infection (sepsis)  low white blood cell count  diarrhea  low red blood cell countThese are not all of the possible side effects of Mycophenolate mofetil capsules. Tell your doctor about any side effect that bothers you or that does not go away.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.  How should I store Mycophenolate mofetil capsules?  Store Mycophenolate mofetil capsules at room temperature, between 59°F to 86°F (15°C to 30°C).Keep Mycophenolate mofetil capsules and all medicines out of the reach of children. General Information about the safe and effective use of Mycophenolate mofetil capsules.Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Mycophenolate mofetil capsules for a condition for which it was not prescribed. Do not give Mycophenolate mofetil capsules to other people, even if they have the same symptoms that you have. It may harm them.This Medication Guide summarizes the most important information about Mycophenolate mofetil capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Mycophenolate mofetil capsules that is written for health professionals. What are the ingredients in Mycophenolate mofetil capsules?Active Ingredient: mycophenolate mofetilInactive Ingredients:microcrystalline cellulose, hydroxypropyl cellulose, povidone (K-90), croscarmellose sodium, talc and magnesium stearate. The capsule shells contain FD&C blue #2, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. The imprinting ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, iron oxide black and potassium hydroxide. Manufactured By:Concord Biotech Limited,297-298/2P, At Valthera Ta. Dholka,Ahmedabad – 382225, Gujarat, India. Any trademarks in this document are property of their respective owner.This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: February 2019

* Please review the disclaimer below.