MYCOPHENOLATE MOFETIL capsuleMYCOPHENOLATE MOFETIL tablet, film coated
For Healthcare Providers >

1. Mycophenolate Mofetil Can Cause Serious Side Effects, Including:
2. What Is Mycophenolate Mofetil?
3. Tell Your Doctor About All Of Your Medical Conditions, Including If You:
4. Especially Tell Your Doctor If You Take:
5. How Should I Take Mycophenolate Mofetil?
6. What Should I Avoid While Taking Mycophenolate Mofetil Capsules And Tablets?
7. The Most Common Side Effects Of Mycophenolate Mofetil Include:
8. Side Effects That Can Happen More Often In Children Than In Adults Taking Mycophenolate Mofetil Include:
9. How Should I Store Mycophenolate Mofetil?
10. Mycophenolate Mofetil 250 Mg Capsules:
11. Mycophenolate Mofetil 500 Mg Tablets:
12. Manufactured For:
13. Who Should Not Take Mycophenolate Mofetil?
14. General Information About Mycophenolate Mofetil:
15. Active Ingredient:
16. Inactive Ingredients:
17. Usual Dosage:
18. Caution:
19. Packaged And Distributed By:
20. Revised: 12/2018document Id:
21. Information For Patients:
22. Patient Information
23. Mycophenolate Mofetil Can Cause Serious Side Effects:
24. Common Side Effects Include:
25. Side Effects That Happen More Often In Children Than In Adults Taking Mycophenolate Mofetil Include:
26. Distributed By:
27. What Is The Most Important Information I Should Know About Mycophenolate Mofetil?mycophenolate Mofetil Can Cause Serious Side Effects:
28. Call Your Doctor Right Away If You Have Any Of The Following Signs And Symptoms Of Infection:
29. Tell Your Doctor About All Of Your Medical Conditions, If You:
30. What Should I Avoid While Taking Mycophenolate Mofetil?
31. What Are The Possible Side Effects Of Mycophenolate Mofetil?mycophenolate Mofetil Can Cause Serious Side Effects:
32. What Are The Ingredients In Mycophenolate Mofetil?active Ingredient:
33. Mycophenolate Mofetil Capsules, Usp 250 Mg:
34. Mycophenolate Mofetil Tablets, Usp 500 Mg:

Mycophenolate Mofetil 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. You should have 1 pregnancy test immediately before starting mycophenolate mofetil 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, and you could become pregnant. If you take birth control pills while using mycophenolate mofetil 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.
• If you are a sexually active male whose female partner can become pregnant while you are taking mycophenolate mofetil, use effective contraception during treatment and for at least 90 days after stopping mycophenolate mofetil.
• 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, 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 1-800-617-8191or
  • By visiting the REMS website at:www.mycophenolateREMS.com

The 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 swelling
• a brown or black skin lesion with uneven borders, or one part of the lesion does not look like the other

• a change in the size and color of a mole
• a new skin lesion or bump
• any other changes to your health

Increased 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 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 body
• you do not care about things you usually care about (apathy)

• you are confused or have problems thinking
• you cannot control your muscles

• Fungal infections.Yeasts and other types of fungal infections can happen with mycophenolate mofetil and can cause serious tissue and blood infections ().

What Is Mycophenolate Mofetil? ⮝

• Mycophenolate mofetil 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 is used with other medicines containing cyclosporine and corticosteroids.

Tell Your Doctor About All Of Your Medical Conditions, Including If You: ⮝

• have any digestive problems, such as ulcers.
• have Lesch-Nyhan syndrome, Kelley-
• 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 or breastfeed.

Tell your healthcare provider about all 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).
• sevelamer (Renagel, Renvela). These products should be taken at least 2 hours after taking mycophenolate mofetil.
• acyclovir (Zovirax), valacyclovir (Valtrex), ganciclovir (CYTOVENE-IV, Vitrasert), valganciclovir (VALCYTE).
• rifampin (Rifater, Rifamate, Rimactane, Rifadin).
• antacids that contain magnesium and aluminum (mycophenolate mofetil and the antacid should not be taken at the same time).
• proton pump inhibitors (PPIs) (Prevacid, Protonix).
• sulfamethoxazole/trimethoprim (BACTRIM, BACTRIM DS).
• norfloxacin (Noroxin) and metronidazole (Flagyl, FlagylER, FlagylIV, Metro IV, Helidac, Pylera).
• ciprofloxacin (Cipro, CiproXR, Ciloxan, ProquinXR) and amoxicillin plus clavulanic acid (Augmentin, Augmentin XR).
• 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? ⮝

• Take mycophenolate mofetil exactly as prescribed.
• Do not stop taking mycophenolate mofetil or change the dose unless your doctor tells you to.
• If you miss a dose of mycophenolate mofetil, or you are not sure when you took your last dose, take your prescribed dose of mycophenolate mofetil 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 and tablets on an empty stomach, unless your doctor tells you otherwise.Do notcrush mycophenolate mofetil tablets.
• Do notopen or crush mycophenolate mofetil capsules.
• If you are not able to swallow mycophenolate mofetil tablets or 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 mix mycophenolate mofetil oral suspension with any other medicine. Mycophenolate mofetil oral suspension should not be mixed with any type of liquids before taking the dose.
• Do notbreathe in (inhale) or let mycophenolate mofetil powder or oral suspension come in contact with your skin or mucous membranes.
  • If you accidentally get the powder or oral suspension on the skin, wash the area well with soap and water.
  • If you accidentally get the powder or oral suspension in your eyes or other mucous membranes, flush with plain water.
• If you take too much mycophenolate mofetil, call your doctor or the poison control center right away.

What Should I Avoid While Taking Mycophenolate Mofetil Capsules And Tablets? ⮝

• Avoid becoming pregnant.
• Limit the amount of time you spend in sunlight. Avoid using tanning beds or sunlamps. People who take mycophenolate mofetil have a higher risk of getting skin cancer (). 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 and for at least 6 weeks after stopping mycophenolate mofetil.
• You should not donate sperm while taking mycophenolate mofetil and for 90 days after stopping mycophenolate mofetil.
• Mycophenolate mofetil may influence your ability to drive and use machines (). If you experience drowsiness, confusion, dizziness, tremor, or low blood pressure during treatment with mycophenolate mofetil, you should be cautious about driving or using heavy machines.

The Most Common Side Effects Of Mycophenolate Mofetil Include: ⮝

• diarrhea
• blood problems including low white and red blood cell counts
• infections
• blood pressure problems
• fast heart beat
• swelling of the lower legs, ankles and feet

• changes in laboratory blood levels, including high levels of blood sugar (hyperglycemia)
• stomach problems including diarrhea, constipation, nausea and vomiting
• rash
• nervous system problems such as headache, dizziness and tremor

Side Effects That Can Happen More Often In Children Than In Adults Taking Mycophenolate Mofetil Include: ⮝

• stomach area pain
• fever
• infection
• pain
• blood infection (sepsis)
• diarrhea

• vomiting
• sore throat
• colds (respiratory tract infections)
• high blood pressure
• low white blood cell count
• low red blood cell count

These are not all of the possible side effects of mycophenolate mofetil. 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.You may also report side effects to Mylan at 1-877-446-3679 (1-877-4-INFO-RX).

How Should I Store Mycophenolate Mofetil? ⮝

• Store mycophenolate mofetil capsules and tablets at room temperature between 20 to 25 C (68 to 77 F).
• Keep mycophenolate mofetil tablets in the light resistant container that it comes in.

Keep mycophenolate mofetil and all medicines out of the reach of children.

General Information about the safe and effective use of mycophenolate mofetil.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use mycophenolate mofetil for a condition for which it was not prescribed. Do not give mycophenolate mofetil 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. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about mycophenolate mofetil that is written for health professionals.

Mycophenolate Mofetil 250 Mg Capsules: ⮝

black iron oxide, colloidal silicon dioxide, croscarmellose sodium, FD&C Blue No. 2, gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. In addition, the imprinting ink contains the following: ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze.

Mycophenolate Mofetil 500 Mg Tablets: ⮝

colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, pregelatinized starch (corn), red iron oxide, sodium lauryl sulfate, talc, titanium dioxide and yellow iron oxide.

Manufactured For: ⮝

Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.

For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).

The brands listed are trademarks of their respective owners.

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

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Revised: 3/2019
MYCO:R10mpbmh/MG:MYCO:R8mpb/ MG:MYCO:R8mh

Who Should Not Take Mycophenolate Mofetil? ⮝

Do not take mycophenolate mofetil if you are allergic to mycophenolate mofetil or any of the ingredients in mycophenolate mofetil capsules and tablets.

General Information About Mycophenolate Mofetil: ⮝

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use mycophenolate mofetil for a condition for which it was not prescribed. Do not give mycophenolate mofetil 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. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about mycophenolate mofetil that is written for healthcare professionals. For more information call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

Active Ingredient: ⮝

mycophenolate mofetil, USP

Inactive Ingredients: ⮝

colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, pregelatinized starch (corn), red iron oxide, sodium lauryl sulfate, talc, titanium dioxide and yellow iron oxide.

The brands listed are trademarks of their respective owners.

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

Manufactured by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Distributed by:
Mylan Institutional Inc.
Rockford, IL 61103 U.S.A.

S-11971 R2
3/16

PRINCIPAL DISPLAY PANEL - 250 mg Capsules

NDC 51079-721-20

Mycophenolate
Mofetil
Capsules, USP
250 mg

100 Capsules (10 x 10)

Each capsule contains:
Mycophenolate mofetil, USP 250 mg

Usual Dosage: ⮝

See accompanying
prescribing information and
Medication Guide.

Caution: ⮝

Special Handling and
Disposal Instructions - see
prescribing information.

Store at 20 to 25 C (68 to 77 F).
[See USP Controlled Room Temperature.]
Protect from light.

Manufactured by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Rx only

S-10456 R5

Packaged And Distributed By: ⮝

Mylan Institutional Inc.

Rockford, IL 61103 U.S.A.

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.

MYCOPHENOLATE MOFETIL mycophenolate mofetil capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:51079-721(NDC:0378-2250) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MYCOPHENOLATE MOFETIL(UNII: 9242ECW6R0) (MYCOPHENOLIC ACID - UNII:HU9DX48N0T) MYCOPHENOLATE MOFETIL 250 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE(UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM(UNII: M28OL1HH48) MAGNESIUM STEARATE(UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE(UNII: OP1R32D61U) STARCH, CORN(UNII: O8232NY3SJ) SODIUM LAURYL SULFATE(UNII: 368GB5141J) FERROSOFERRIC OXIDE(UNII: XM0M87F357) FD&C BLUE NO. 2(UNII: L06K8R7DQK) GELATIN, UNSPECIFIED(UNII: 2G86QN327L) FERRIC OXIDE RED(UNII: 1K09F3G675) TITANIUM DIOXIDE(UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW(UNII: EX438O2MRT) AMMONIA(UNII: 5138Q19F1X) PROPYLENE GLYCOL(UNII: 6DC9Q167V3) SHELLAC(UNII: 46N107B71O)

Product Characteristics Color brown (caramel opaque) , purple (lavender opaque) Score no score Shape CAPSULE Size 19mm Flavor Imprint Code MYLAN;2250 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:51079-721-20 100 in 1 CARTON 06/01/2009 1 NDC:51079-721-01 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065520 06/01/2009

MYCOPHENOLATE MOFETIL mycophenolate mofetil tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:51079-379(NDC:0378-4472) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MYCOPHENOLATE MOFETIL(UNII: 9242ECW6R0) (MYCOPHENOLIC ACID - UNII:HU9DX48N0T) MYCOPHENOLATE MOFETIL 500 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE(UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM(UNII: M28OL1HH48) MAGNESIUM STEARATE(UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE(UNII: OP1R32D61U) POLYETHYLENE GLYCOL, UNSPECIFIED(UNII: 3WJQ0SDW1A) POLYVINYL ALCOHOL, UNSPECIFIED(UNII: 532B59J990) POVIDONE, UNSPECIFIED(UNII: FZ989GH94E) STARCH, CORN(UNII: O8232NY3SJ) FERRIC OXIDE RED(UNII: 1K09F3G675) SODIUM LAURYL SULFATE(UNII: 368GB5141J) TALC(UNII: 7SEV7J4R1U) TITANIUM DIOXIDE(UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW(UNII: EX438O2MRT)

Product Characteristics Color pink (light pink) Score no score Shape OVAL Size 19mm Flavor Imprint Code MYLAN;472 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:51079-379-20 100 in 1 CARTON 06/01/2009 1 NDC:51079-379-01 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065521 06/01/2009

Labeler -Mylan Institutional Inc. (039615992)

Revised: 12/2018document Id: ⮝

7cffd66f-5f6f-9b8e-e053-2a91aa0a468734391-3Set id: 52907069-4a29-4351-a830-a9ee86b5ff7cVersion: 6Effective Time: 20181214Mylan Institutional Inc.

Information For Patients: ⮝

See FDA-approved patient labeling (Medication Guide and Instructions for Use).

17.1 Embryofetal Toxicity

Pregnancy loss and malformations

• Inform females of reproductive potential and pregnant women that use of mycophenolate mofetil 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[seeWarnings 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[seeUse in Specific Populations (8.1)].

Contraception

• Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential[seeUse in Specific Populations (8.3)].
• Females of reproductive potential must use an acceptable form of birth control during the entire mycophenolate mofetil therapy and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses abstinence. Mycophenolate mofetil may reduce effectiveness of oral contraceptives. Use of additional barrier contraceptive methods is recommended[seeUse 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 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[seeUse 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[seeWarnings 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[seeWarnings and Precautions (5.4)].

17.5 Gastrointestinal Tract Complications

Inform patients that mycophenolate mofetil 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[seeWarnings and Precautions (5.5)].

17.6 Immunizations

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

17.7 Administration Instructions

• Advise patients not to crush mycophenolate mofetil tablets and 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 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.

17.9 Semen Donation

Advise males of childbearing potential not to donate semen during therapy and for 90 days following discontinuation of mycophenolate mofetil.

17.10 Potential to Impair Driving and Use of Machinery

Advise patients that mycophenolate mofetil can affect the ability to drive or operate machines. Patients should avoid driving or operating machines if they experience somnolence, confusion, dizziness, tremor or hypotension during treatment with mycophenolate mofetil.

Patient Information ⮝

Information for Patients

See FDA-approved patient labeling (Medication Guide and Instructions for Use).

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 capsule 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.

17.10 Potential to Impair Driving and Use of Machinery

Advise patients that mycophenolate mofetil capsules can affect the ability to drive or operate machines. Patients should avoid driving or operating machines if they experience somnolence, confusion, dizziness, tremor or hypotension during treatment with mycophenolate mofetil capsules.

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA, Inc.

Manufactured In Czech Republic By:
Teva Czech Industries, s.r.o.
Opava-Komarov, Czech Republic

Manufactured For:
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454

Rev. N 2/2019

Mycophenolate Mofetil Can Cause Serious Side Effects: ⮝

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 ofmiscarriageduring 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:

1.

your doctor must talk with you about acceptable birth control methods (contraceptive counseling) to use while taking mycophenolate mofetil.

2.

you should have one pregnancy test immediately before starting mycophenolate mofetil 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.

3.

you must use acceptable birth control during your entire mycophenolate mofetil therapy 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, and you could become pregnant. If you take birth control pills while using mycophenolate mofetil 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.

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,do notstop taking mycophenolate mofetil. Call your doctor right away.In certain situations, you and your doctor may decide that taking mycophenolate mofetil is more important to your health than the possible risks to your unborn baby.

4.

You and your doctor should report your pregnancy to:
Mycophenolate Pregnancy Registry (1-800-617-8191)
Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX)

The purpose of this registry is to gather information about the health of you and your baby.

Increased 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 and can lead to death. These serious infections can include:

5.

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:

1.

Shingles, other herpes infections, and cytomegalovirus (CMV). CMV can cause serious tissue and blood infections.

2.

BK virus. BK virus can affect how your kidney works and cause your transplanted kidney to fail.

3.

Hepatitis B and C viruses. Hepatitis viruses can affect how your liver works. Talk to your doctor about how hepatitis viruses may affect you.

6.

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. You should tell your doctor right away if you have any of the following symptoms:

4.

Weakness on one side of the body

5.

You do not care about things that you usually care about (apathy)

6.

You are confused or have problems thinking

7.

You can not control your muscles

7.

Fungal infections.Yeasts and other types of fungal infections can happen with mycophenolate mofetil and can cause serious tissue and blood infections ().

Common Side Effects Include: ⮝

diarrhea. Call your doctor right away if you have diarrhea. Do not stop taking mycophenolate mofetil without first talking with your doctor.

vomiting

pain

stomach area pain

swelling of the lower legs, ankles and feet

high blood pressure

Side Effects That Happen More Often In Children Than In Adults Taking Mycophenolate Mofetil Include: ⮝

stomach area pain

fever

infection

pain

blood infection (sepsis)

diarrhea

vomiting

sore throat

colds (respiratory tract infections)

high blood pressure

low white blood cell count

low red blood cell count

These are not all of the possible side effects of mycophenolate mofetil. 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 the FDA at 1-800-FDA-1088 or to Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

Distributed By: ⮝

Cardinal Health

Dublin, OH 43017

L45913010318

L45912280318

S-11971 R2
3/16

What Is The Most Important Information I Should Know About Mycophenolate Mofetil?mycophenolate Mofetil Can Cause Serious Side Effects: ⮝

• 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 ofmiscarriageduring 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.
  • you should have one pregnancy test immediately before starting mycophenolate mofetil tablets 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 tablets therapy and for 6 weeks after stopping mycophenolate mofetil tablets, 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, and you could become pregnant. If you take birth control pills while using mycophenolate mofetil 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.
  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,do notstop taking Mycophenolate mofetil. Call your doctor right away.In certain situations, you and your doctor may decide that taking mycophenolate mofetil is more important to your health than the possible risks to your unborn baby.

• You and your doctor should report your pregnancy to
  Mycophenolate Pregnancy Registry (1-800-617-8191)

The purpose of this registry is to gather information about the health of you and your baby.

• Increased 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 and can lead to death. Types of 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. You should tell your doctor right away if you have any of the following symptoms:
• Weakness on one side of the body
• You do not care about things that you usually care about (apathy)
• You are confused or have problems thinking
• You cannot control your muscles
• Fungal infections.Yeasts and other types of fungal infections can happen with mycophenolate mofetil and can cause serious tissue and blood infections ().

Call Your Doctor Right Away If You Have Any Of The Following Signs And Symptoms Of Infection: ⮝

• • Temperature of 100.5 F or greater
  • Cold symptoms, such as a runny nose or sore throat
  • Flu symptoms, such as an upset stomach, stomach pain, vomiting or diarrhea
  • Earache or headache
  • Pain during urination
  • White patches in the mouth or throat
  • Unexpected bruising or bleeding
  • Cuts, scrapes or incisions that are red, warm and oozing pus
• 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 swelling.
  • a brown or black skin lesion with uneven borders, or one part of the lesion does not look like the other
  • a change in the size and color of a mole
  • a new skin lesion or bump
  • any other changes to your health

Mycophenolate mofetil 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 is used with other medicines called cyclosporines (Sandimmune, Gengraf, Neoral) and corticosteroids.

Mycophenolate mofetil has been used safely and works in children who received a kidney transplant as it does in adults. It is not known if mycophenolate mofetil is safe and works in children who receive a heart or liver transplant.

Who should not take Mycophenolate mofetil?
Do not take mycophenolate mofetil if you are allergic to mycophenolate mofetil or any of the ingredients in mycophenolate mofetil capsules, USP and mycophenolate mofetil tablets, USP.

Tell Your Doctor About All Of Your Medical Conditions, If You: ⮝

• have any digestive problems,such as ulcers.
• have Phenylketonuria (PKU).
• have Lesch-Nyhan or Kelley-
• 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 or breastfeed.

Tell your healthcare provider about all of the medicines you are taking including prescription and nonprescription 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).
• sevelamer (Renagel, Renvela ). These products should be taken 2 hours after taking mycophenolate mofetil.
• acyclovir (Zovirax), valacyclovir (Valtrex), ganciclovir (CYTOVENEIV, Vitrasert), valganciclovir (VALCYTE).
• rifampin (Rifater, Rifamate, Rimactane, Rifadin).
• antacids that contain magnesium and aluminum (Mycophenolate mofetil and the antacid should not be taken at the same time).
• proton pump inhibitors (PPIs) (Prevacid, Protonix).
• sulfamethoxazole/trimethoprim (BACTRIM , BACTRIM DS ).
• norfloxacin (Noroxin) and metronidazole (Flagyl, FlagylER, FlagylIV, Metro IV, Helidac, Pylera ).
• ciprofloxacin (Cipro, CiproXR, Ciloxan, ProquinXR) and amoxicillin plus clavulanic acid (Augmentin, Augmentin XR ).
• 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.

What Should I Avoid While Taking Mycophenolate Mofetil? ⮝

• Avoid pregnancy. ) Wear protective clothing when you are in the sun and use a sunscreen with a high protection factor (SPF 30 and above). This is especially important if your skin is very fair or if you have a family history of skin cancer.

What Are The Possible Side Effects Of Mycophenolate Mofetil?mycophenolate Mofetil Can Cause Serious Side Effects: ⮝

• • Store mycophenolate mofetil tablets USP and mycophenolate mofetil capsules USP at at 20 to 25 C (68 to 77 F). [See USP controlled room temperature].
  • Keep mycophenolate mofetil and all medicines out of the reach of children.

  General Information about mycophenolate mofetil
  Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use mycophenolate mofetil for a condition for which it was not prescribed. Do not give mycophenolate mofetil 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. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about mycophenolate mofetil that is written for healthcare professionals. For more information call Sandoz Inc. at 1-800-438-1985.

What Are The Ingredients In Mycophenolate Mofetil?active Ingredient: ⮝

Mycophenolate Mofetil

Mycophenolate Mofetil Capsules, Usp 250 Mg: ⮝

Croscarmellose sodium, magnesium stearate, povidone (K-30) and microcrystalline cellulose. The capsule shells contain yellow iron oxide, FD & C red # 3, gelatin, sodium lauryl sulfate, and titanium dioxide.

Mycophenolate Mofetil Tablets, Usp 500 Mg: ⮝

Microcrystalline cellulose, croscarmellose sodium, povidone [K-30], magnesium stearate (Vegetable), opadry brown, opacode black. The opadry brown contains FD & C blue #1 aluminum lake, FD & C red #40 aluminum lake, hypromellose, iron oxide red, polyethylene glycol and titanium dioxide.

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

Distributed by:
American Health Packaging
Columbus, OH 43217

8442701/1218

1. No Title 1572554723
2. Mycophenolate Mofetil Capsulesmycophenolate Mofetil Tablets
3. Description
4. Clinical Pharmacology
5. Warnings
6. Precautions
7. Overdosage
8. How Supplied
9. Storage And Handling
10. Package Label.principal Display Panel
11. Warning
12. Clinical Studies
13. How Supplied:
14. Package/label Display Panel
15. Warning: Embryofetal Toxicity, Malignancies And Serious Infections
16. Principal Display Panel
17. Warning: Embryofetal Toxicity, Malignancies And Serious Infections
18. Packaging Information
19. Package/label Display Panel Carton 250 Mg
20. Package/label Display Panel Blister 250 Mg
21. Package/label Display Panel Carton 500 Mg
22. Package/label Display Panel Blister 500 Mg
23. 1 Indications And Usage
24. 2 Dosage And Administration
25. 3 Dosage Forms And Strengths
26. 4 Contraindications
27. 5 Warnings And Precautions
28. 6 Adverse Reactions
29. 7 Drug Interactions
30. 8 Use In Specific Populations
31. 10 Overdosage
32. 11 Description
33. 12 Clinical Pharmacology
34. 13 Nonclinical Toxicology
35. 14 Clinical Studies
36. 15 References
37. 16 How Supplied/storage And Handling
38. No Title 1572455317
39. Principal Display Panel
40. Package/label Principal Display Panel 250 Mg
41. Package/label Principal Display Panel 500 Mg
42. Highlights Of Prescribing Information
43. See Full Prescribing Information For Complete Boxed Warning
44. Recent Major Changes
45. Indications And Usage
46. Dosage And Administration
47. Dosage Forms And Strengths
48. Contraindications
49. Warnings And Precautions
50. Adverse Reactions
51. Drug Interactions
52. Use In Specific Populations
53. Warning: Embryofetal Toxicity, Malignancies And Serious Infections
54. 1 Indications And Usage
55. 2 Dosage And Administration
56. 3 Dosage Forms And Strengths
57. 4 Contraindications
58. 5 Warnings And Precautions
59. 6 Adverse Reactions
60. 7 Drug Interactions
61. 8 Use In Specific Populations
62. 10 Overdosage
63. 11 Description
64. 12 Clinical Pharmacology
65. 13 Nonclinical Toxicology
66. 14 Clinical Studies
67. 15 References
68. 16 How Supplied/storage And Handling
69. Package/label Principal Display Panel 250 Mg
70. Package/label Principal Display Panel 500 Mg

No Title 1572554723 ⮝

WARNING: EMBRYOFETAL TOXICITY, MALIGNANCIES and SERIOUS INFECTIONS

• 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 Capsulesmycophenolate Mofetil Tablets  ⮝

WARNING

Immunosuppression may lead to increased susceptibility to infection and the possible development of lymphoma. Only physicians experienced in immunosuppressive therapy and management of renal, cardiac or hepatic transplant patients should use mycophenolate mofetil capsules and mycophenolate mofetil tablets. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Female users of childbearing potential must use contraception. Use of mycophenolate mofetil capsules and mycophenolate mofetil tablets during pregnancy is associated with increased risk of pregnancy loss and congenital malformations.

Description ⮝

Mycophenolate mofetil 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 C 23H 31NO 7, a molecular weight of 433.50, and the following structural formula:

Mycophenolate mofetil is a white to off-white crystalline powder. It is slightly soluble in water (43 g/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 mycophenolate mofetil are 5.6 for the morpholino group and 8.5 for the phenolic group.

Mycophenolate mofetil 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 mycophenolate mofetil, and tablets containing 500 mg of mycophenolate mofetil.

Inactive ingredients in mycophenolate mofetil capsules, USP 250 mg include croscarmellose sodium, magnesium stearate, povidone (K-30), microcrystalline cellulose. The capsule shells contain yellow iron oxide, FD&C red # 3, gelatin, sodium lauryl sulfate, and titanium dioxide.

Inactive ingredients in mycophenolate mofetil tablets, USP 500 mg include microcrystalline cellulose, croscarmellose sodium, povidone [K-30], magnesium stearate (Vegetable) and opadry brown.

The opadry brown contains FD & C blue #1 aluminum lake, FD & C red #40 aluminum lake, hypromellose, iron oxide red, polyethylene glycol and titanium dioxide.

Clinical Pharmacology ⮝

Mechanism of Action

Mycophenolate mofetil has been demonstrated in experimental animal models to prolong the survival of allogeneic transplants (kidney, heart, liver, intestine, limb, small bowel, pancreatic islets, and bone marrow).

Mycophenolate mofetil has also been shown to reverse ongoing acute rejection in the canine renal and rat cardiac allograft models. Mycophenolate mofetil also inhibited proliferative arteriopathy in experimental models of aortic and cardiac allografts in rats, as well as in primate cardiac xenografts. Mycophenolate mofetil was used alone or in combination with other immunosuppressive agents in these studies. Mycophenolate mofetil has been demonstrated to inhibit immunologically mediated inflammatory responses in animal models and to inhibit tumor development and prolong survival in murine tumor transplant models.

Mycophenolate mofetil is rapidly absorbed following oral administration and hydrolyzed to form MPA, which is the active metabolite. MPA is a potent, 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. Mycophenolate mofetil 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.

Pharmacokinetics

Following oral and intravenous administration, mycophenolate mofetil undergoes rapid and complete metabolism to MPA, the active metabolite. Oral absorption of the drug is rapid and essentially complete. MPA is metabolized to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. The parent drug, mycophenolate mofetil, can be measured systemically during the intravenous infusion; however, shortly (about 5 minutes) after the infusion is stopped or after oral administration, MMF concentration is below the limit of quantitation (0.4 mcg/mL).

Absorption

In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil (based on MPA AUC) was 94%. The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in renal transplant patients receiving multiple doses of mycophenolate mofetil up to a daily dose of 3 g (see Table 1).

Food (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g bid to renal transplant patients. However, MPA C max was decreased by 40% in the presence of food (see DOSAGE AND ADMINISTRATION).

Distribution

The mean ( SD) apparent volume of distribution of MPA in 12 healthy volunteers is approximately 3.6 ( 1.5) and 4.0 ( 1.2) L/kg following intravenous and oral administration, respectively. MPA, at clinically relevant concentrations, is 97% bound to plasma albumin. MPAG is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable renal transplant patients; however, at higher MPAG concentrations (observed in patients with renal impairment or delayed renal 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 HSA) and MPAG (at 460 mcg/mL with plasma proteins) increased the free fraction of MPA. At concentrations that exceeded what is encountered clinically, cyclosporine, digoxin, naproxen, prednisone, propranolol, tacrolimus, theophylline, tolbutamide, and warfarin did not increase 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%.

Metabolism

Following oral and intravenous dosing, mycophenolate mofetil undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo, MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.

Secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to 12 hours postdose. The coadministration of cholestyramine (4 g tid) resulted in approximately a 40% decrease in the MPA AUC (largely as a consequence of lower concentrations in the terminal portion of the profile). These observations suggest that enterohepatic recirculation contributes to MPA plasma concentrations.

Increased plasma concentrations of mycophenolate mofetil metabolites (MPA 50% increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal insufficiency (see CLINICAL PHARMACOLOGY: Special Populations).

Excretion

Negligible amount of drug is excreted as MPA (< 1% of dose) in the urine. Orally administered radiolabeled mycophenolate mofetil 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. Bile acid sequestrants, such as cholestyramine, reduce MPA AUC by interfering with enterohepatic circulation of the drug (see OVERDOSAGE).

Mean ( 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.

Pharmacokinetics in Healthy Volunteers, Renal, Cardiac, and Hepatic Transplant Patients
Shown below are the mean ( SD) pharmacokinetic parameters for MPA following the administration of mycophenolate mofetil given as single doses to healthy volunteers and multiple doses to renal, cardiac, and hepatic transplant patients. In the early posttransplant period (< 40 days posttransplant), renal, cardiac, and hepatic transplant patients had mean MPA AUCs approximately 20% to 41% lower and mean C max approximately 32% to 44% lower compared to the late transplant period (3 to 6 months posttransplant).

Mean MPA AUC values following administration of 1 g bid intravenous mycophenolate mofetil over 2 hours to renal transplant patients for 5 days were about 24% higher than those observed after oral administration of a similar dose in the immediate posttransplant phase. In hepatic transplant patients, administration of 1 g bid intravenous mycophenolate mofetil followed by 1.5 g bid oral mycophenolate mofetil resulted in mean MPA AUC values similar to those found in renal transplant patients administered 1 g mycophenolate mofetil bid.

Table 1 Pharmacokinetic Parameters for MPA [mean ( SD)] Following Administration of Mycophenolate Mofetil to Healthy Volunteers (Single Dose), Renal, Cardiac, and Hepatic Transplant Patients (Multiple Doses)

* AUC(0-12h) values quoted are extrapolated from data from samples collected over 4 hours.
	Dose/Route	T max (h)	C max ( g/mL)	Total AUC ( g h/mL)
Healthy Volunteers (single dose)	1 g/oral	0.80 ( 0.36) (n=129)	24.5 ( 9.5) (n=129)	63.9 ( 16.2) (n=117)
Renal Transplant Patients (bid dosing) Time After Transplantation	Dose/Route	T max (h)	C max ( g/mL)	Interdosing Interval AUC (0 12h) ( g 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) (n=31)
Early (< 40 days)	1 g/oral	1.31 ( 0.76) (n=25)	8.16 ( 4.50) (n=25)	27.3 ( 10.9) (n=25)
Early (< 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 (>3 months)	1.5 g/oral	0.90 ( 0.24) (n=23)	24.1 ( 12.1) (n=23)	65.3 ( 35.4) (n=23)
Cardiac Transplant Patients (bid dosing) Time After Transplantation	Dose/Route	T max (h)	C max ( g/mL)	Interdosing Interval AUC (0 12h) ( g 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 (> 6 months)	1.5 g/oral	1.1 ( 0.7) (n=52)	20.0 ( 9.4) (n=52)	54.1 * ( 20.4) (n=49)
Hepatic Transplant Patients (bid dosing) Time After Transplantation	Dose/Route	T max (h)	C max ( g/mL)	Interdosing Interval AUC (0 12h) ( g 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 (> 6 months)	1.5 g/oral	1.54 ( 0.51) (n=6)	19.3 ( 11.7) (n=6)	49.3 ( 14.8) (n=6)

Two 500 mg tablets have been shown to be bioequivalent to four 250 mg capsules. Five mL of the 200 mg/mL constituted oral suspension have been shown to be bioequivalent to four 250 mg capsules.

Special Populations

Shown below are the mean ( SD) pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil given as single doses to non-transplant subjects with renal or hepatic impairment.

Table 2 Pharmacokinetic Parameters for MPA [mean ( SD)] Following Single Doses of Mycophenolate Mofetil Capsules in Chronic Renal and Hepatic Impairment

Renal Impairment (no. of patients)	Dose	T max (h)	C max ( g/mL)	AUC (0 96h) ( g h/mL)
Healthy Volunteers GFR > 80 mL/min/1.73 m 2 (n=6)	1 g	0.75 ( 0.27)	25.3 ( 7.99)	45 ( 22.6)
Mild Renal Impairment GFR 50 to 80 mL/min/1.73 m 2 (n=6)	1 g	0.75 ( 0.27)	26 ( 3.82)	59.9 ( 12.9)
Moderate Renal Impairment GFR 25 to 49 mL/min/1.73 m 2 (n=6)	1 g	0.75 ( 0.27)	19 ( 13.2)	52.9 ( 25.5)
Severe Renal Impairment GFR < 25 mL/min/1.73 m 2 (n=7)	1 g	1 ( 0.41)	16.3 ( 10.8)	78.6 ( 46.4)
Hepatic Impairment (no. of patients)	Dose	T max (h)	C max ( g/mL)	AUC (0 48h) ( g h/mL)
Healthy Volunteers (n=6)	1 g	0.63 ( 0.14)	24.3 ( 5.73)	29 ( 5.78)
Alcoholic Cirrhosis (n=18)	1 g	0.85 ( 0.58)	22.4 ( 10.1)	29.8 ( 10.7)

Renal Insufficiency

In a single-dose study, MMF was administered as capsule or intravenous infusion over 40 minutes. Plasma MPA AUC observed after oral dosing to volunteers with severe chronic renal impairment [glomerular filtration rate (GFR) < 25 mL/min/1.73 m 2] was about 75% higher relative to that observed in healthy volunteers (GFR > 80 mL/min/1.73 m 2). 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 m 2) was 62.4 g h/mL ( 19.3). Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied (see PRECAUTIONS: Patients with Renal Impairment and DOSAGE AND ADMINISTRATION).

In patients with delayed renal graft function posttransplant, mean MPA AUC (0-12h) was comparable to that seen in posttransplant 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 posttransplant patients without delayed renal graft function (see PRECAUTIONS: Patients with Renal Impairment and DOSAGE AND ADMINISTRATION).

In 8 patients with primary graft non-function following renal 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 mycophenolate mofetil are not altered by hemodialysis. Hemodialysis usually does not remove MPA or MPAG. At high concentrations of MPAG (> 100 g/mL), hemodialysis removes only small amounts of MPAG.

Hepatic Insufficiency

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. Effects of hepatic disease on this process probably depend on the particular disease. Hepatic disease with other etiologies, such as primary biliary cirrhosis, may show a different effect. 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 g h/mL ( 15.5).

Pediatrics

The 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/m 2 bid (up to a maximum of 1 g bid) after allogeneic renal transplantation. The pharmacokinetic data for MPA is provided in Table 3.

Table 3 Mean ( SD) Computed Pharmacokinetic Parameters for MPA by Age and Time After Allogeneic Renal Transplantation

* adjusted to a dose of 600 mg/m2 a subset of 1 to < 6 yr n=20 n=16
Age Group (n)	Time	T max (h)	Dose Adjusted* C max ( g/mL)	Dose Adjusted* AUC (0 12h) ( g h/mL)
1 to < 2 yr (6)	Early (Day 7)	3.03 (4.70)	10.3 (5.80)	22.5 (6.66)
1 to < 6 yr (17)		1.63 (2.85)	13.2 (7.16)	27.4 (9.54)
6 to < 12 yr (16)		0.940 (0.546)	13.1 (6.30)	33.2 (12.1)
12 to 18 yr (21)		1.16 (0.830)	11.7 (10.7)	26.3 (9.14)
1 to < 2 yr (4)	Late (Month 3)	0.725 (0.276)	23.8 (13.4)	47.4 (14.7)
1 to < 6 yr (15)		0.989 (0.511)	22.7 (10.1)	49.7 (18.2)
6 to < 12 yr (14)		1.21 (0.532)	27.8 (14.3)	61.9 (19.6)
12 to 18 yr (17)		0.978 (0.484)	17.9 (9.57)	53.6 (20.3)
1 to < 2 yr (4)	Late (Month 9)	0.604 (0.208)	25.6 (4.25)	55.8 (11.6)
1 to < 6 yr (12)		0.869 (0.479)	30.4 (9.16)	61.0 (10.7)
6 to < 12 yr (11)		1.12 (0.462)	29.2 (12.6)	66.8 (21.2)
12 to 18 yr (14)		1.09 (0.518)	18.1 (7.29)	56.7 (14)

The Mycophenolate Mofetil oral suspension dose of 600 mg/m 2 bid (up to a maximum of 1 g bid) achieved mean MPA AUC values in pediatric patients similar to those seen in adult renal transplant patients receiving Mycophenolate Mofetil Capsules at a dose of 1 g bid in the early posttransplant period. There was wide variability in the data. As observed in adults, early posttransplant MPA AUC values were approximately 45% to 53% lower than those observed in the later posttransplant period (> 3 months). MPA AUC values were similar in the early and late posttransplant period across the 1 year to 18 year age range.

Gender

Data 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 C max 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.

Geriatrics

Pharmacokinetics in the elderly have not been studied.

Warnings ⮝

(see boxed WARNING)

Embryofetal Toxicity

Mycophenolate mofetil (MMF) can cause fetal harm when administered to a pregnant female. 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 (see PRECAUTIONS: Pregnancy).

Pregnancy Exposure Prevention and Planning

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. For recommended pregnancy testing and contraception methods (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning).

Lymphoma and Malignancy

Patients receiving immunosuppressive regimens involving combinations of drugs, including mycophenolate mofetil, as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see ADVERSE REACTIONS).The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

As usual 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.

Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and hepatic transplant patients (see ADVERSE REACTIONS).

In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed (see ADVERSE REACTIONS).

Combination with Other Immunosuppressive Agents

Mycophenolate mofetil has been administered in combination with the following agents in clinical trials: antithymocyte globulin (ATGAM ), OKT3 (Orthoclone OKT 3), cyclosporine (Sandimmune , Neoral ) and corticosteroids. The efficacy and safety of the use of mycophenolate mofetil in combination with other immunosuppressive agents have not been determined.

Serious Infections

Patients receiving immunosuppressants, including mycophenolate mofetil, are at increased risk of developing bacterial, fungal, protozoal and new or reactivated viral infections, including opportunistic infections. These infections may lead to serious, including fatal outcomes. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution (see ADVERSE REACTIONS).

New or Reactivated Viral Infections

Polyomavirus associated nephropathy (PVAN), JC virus associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including Mycophenolate Mofetil. Reduction in immunosuppression should be considered for patients who develop evidence of new or reactivated viral infections. Physicians should also consider 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: Postmarketing Experience). 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. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function (see ADVERSE REACTIONS: Postmarketing Experience). In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

The risk of CMV viremia and CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive 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.

Neutropenia

Severe neutropenia [absolute neutrophil count (ANC) < 0.5 x 10 3/ L] developed in up to 2% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant patients receiving mycophenolate mofetil 3 g daily (see ADVERSE REACTIONS). Patients receiving mycophenolate mofetil should be monitored for neutropenia (see PRECAUTIONS: Laboratory Tests).The development of neutropenia may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or some combination of these causes. If neutropenia develops (ANC < 1.3 x 10 3/ L), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see DOSAGE AND ADMINISTRATION). Neutropenia has been observed most frequently in the period from 31 to 180 days posttransplant in patients treated for prevention of renal, cardiac, and hepatic rejection.

Patients receiving mycophenolate mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.

Pure Red Cell Aplasia (PRCA)

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents. The mechanism for mycophenolate mofetil induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppression regimen are also unknown. 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.

CAUTION: MYCOPHENOLATE MOFETIL INTRAVENOUS SOLUTION MUST NOT BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION.

Precautions ⮝

Pregnancy Exposure Prevention and Planning

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.

Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not passed through menopause. Menopause is the permanent end of menstruation and fertility. Menopause should be clinically confirmed by a patient s healthcare practitioner. Some commonly used diagnostic criteria include 1) 12 months of spontaneous amenorrhea (not amenorrhea induced by a medical condition or medical therapy) or 2) postsurgical from a bilateral oophorectomy.

Pregnancy Testing

To prevent unplanned exposure during pregnancy, 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. 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, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations.

Contraception

Females of reproductive potential taking mycophenolate mofetil must receive contraceptive counseling and use acceptable contraception (see Table 8 for acceptable contraception methods). Patients must use acceptable birth control during entire mycophenolate mofetil therapy, and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely).

Patients should be aware that mycophenolate mofetil reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness (see PRECAUTIONS: Information for Patients and PRECAUTIONS: Drug Interactions: Oral Contraceptives).

Table 8 Acceptable Contraception Methods for Females of Reproductive Potential Pick from the following birth control options:

Option 1 Methods to Use Alone	Intrauterine devices (IUDs) Tubal sterilization Patient s partner had a vasectomy
OR
Option 2	Hormone Methods choose 1		Barrier Methods choose 1
Choose One Hormone Method AND One Barrier Method	Estrogen and Progesterone Oral Contraceptive Pill Transdermal patch Vaginal ring Progesterone-only Injection Implant	AND	Diaphragm with spermicide Cervical cap with spermicide Contraceptive sponge Male condom Female 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 spermicide Cervical cap with spermicide Contraceptive sponge	AND	Male condom Female condom

Pregnancy Planning

For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of Mycophenolate mofetil should be discussed with the patient.

Gastrointestinal Disorders

Gastrointestinal bleeding (requiring hospitalization) has been observed in approximately 3% of renal, in 1.7% of cardiac, and in 5.4% of hepatic transplant patients treated with Mycophenolate mofetil 3 g daily. In pediatric renal transplant patients, 5/148 cases of gastrointestinal bleeding (requiring hospitalization) were observed.

Gastrointestinal perforations have rarely been observed. Most patients receiving Mycophenolate mofetil were also receiving other drugs known to be associated with these complications. Patients with active peptic ulcer disease were excluded from enrollment in studies with mycophenolate mofetil. Because Mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hemorrhage, and perforation, Mycophenolate mofetil should be administered with caution in patients with active serious digestive system disease.

Patients with Renal Impairment

Subjects with severe chronic renal impairment (GFR < 25 mL/min/1.73 m 2) who have received single doses of Mycophenolate mofetil showed higher plasma MPA and MPAG AUCs relative to subjects with lesser degrees of renal impairment or normal healthy volunteers. No data are available on the safety of long-term exposure to these levels of MPAG. Doses of Mycophenolate mofetil greater than 1 g administered twice a day to renal transplant patients should be avoided and they should be carefully observed (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).

No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.

In patients with delayed renal graft function posttransplant, mean MPA AUC (0-12h) was comparable, but MPAG AUC (0-12h) was 2-fold to 3-fold higher, compared to that seen in posttransplant patients without delayed renal graft function. In the three controlled studies of prevention of renal rejection, there were 298 of 1483 patients (20%) with delayed graft function. Although patients with delayed graft function have a higher incidence of certain adverse events (anemia, thrombocytopenia, hyperkalemia) than patients without delayed graft function, these events were not more frequent in patients receiving mycophenolate mofetil than azathioprine or placebo. No dose adjustment is recommended for these patients; however, they should be carefully observed (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).

Infections in Cardiac Transplant Patients

In cardiac transplant patients, the overall incidence of opportunistic infections was approximately 10% higher in patients treated with Mycophenolate mofetil than in those receiving azathioprine therapy, but this difference was not associated with excess mortality due to infection/sepsis among patients treated with Mycophenolate mofetil (see ADVERSE REACTIONS).

There were more herpes virus (H. simplex, H. zoster, and cytomegalovirus) infections in cardiac transplant patients treated with Mycophenolate mofetil compared to those treated with azathioprine (see ADVERSE REACTIONS).

Concomitant Medications

It is recommended that Mycophenolate mofetil not be administered concomitantly with azathioprine because both have the potential to cause bone marrow suppression and such concomitant administration has not been studied clinically.

In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be used in the concomitant administration of Mycophenolate mofetil with drugs that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of Mycophenolate mofetil (see PRECAUTIONS: Drug Interactions).

Patients with HGPRT Deficiency

Mycophenolate mofetil is an IMPDH (inosine monophosphate dehydrogenase) inhibitor; therefore it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

Immunizations

During treatment with Mycophenolate mofetil, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective (see PRECAUTIONS: Drug Interactions: Live Vaccines).

Information for Patients

See Medication Guide

• Inform females of reproductive potential that use of mycophenolate mofetil during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, and advise them as to the appropriate steps to manage these risks, including that they must use acceptable contraception (see WARNINGS: Embryofetal Toxicity, PRECAUTIONS: Pregnancy Exposure Prevention and Planning).
• Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential. In the event of a positive pregnancy test, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations.
• Females of reproductive potential must use acceptable birth control during entire mycophenolate mofetil therapy and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses to avoid heterosexual intercourse completely (abstinence) (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning,Table 8).
• For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of mycophenolate mofetil should be discussed with the patient.
• Give patients complete dosage instructions and inform them about the increased risk of lymphoproliferative disease and certain other malignancies.
• Inform patients that they need repeated appropriate laboratory tests while they are taking mycophenolate mofetil.
• Advise patients that they should not breastfeed during mycophenolate mofetil therapy.

Laboratory Tests

Complete blood counts should be performed weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year (see WARNINGS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Drug Interactions

Drug interaction studies with mycophenolate mofetil have been conducted with acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives, sevelamer, trimethoprim/sulfamethoxazole, norfloxacin and metronidazole. Drug interaction studies have not been conducted with other drugs that may be commonly administered to renal, cardiac or hepatic transplant patients. Mycophenolate mofetil has not been administered concomitantly with azathioprine.

Acyclovir

Coadministration of mycophenolate mofetil (1 g) and acyclovir (800 mg) to 12 healthy volunteers resulted in no significant change in MPA AUC and C max. However, MPAG and acyclovir plasma AUCs were increased 10.6% and 21.9%, respectively. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its prodrug (e.g., valacyclovir) to compete for tubular secretion, further increasing the concentrations of both drugs.

Antacids with Magnesium and Aluminum Hydroxides

Absorption of a single dose of mycophenolate mofetil (2 g) was decreased when administered to ten rheumatoid arthritis patients also taking Maalox TC (10 mL qid). The C max and AUC (0-24h) for MPA were 33% and 17% lower, respectively, than when mycophenolate mofetil was administered alone under fasting conditions. Mycophenolate mofetil may be administered to patients who are also taking antacids containing magnesium and aluminum hydroxides; however, it is recommended that Mycophenolate mofetil and the antacid not be administered simultaneously.

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 mycophenolic acid (MPA). An approximate reduction of 30 to 70% in the C max 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. The clinical impact of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and Mycophenolate mofetil. Because clinical relevance has not been established, PPIs should be used with caution when coadministered to transplant patients being treated with Mycophenolate mofetil.

Cholestyramine

Following single-dose administration of 1.5 g mycophenolate mofetil to 12 healthy volunteers pretreated with 4 g tid 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. Some degree of enterohepatic recirculation is also anticipated following intravenous administration of mycophenolate mofetil. Therefore, mycophenolate mofetil is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation.

Cyclosporine

Cyclosporine (Sandimmune ) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 g bid of mycophenolate mofetil in 10 stable renal transplant patients. The mean ( SD) AUC (0-12h) and C max of cyclosporine after 14 days of multiple doses of mycophenolate mofetil 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 mycophenolate mofetil.

Cyclosporine A interferes with MPA enterohepatic recirculation. In renal transplant patients, mean MPA exposure (AUC 0-12h) was approximately 30 to 50% greater when mycophenolate mofetil is administered without cyclosporine compared with when mycophenolate mofetil 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; changes in MPA exposure should be expected when switching patients from cyclosporine A to one of the immunosuppressants which do not interfere with MPA's enterohepatic cycle (e.g. tacrolimus; belatacept).

Telmisartan

Concomitant administration of telmisartan and mycophenolate Mofetil resulted in an approximately 30% decrease in mycophenolic acid (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 activity.

Ganciclovir

Following single-dose administration to 12 stable renal transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 g) and intravenous ganciclovir (5 mg/kg). Mean ( SD) ganciclovir AUC and C max (n=10) were 54.3 ( 19.0) g h/mL and 11.5 ( 1.8) g/mL, respectively, after coadministration of the two drugs, compared to 51.0 ( 17) g h/mL and 10.6 ( 2.0) g/mL, respectively, after administration of intravenous ganciclovir alone. The mean ( SD) AUC and C max of MPA (n=12) after coadministration were 80.9 ( 21.6) g h/mL and 27.8 ( 13.9) g/mL, respectively, compared to values of 80.3 ( 16.4) g h/mL and 30.9 ( 11.2) g/mL, respectively, after administration of mycophenolate mofetil alone. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the two drugs will compete for tubular secretion and thus further increases in concentrations of both drugs may occur. In patients with renal impairment in which MMF and ganciclovir or its prodrug (e.g., valganciclovir) are coadministered, patients should be monitored carefully.

Oral Contraceptives

A study of coadministration of mycophenolate mofetil (1 g bid) 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 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. Mean serum levels of LH, FSH and progesterone were not significantly affected. Mycophenolate mofetil may not have any influence on the ovulation-suppressing action of the studied oral contraceptives. It is recommended to coadminister mycophenolate mofetil with hormonal contraceptives (e.g., birth control pill, transdermal patch, vaginal ring, injection, and implant) with caution and additional barrier contraceptive methods must be used (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning).

Sevelamer

Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA C max and AUC 0-12h by 36% and 26% respectively. This data suggest that sevelamer and other calcium free phosphate binders should not be administered simultaneously with mycophenolate mofetil. Alternatively, it is recommended that sevelamer and other calcium free phosphate binders preferentially could be given 2 hours after mycophenolate mofetil intake to minimize the impact on the absorption of MPA.

Trimethoprim/sulfamethoxazole

Following single-dose administration of mycophenolate mofetil (1.5 g) to 12 healthy male volunteers on day 8 of a 10 day course of trimethoprim 160 mg/sulfamethoxazole 800 mg administered bid, no effect on the bioavailability of MPA was observed. The mean ( SD) AUC and C max of MPA after concomitant administration were 75.2 ( 19.8) g h/mL and 34.0 ( 6.6) g/mL, respectively, compared to 79.2 ( 27.9) g h/mL and 34.2 ( 10.7) g/mL, respectively, after administration of mycophenolate mofetil alone.

Norfloxacin and Metronidazole

Following single-dose administration of mycophenolate mofetil (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 mycophenolate mofetil alone (p<0.05). Therefore, mycophenolate mofetil is not recommended to be given with the combination of norfloxacin and metronidazole. There was no significant effect on mean MPA AUC 0-48h when mycophenolate mofetil was concomitantly administered with norfloxacin or metronidazole separately. The mean ( SD) MPA AUC 0-48h after coadministration of mycophenolate mofetil with norfloxacin or metronidazole separately was 48.3 ( 24) g h/mL and 42.7 ( 23) g h/mL, respectively, compared with 56.2 ( 24) g h/mL after administration of mycophenolate mofetil alone.

Ciprofloxacin and Amoxicillin plus Clavulanic Acid

A total of 64 mycophenolate mofetil-treated renal transplant recipients received either oral ciprofloxacin 500 mg bid or amoxicillin plus clavulanic acid 375 mg tid for 7 or at least 14 days. Approximately 50% reductions in median trough MPA concentrations (predose) from baseline (mycophenolate 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 antibiotic therapy and ceased within 3 days after discontinuation of antibiotics. The postulated mechanism for this interaction is an antibiotic-induced reduction in glucuronidase-possessing enteric organisms leading to a decrease in enterohepatic recirculation of MPA. The change in trough level may not accurately represent changes in overall MPA exposure; therefore, clinical relevance of these observations is unclear.

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 mycophenolate mofetil and rifampin. Therefore, mycophenolate mofetil is not recommended to be given with rifampin concomitantly unless the benefit outweighs the risk.

Other Interactions

The measured value for renal clearance of MPAG indicates removal occurs by renal tubular secretion as well as glomerular filtration. Consistent with this, coadministration of probenecid, a known inhibitor of tubular secretion, with mycophenolate mofetil in monkeys results in a 3-fold increase in plasma MPAG AUC and a 2-fold increase in plasma MPA AUC. Thus, other drugs known to undergo renal tubular secretion may compete with MPAG and thereby raise plasma concentrations of MPAG or the other drug undergoing tubular secretion.

Drugs that alter the gastrointestinal flora may interact with mycophenolate mofetil by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption.

Live Vaccines

During treatment with mycophenolate mofetil, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective (see PRECAUTIONS: Immunizations).Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week oral carcinogenicity study in mice, mycophenolate mofetil in daily doses up to 180 mg/kg was not tumorigenic. The highest dose tested was 0.5 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, mycophenolate mofetil in daily doses up to 15 mg/kg was not tumorigenic. The highest dose was 0.08 times the recommended clinical dose in renal transplant patients and 0.05 times the recommended clinical dose in cardiac 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).

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

Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. This dose represents 0.1 times the recommended clinical dose in renal transplant patients and 0.07 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.

Pregnancy

Pregnancy Category D

See WARNINGS section.

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. In animal studies, congenital malformations and pregnancy loss occurred when pregnant rats and rabbits received mycophenolic acid at dose multiples similar to and less than clinical doses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Risks and benefits of mycophenolate mofetil should be discussed with the patient. When appropriate, consider alternative immunosuppressants with less potential for embryofetal toxicity. In certain situations, the patient and her healthcare practitioner may decide that the maternal benefits outweigh the risks to the fetus. For those females using mycophenolate mofetil at any time during pregnancy and those becoming pregnant within 6 weeks of discontinuing therapy, the healthcare practitioner should report the pregnancy to the Mycophenolate Pregnancy Registry (1-800-617-8191). The healthcare practitioner should strongly encourage the patient to enroll in the pregnancy registry. The information provided to the registry will help the healthcare community better understand the effects of mycophenolate in pregnancy.

In the National Transplantation Pregnancy Registry (NTPR), there were data on 33 MMF-exposed pregnancies in 24 transplant patients; there were 15 spontaneous abortions (45%) and 18 live-born infants. Four of these 18 infants had structural malformations (22%). In postmarketing data (collected 1995-2007) on 77 females exposed to systemic MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or fetus. Six of 14 malformed offspring had ear abnormalities. Because these postmarketing data are reported voluntarily, it is not always possible to reliably estimate the frequency of particular adverse outcomes. These malformations are similar to findings in animal reproductive toxicology studies. For comparison, the background rate for congenital anomalies in the United States is about 3%, and NTPR data show a rate of 4 - 5% among babies born to organ transplant patients using other immunosuppressive drugs.

In animal reproductive toxicology studies, there were increased rates of fetal resorptions and malformations in the absence of maternal toxicity. Female rats and rabbits received mycophenolate mofetil (MMF) doses equivalent to 0.02 to 0.9 times the recommended human dose for renal and cardiac transplant patients, based on body surface area conversions. In rat offspring, malformations included anophthalmia, agnathia, and hydrocephaly. In rabbit offspring, malformations included ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia.

Nursing Mothers

Studies in rats treated with mycophenolate mofetil have shown mycophenolic acid to be excreted in milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from mycophenolate mofetil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Based on pharmacokinetic and safety data in pediatric patients after renal transplantation, the recommended dose of mycophenolate mofetil oral suspension is 600 mg/m 2 bid (up to a maximum of 1 g bid). Also see CLINICAL PHARMACOLOGY, CLINICAL STUDIES, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION.

Safety and effectiveness in pediatric patients receiving allogenic cardiac or hepatic transplants have not been established.

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 be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant or other drug therapy. Elderly patients may be at an increased risk of adverse reactions compared with younger individuals (see ADVERSE REACTIONS).

Overdosage ⮝

The experience with overdose of mycophenolate mofetil in humans is very limited. The events received from reports of overdose fall within the known safety profile of the drug. The highest dose administered to renal transplant patients in clinical trials has been 4 g/day. In limited experience with cardiac and hepatic 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, principally neutropenia, leading to a need to reduce or discontinue dosing.

In acute oral toxicity studies, no deaths occurred in adult mice at doses up to 4000 mg/kg or in adult monkeys at doses up to 1000 mg/kg; these were the highest doses of mycophenolate mofetil tested in these species. These doses represent 11 times the recommended clinical dose in renal transplant patients and approximately 7 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. In adult rats, deaths occurred after single-oral doses of 500 mg/kg of mycophenolate mofetil. The dose represents approximately 3 times the recommended clinical dose in cardiac transplant patients when corrected for BSA.

MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 mcg/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: Pharmacokinetics).

How Supplied ⮝

Mycophenolate Mofetil Capsules, USP 250 mg
White to off-white blend of mycophenolate mofetil filled in size '1' hard gelatin capsule with Ivory Cap and Ivory Body, printed 'SAL' on cap and '726' on body in black. Supplied in the following presentations:
Unit dose packages of 100 (10 x 10) NDC 60687-427-01

Storage
Store at 20 to 25 C (68 to 77 F). [See USP controlled room temperature].

Mycophenolate Mofetil Tablets, USP 500 mg

Pinkish brown colored, capsule shaped, film coated tablet with "SAL" engraved on one side and engraved "725" on other side. Supplied in the following presentations:
Unit dose packages of 100 (10 x 10) NDC 60687-438-01

Storage and Dispensing Information:
Store at 20 to 25 C (68 to 77 F) [see USP controlled room temperature].

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

Storage And Handling ⮝

Store at 25 C (77 F); excursions permitted to 15 to 30 C (59 to 86 F). [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP with a child-resistant cap.

Sandimmune is a registered trademark of Novartis Pharmaceuticals Corporation.

ATGAM is a registered trademark of Pharmacia and Upjohn Company.

Neoral is a registered trademark of Novartis Pharmaceuticals Corporation.

Orthoclone OKT is a registered trademark of Ortho Biotech Inc.

Maalox is a registered trademark of Novartis Consumer Health, Inc.

Mycophenolate Mofetil Capsules

Mycophenolate Mofetil Tablets

Read the Medication Guide that comes with mycophenolate mofetil capsules and mycopheolate mofetil tablets 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 healthcare provider about your medical condition or your treatment.

What is the most important information I should know about mycophenolate mofetil?

Mycophenolate mofetil can cause serious side effects:

• Possible loss of a pregnancy and higher risk of birth defects. Women who take mycophenolate mofetil during pregnancy have a higher risk of losing a pregnancy (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 and are able to become pregnant

your healthcare provider must talk with you about effective birth control methods (contraceptive counseling)

you should have a negative pregnancy test within 1 week before you start to take mycophenolate mofetil

you must use 2 different types of effective birth control at the same time, for 4 weeks before you start taking mycophenolate mofetil, during your entire mycophenolate mofetil therapy and for 6 weeks after stopping mycophenolate mofetil, unless you choose to avoid sexual intercourse completely (abstinence). 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, and you could become pregnant

If you plan to become pregnant, talk with your healthcare provider. Your healthcare provider will decide if other medicines to prevent rejection may be right for you. In certain situations, you and your healthcare provider may decide that taking mycophenolate mofetil is more important to your health than the possible risks to your unborn baby.

If you get pregnant while taking mycophenolate mofetil, do not stop taking mycophenolate mofetil. Call your healthcare provider right away. You and your healthcare provider should report any cases of pregnancies to

FDA MedWatch at 1-800-FDA-1088.

Zydus Professional Drug Safety at 1-877-993-8779..

Talk to your healthcare provider about joining the National Transplantation Pregnancy Registry at 1-877-955-6877.

Increased 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 and can lead to death. Types of 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 mofetl capsules and mycophenolate mofetil tablets 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.

• 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. You should tell your healthcare provider right away if you have any of the following symptoms:

Weakness on one side of the body

You do not care about things that you usually care about (apathy)

You are confused or have problems thinking

You can not control your muscles

Fungal 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?")

Call your healthcare provider right away if you have any of the following signs and symptoms of infection:

Temperature of 100.5 F or greater

Cold symptoms, such as a runny nose or sore throat

Flu symptoms, such as an upset stomach, stomach pain, vomiting or diarrhea

Earache or headache

Pain during urination

White patches in the mouth or throat

Unexpected bruising or bleeding

Cuts, scrapes or incisions that are red, warm and oozing pus

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 healthcare provider if you have:

• unexplained fever, prolonged tiredness, weight loss or lymph node swelling
• a brown or black skin lesion with uneven borders, or one part of the lesion does not look like the other
• a change in the size and color of a mole
• a new skin lesion or bump
• any other changes to your health

See the section "What are the possible side effects of mycophenolate mofetil?" for information about other serious side effects.

What is mycophenolate mofetil?

Mycophenolate mofetil 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 is used with other medicines called cyclosporine (Sandimmune , Gengraf , Neoral ) and corticosteroids. These medicines work together to prevent rejection to your transplanted organ.

Mycophenolate mofetil has been used safely and works in children who received a kidney transplant as it does in adults. It is not known if mycophenolate mofetil is safe and works in children who receive a heart or liver transplant.

Who should not take mycophenolate mofetil?

Do not take mycophenolate mofetil if you are allergic to mycophenolate mofetil or any of the ingredients in mycophenolate mofetil capsules and mycopheolate mofetil tablets. See the end of this Medication Guide for a complete list of ingredients in mycophenolate mofetil capsules and mycopheolate mofetil tablets.

What should I tell my healthcare provider before taking mycophenolate mofetil?

Tell your healthcare provider about all of your medical conditions, 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 if you have one of these disorders
• plan to receive any vaccines. People taking mycophenolate mofetil should not take live vaccines. Some vaccines may not work as well during treatment with mycophenolate mofetil
• are pregnant or are planning to become pregnant. See "What is the most important information I should know about mycophenolate mofetil?"
• are breastfeeding. It is not known if mycophenolate mofetil passes into breast milk. You and your healthcare provider will decide if you will take mycophenolate mofetil or breastfeed. You should not do both without first talking with your healthcare provider

Tell your healthcare provider about all of the medicines you are taking including prescription and nonprescription 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 healthcare provider if you take:

• birth control pills (oral contraceptives). See "What is the most important information I should know about mycophenolate mofetil?"
• sevelamer (Renagel , Renvela ). These products should be taken 2 hours after taking mycophenolate mofetil
• acyclovir (Zovirax ), valacyclovir (Valtrex ), ganciclovir (Cytovene -IV, Vitrasert ), valganciclovir (Valcyte )
• rifampin (Rifater , Rifamate , Rimactane , Rifadin )
• antacids that contain magnesium and aluminum (mycophenolate mofetil and the antacid should not be taken at the same time)
• sulfamethoxazole/trimethoprim (Bactrim , Bactrim DS )
• ciprofloxacin (Cipro , Cipro XR, Ciloxan , Proquin XR) and amoxicillin plus clavulanic acid (Augmentin , Augmentin XR )
• 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 healthcare provider and pharmacist when you get a new medicine. Do not take any new medicine without talking with your healthcare provider.

How should I take mycophenolate mofetil?

• Take mycophenolate mofetil exactly as prescribed
• Do not stop taking mycophenolate mofetil or change the dose unless your healthcare provider tells you to
• If you miss a dose of mycophenolate mofetil, or are not sure when you took your last dose, take the regular amount of mycophenolate mofetil prescribed as soon as you remember. If it is time for your next dose, skip the missed dose. Do not take 2 doses at the same time. Call your healthcare provider if you are not sure what to do
• Take mycophenolate mofetil capsules, mycopheolate mofetil tablets and mycophenolate mofetil oral suspension on an empty stomach, either 1 hour before or 2 hours after a meal, unless your healthcare provider tells you otherwise. With the approval of your healthcare provider, in stable kidney transplant patients, mycophenolate mofetil can be taken with food if necessary. Most people take mycophenolate mofetil by mouth either as blue and orange capsules or lavender tablets. Some people may get mycophenolate mofetil soon after their transplant surgery as an infusion into a vein
• Do not crush mycophenolate mofetil tablets. Do not open or crush mycophenolate mofetil capsules
• If you are not able to swallow mycophenolate mofetil capsules or mycopheolate mofetil tablets, your healthcare provider may prescribe mycophenolate mofetil oral suspension. This is a liquid form of mycophenolate mofetil. Your pharmacist will mix the medicine before giving it to you
• Do not mix mycophenolate mofetil oral suspension with any other medicine
• If you take too much mycophenolate mofetil, call your healthcare provider or the poison control center right away

What should I avoid while taking mycophenolate mofetil?

• Avoid pregnancy. See "What is the most important information I should know about mycophenolate mofetil?"
• Limit the amount of time you spend in sunlight. Avoid using tanning beds or sunlamps. People who take mycophenolate mofetil have a higher risk of getting skin cancer. (See "What is the most important information I should know about mycophenolate mofetil?") Wear protective clothing when you are in the sun and use a sunscreen with a high protection factor (SPF 30 and above). This is especially important if your skin is very fair or if you have a family history of skin cancer

What are the possible side effects of mycophenolate mofetil?

Mycophenolate mofetil can cause serious side effects:

• See "What is the most important information I should know about mycophenolate mofetil?"
• Low blood cell counts. People taking high doses of mycophenolate mofetil 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 3 months 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 healthcare provider will do blood tests before you start taking mycophenolate mofetil and during treatment with mycophenolate mofetil to check your blood cell counts.

Tell your healthcare provider right away if you have any signs of infection (see "What is the most important information I should know about mycophenolate mofetil?"), or any unexpected bruising or bleeding. Also, tell your healthcare provider if you have unusual tiredness, lack of energy, dizziness or fainting.

• Stomach problems. Stomach and intestinal bleeding can happen in people who take high doses of mycophenolate mofetil. Bleeding can be severe and you may have to be hospitalized for treatment

Common side effects include:

• diarrhea. Call your healthcare provider right away if you have diarrhea. Do not stop taking mycophenolate mofetil without first talking with your healthcare provider
• vomiting
• pain
• stomach area pain
• swelling of the lower legs, ankles and feet
• high blood pressure

Side effects that happen more often in children than in adults taking mycophenolate mofetil include:

stomach area pain sore throat

fever colds (respiratory tract infections)

infection high blood pressure

pain low white blood cell count

blood infection (sepsis) low red blood cell count

diarrhea

vomiting

These are not all of the possible side effects of mycophenolate mofetil. Tell your healthcare provider 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 the FDA at 1-800-FDA-1088. or to Zydus Professional Drug Safety at 1-877-993-8779.

How should I store mycophenolate mofetil?

• Store at 25 C (77 F); excursions permitted to 15 to 30 C (59 to 86 F). [See USP Controlled Room Temperature]. Keep the container closed tightly
• Keep mycophenolate mofetil and all medicines out of the reach of children

General Information about Mycophenolate Mofetil

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use mycophenolate mofetil for a condition for which it was not prescribed. Do not give mycophenolate mofetil 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. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about mycophenolate mofetil that is written for healthcare professionals. Please address medical inquiries to, (MedicalAffairs@zydususa.com) Tel.: 1-877-993-8779.

What are the ingredients in mycophenolate mofetil capsules and mycopheolate mofetil tablets?

Active Ingredient: mycophenolate mofetil

Inactive Ingredients:

Mycophenolate Mofetil Capsules, 250 mg:

Colloidal silicon dioxide, croscarmellose sodium, FD&C blue # 1, FD&C red # 3, gelatin, magnesium stearate, povidone (K-90), pregelatinized starch, sodium lauryl sulfate and titanium dioxide.

Mycopheolate Mofetil Tablets, 500 mg:

Colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc and titanium dioxide.

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

Cytovene-IV, and Valcyte are registered trademarks of Hoffmann-La Roche Inc.

Bactrim and Bactrim DS are trademarks of Hoffmann-La Roche Inc.

Any other trademarks in this document are the property of their respective owners.

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Rev.:04/11

Revision Date: 29/04/2011

For additional copies of this Medication Guide, please call 1-877-993-8779 or visit www.zydususa.com.

Package Label.principal Display Panel ⮝

NDC 68382-130-01 in bottle of 100 capsules

Mycophenolate Mofetil Capsules, 250 mg

Rx only

100 capsules

ZYDUS

NDC 68382-131-01 in bottle of 100 tablets

Mycophenolate Mofetil Tablets, 500 mg

Rx only

100 tablets

ZYDUS

MYCOPHENOLATE MOFETIL mycophenolate mofetil capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68382-130 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MYCOPHENOLATE MOFETIL (UNII: 9242ECW6R0) (MYCOPHENOLIC ACID - UNII:HU9DX48N0T) MYCOPHENOLATE MOFETIL 250 mg

Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C RED NO. 3 (UNII: PN2ZH5LOQY) MAGNESIUM STEARATE (UNII: 70097M6I30) GELATIN (UNII: 2G86QN327L) SODIUM LAURYL SULFATE (UNII: 368GB5141J) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) POVIDONE K90 (UNII: RDH86HJV5Z) STARCH, PREGELATINIZED CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color BLUE (OPAQUE BLUE) , WHITE (OPAQUE WHITE) Score no score Shape CAPSULE (CAPSULE) Size 19mm Flavor Imprint Code 130 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68382-130-01 100 in 1 BOTTLE 2 NDC:68382-130-19 120 in 1 BOTTLE 3 NDC:68382-130-05 500 in 1 BOTTLE 4 NDC:68382-130-10 1000 in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065433 05/04/2009

MYCOPHENOLATE MOFETIL mycophenolate mofetil tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68382-131 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MYCOPHENOLATE MOFETIL (UNII: 9242ECW6R0) (MYCOPHENOLIC ACID - UNII:HU9DX48N0T) MYCOPHENOLATE MOFETIL 500 mg

Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) HYPROMELLOSES (UNII: 3NXW29V3WO) MAGNESIUM STEARATE (UNII: 70097M6I30) POLYETHYLENE GLYCOL (UNII: 3WJQ0SDW1A) POVIDONE (UNII: FZ989GH94E) TALC (UNII: 7SEV7J4R1U) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color WHITE (WHITE TO OFF-WHITE) Score no score Shape OVAL (CAPSULE) Size 18mm Flavor Imprint Code ZA49 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68382-131-01 100 in 1 BOTTLE 2 NDC:68382-131-05 500 in 1 BOTTLE 3 NDC:68382-131-10 1000 in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065477 05/04/2009

Labeler - Zydus Pharmaceuticals (USA) Inc. (156861945)

Registrant - Zydus Pharmaceuticals (USA) Inc. (156861945)

Establishment
Name	Address	ID/FEI	Business Operations
Cadila Healthcare Limited		918596198	Analysis, Manufacture

Revised: 4/2011 Document Id: f67f2a1b-167a-49c7-bbb1-8f6d5c5b3cdc 34391-3 Set id: 68336a39-5634-4286-b168-24ff06024da7 Version: 2 Effective Time: 20110428 Zydus Pharmaceuticals (USA) Inc.

Warning  ⮝

Embryofetal Toxicity, Malignancies and Serious Infections: Use during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations. Females of reproductive potential (FRP) must be counseled regarding pregnancy prevention and planning (see WARNINGS and PRECAUTIONS). Immunosuppression may lead to increased susceptibility to infection and possible development of lymphoma. Only physicians experienced in immunosuppressive therapy and management of renal, cardiac or hepatic transplant patients should prescribe mycophenolate mofetil. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient (see WARNINGS and PRECAUTIONS).

Clinical Studies ⮝

Adults

The safety and efficacy of mycophenolate mofetil in combination with corticosteroids and cyclosporine for the prevention of organ rejection were assessed in randomized, double-blind, multicenter trials in renal (3 trials), in cardiac (1 trial), and in hepatic (1 trial) adult transplant patients.

Renal Transplant

Adults

The three renal studies compared two dose levels of oral mycophenolate mofetil (1 g bid and 1.5 g bid) 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 antithymocyte globulin (ATGAM ) induction therapy. These studies are described by geographic location of the investigational sites. One study was conducted in the USA at 14 sites, one study was conducted in Europe at 20 sites, and one study was conducted in Europe, Canada, and Australia at a total of 21 sites.

The primary efficacy endpoint was the proportion of patients in each treatment group who experienced treatment failure within the first 6 months after transplantation (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, when administered with antithymocyte globulin (ATGAM ) induction (one study) and with cyclosporine and corticosteroids (all three studies), was compared to the following three therapeutic regimens: (1) antithymocyte globulin (ATGAM ) induction/azathioprine/cyclosporine/corticosteroids, (2) azathioprine/cyclosporine/corticosteroids, and (3) cyclosporine/corticosteroids.

Mycophenolate mofetil, in combination with corticosteroids and cyclosporine reduced (statistically significant at 0.05 level) the incidence of treatment failure within the first 6 months following transplantation. Table 4 and Table 5 summarize the results of these studies. These tables show (1) the proportion of patients experiencing treatment failure, (2) the proportion of patients who experienced biopsy-proven acute rejection on treatment, and (3) early termination, for any reason other than graft loss or death, without a prior biopsy-proven acute rejection episode. 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 are summarized separately. Patients who prematurely discontinued treatment were not followed for the occurrence of acute rejection after termination. More patients receiving mycophenolate mofetil discontinued without prior biopsy-proven rejection, death or graft loss than discontinued in the control groups, with the highest rate in the mycophenolate mofetil 3 g/day group. Therefore, the acute rejection rates may be underestimates, particularly in the mycophenolate mofetil 3 g/day group.

Table 4 Renal Transplant Studies Incidence of Treatment Failure (Biopsy-proven Rejection or Early Termination for Any Reason)

* Antithymocyte globulin induction/MMF or azathioprine/cyclosporine/corticosteroids. Does not include death and graft loss as reason for early termination. MMF or azathioprine/cyclosporine/corticosteroids. MMF or placebo/cyclosporine/corticosteroids.
USA Study* (N=499 patients)	Mycophenolate mofetil 2 g/day (n=167 patients)	Mycophenolate mofetil 3 g/day (n=166 patients)	Azathioprine 1 to 2 mg/kg/day (n=166 patients)
All treatment failures	31.1%	31.3%	47.6%
Early termination without prior acute rejection	9.6%	12.7%	6.0%
Biopsy-proven rejection episode on treatment	19.8%	17.5%	38%
Europe/Canada/ Australia Study (N=503 patients)	Mycophenolate mofetil 2 g/day (n=173 patients)	Mycophenolate mofetil 3 g/day (n=164 patients)	Azathioprine 100 to 150 mg/kg/day (n=166 patients)
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)
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%

The cumulative incidence of 12-month graft loss or patient death is presented below. No advantage of mycophenolate mofetil with respect to graft loss or patient death was established. 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 5 Renal Transplant 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 (Azathioprine 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

One open-label, safety and pharmacokinetic study of mycophenolate mofetil oral suspension 600 mg/m 2 bid (up to 1 g bid) in combination with cyclosporine and corticosteroids was performed at centers in the US (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), and the pharmacokinetics profile was similar to that seen in adult patients dosed with 1 g bid mycophenolate mofetil capsules (see CLINICAL PHARMACOLOGY: Pharmacokinetics). 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 posttransplant was similar to that observed in adult renal transplant patients.

Cardiac Transplant

A double-blind, randomized, comparative, parallel-group, multicenter study in primary cardiac transplant recipients was performed at 20 centers in the United States, 1 in Canada, 5 in Europe and 2 in Australia. The total number of patients enrolled was 650; 72 never received study drug and 578 received study drug. Patients received mycophenolate mofetil 1.5 g bid (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. 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 retransplanted or died, within the first 6 months, and (2) the proportion of patients who died or were retransplanted 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.

1. Rejection: No difference was established between mycophenolate mofetil and azathioprine (AZA) with respect to biopsy-proven rejection with hemodynamic compromise.
2. Survival: Mycophenolate mofetil was shown to be at least as effective as AZA in preventing death or retransplantation at 1 year (see Table 6).

Table 6 Rejection at 6 Months/Death or Retransplantation at 1 Year

* Hemodynamic 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.
	All Patients		Treated Patients
	AZA N = 323	Mycophenolate mofetil N = 327	AZA N = 289	Mycophenolate mofetil N = 289
Biopsy-proven rejection with hemodynamic compromise at 6 months *	121 (38%)	120 (37%)	100 (35%)	92 (32%)
Death or retransplantation at 1 year	49 (15.2%)	42 (12.8%)	33 (11.4%)	18 (6.2%)

Hepatic Transplant

A double-blind, randomized, comparative, parallel-group, multicenter study in primary hepatic transplant recipients was performed at 16 centers in the United States, 2 in Canada, 4 in Europe and 1 in Australia. The total number of patients enrolled was 565. Per protocol, patients received mycophenolate mofetil 1 g bid intravenously for up to 14 days followed by mycophenolate mofetil 1.5 g bid 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 actual median oral dose of azathioprine 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 posttransplantation, one or more episodes of biopsy-proven and treated rejection or death or retransplantation, and (2) the proportion of patients who experienced graft loss (death or retransplantation) during the first 12 months posttransplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection and for the occurrence of graft loss (death or retransplantation) for 1 year.

Results

In combination with corticosteroids and cyclosporine, mycophenolate mofetil obtained a lower rate of acute rejection at 6 months and a similar rate of death or retransplantation at 1 year compared to azathioprine.

Table 7 Rejection at 6 Months/Death or Retransplantation at 1 Year

	AZA N = 287	Mycophenolate mofetil N = 278
Biopsy-proven, treated rejection at 6 months (includes death or retransplantation)	137 (47.7%)	107 (38.5%)
Death or retransplantation at 1 year	42 (14.6%)	41 (14.7%)

How Supplied: ⮝

Mycophenolate Mofetil Capsules, USP are available containing 250 mg of mycophenolate mofetil, USP.

The 250 mg capsule is a caramel opaque cap/lavender opaque body, hard-shell gelatin capsule filled with white to off-white powder. The capsule is axially printed with MYLAN over 2250 in black ink on both the cap and body. They are available as follows:

Overbagged with 10 capsules per bag, NDC 55154-6262-0

Mycophenolate Mofetil Tablets, USP are available containing 500 mg of mycophenolate mofetil, USP.

The 500 mg tablet is a light pink film-coated, oval, unscored tablet debossed with MYLAN on one side of the tablet and 472 on the other side. They are available as follows:

Overbagged with 10 tablets per bag, NDC 55154-5382-0

Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.]
Protect from light.

PHARMACIST: Dispense a Medication Guide with each prescription.

Package/label Display Panel  ⮝

Mycophenolate Mofetil Tablets, USP

500 mg

10 Tablets

MYCOPHENOLATE MOFETIL mycophenolate mofetil capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55154-6262(NDC:51079-721) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MYCOPHENOLATE MOFETIL (UNII: 9242ECW6R0) (MYCOPHENOLIC ACID - UNII:HU9DX48N0T) MYCOPHENOLATE MOFETIL 250 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) STARCH, CORN (UNII: O8232NY3SJ) SODIUM LAURYL SULFATE (UNII: 368GB5141J) FERROSOFERRIC OXIDE (UNII: XM0M87F357) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) FERRIC OXIDE RED (UNII: 1K09F3G675) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT) AMMONIA (UNII: 5138Q19F1X) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) SHELLAC (UNII: 46N107B71O)

Product Characteristics Color BROWN (caramel opaque) , PURPLE (lavender opaque) Score no score Shape CAPSULE Size 19mm Flavor Imprint Code MYLAN;2250 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55154-6262-0 10 in 1 BAG 10/25/2011 1 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065520 10/25/2011

MYCOPHENOLATE MOFETIL mycophenolate mofetil tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55154-5382(NDC:51079-379) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MYCOPHENOLATE MOFETIL (UNII: 9242ECW6R0) (MYCOPHENOLIC ACID - UNII:HU9DX48N0T) MYCOPHENOLATE MOFETIL 500 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A) POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990) POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) STARCH, CORN (UNII: O8232NY3SJ) FERRIC OXIDE RED (UNII: 1K09F3G675) SODIUM LAURYL SULFATE (UNII: 368GB5141J) TALC (UNII: 7SEV7J4R1U) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color PINK (light pink) Score no score Shape OVAL Size 19mm Flavor Imprint Code MYLAN;472 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55154-5382-0 10 in 1 BAG 10/25/2011 1 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065521 10/25/2011

Labeler - Cardinal Health (603638201)

Revised: 12/2018 Document Id: 881f280a-8a20-4763-8863-73a94d45e63c 34391-3 Set id: e1904c28-8c19-44da-b395-1e4bd08d6122 Version: 8 Effective Time: 20181209 Cardinal Health

Warning: Embryofetal Toxicity, Malignancies And Serious Infections  ⮝

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)].

Principal Display Panel  ⮝

NDC 0781-5175-01

MycophenolateMofetil Tablets

500 mg*

PHARMACIST: Please dispense with Medication Guide provided separately.

100 Tablets

MYCOPHENOLATE MOFETIL mycophenolate mofetil capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0781-2067 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MYCOPHENOLATE MOFETIL (UNII: 9242ECW6R0) (MYCOPHENOLIC ACID - UNII:HU9DX48N0T) MYCOPHENOLATE MOFETIL 250 mg

Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE K90 (UNII: RDH86HJV5Z) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) FERROSOFERRIC OXIDE (UNII: XM0M87F357) ISOPROPYL ALCOHOL (UNII: ND2M416302) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) WATER (UNII: 059QF0KO0R) SHELLAC (UNII: 46N107B71O) ALCOHOL (UNII: 3K9958V90M) POTASSIUM HYDROXIDE (UNII: WZH3C48M4T) AMMONIA (UNII: 5138Q19F1X) STARCH, CORN (UNII: O8232NY3SJ)

Product Characteristics Color BLUE (BLUE) , WHITE (WHITE) Score no score Shape CAPSULE (CAPSULE) Size 19mm Flavor Imprint Code 655 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0781-2067-89 12 in 1 CARTON; Type 0: Not a Combination Product 10/15/2008 2 NDC:0781-2067-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 10/15/2008 3 NDC:0781-2067-05 500 in 1 BOTTLE; Type 0: Not a Combination Product 10/15/2008 4 NDC:0781-2067-72 120 in 1 BOTTLE; Type 0: Not a Combination Product 10/15/2008

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065379 10/15/2008

MYCOPHENOLATE MOFETIL mycophenolate mofetil tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0781-5175 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MYCOPHENOLATE MOFETIL (UNII: 9242ECW6R0) (MYCOPHENOLIC ACID - UNII:HU9DX48N0T) MYCOPHENOLATE MOFETIL 500 mg

Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE K90 (UNII: RDH86HJV5Z) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) TALC (UNII: 7SEV7J4R1U) HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4) HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 9XZ8H6N6OH) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERROSOFERRIC OXIDE (UNII: XM0M87F357) FERRIC OXIDE RED (UNII: 1K09F3G675) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)

Product Characteristics Color PURPLE (Lavender) Score no score Shape ROUND (bioconvex) Size 18mm Flavor Imprint Code SZ;327 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0781-5175-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 10/15/2008 2 NDC:0781-5175-05 500 in 1 BOTTLE; Type 0: Not a Combination Product 10/15/2008 3 NDC:0781-5175-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/15/2008

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065451 10/15/2008

Labeler - Sandoz Inc (110342024)

Revised: 3/2019 Document Id: a3fcc7ca-f019-43fe-b704-1e2ddf5435a6 34391-3 Set id: 99b2eb58-8d14-48fc-bbe1-aacb711a783e Version: 12 Effective Time: 20190325 Sandoz Inc

Warning: Embryofetal Toxicity, Malignancies And Serious Infections ⮝

Use during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations. Females of reproductive potential (FRP) must be counseled regarding pregnancy prevention and planning (see WARNINGS and PRECAUTIONS).

Immunosuppression may lead to increased susceptibility to infection and possible development of lymphoma. Only physicians experienced in immunosuppressive therapy and management of renal, cardiac or hepatic transplant patients should prescribe Mycophenolate mofetil. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient (see WARNINGS and PRECAUTIONS).

Packaging Information ⮝

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Strides Pharma Inc. as follows:
(250 mg / 100 UD) NDC 60687-427-01 packaged from NDC 64380-726
(250 mg / 100 UD) NDC 60687-438-01 packaged from NDC 64380-725

Distributed by:
American Health Packaging
Columbus, OH 43217

8442701/1218

Package/label Display Panel Carton 250 Mg ⮝

NDC 60687- 427-01

Mycophenolate
Mofetil Capsules, USP

250 mg

100 Capsules (10 x 10) Rx Only

PHARMACIST: Dispense with the accompanying Medication
Guide to each patient.

Each Capsule Contains:
Mycophenolate mofetil, USP...................................... 250 mg

Usual Dosage: See package insert for full prescribing
information.

CAUTION: Special handling and Disposal instructions see
insert.

Store at 20 to 25 C (68 to 77 F); excursions permitted
between 15 to 30 C (59 to 86 F) [see USP Controlled
Room Temperature].

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or
broken.

The drug product contained in this package is from
NDC # 64380-726, Strides Pharma Inc.

Packaged and Distributed by:
American Health Packaging
Columbus, Ohio 43217

742701
0442701/1218

Package/label Display Panel Blister 250 Mg ⮝

Mycophenolate Mofetil
Capsule, USP

250 mg

Package/label Display Panel Carton 500 Mg ⮝

NDC 60687- 438-01

Mycophenolate
Mofetil Tablets, USP

500 mg

100 Tablets (10 x 10) Rx Only

PHARMACIST: Dispense with the accompanying Medication
Guide to each patient.

Each Film-Coated Tablet Contains:
Mycophenolate mofetil, USP......................................500 mg

Usual Dosage: See package insert for full prescribing
information.

CAUTION: Special handling and Disposal instructions see
insert.

Store at 20 to 25 C (68 to 77 F); excursions permitted
between 15 to 30 C (59 to 86 F) [see USP Controlled
Room Temperature].

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or
broken.

The drug product contained in this package is from
NDC # 64380-725, Strides Pharma Inc.

Packaged and Distributed by:
American Health Packaging
Columbus, Ohio 43217

743801
0443801/1218

Package/label Display Panel Blister 500 Mg ⮝

Mycophenolate Mofetil
Tablet, USP

500 mg

MYCOPHENOLATE MOFETIL mycophenolate mofetil capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60687-427(NDC:64380-726) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MYCOPHENOLATE MOFETIL (UNII: 9242ECW6R0) (MYCOPHENOLIC ACID - UNII:HU9DX48N0T) MYCOPHENOLATE MOFETIL 250 mg

Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE K30 (UNII: U725QWY32X) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) FERRIC OXIDE YELLOW (UNII: EX438O2MRT) FD&C RED NO. 3 (UNII: PN2ZH5LOQY) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) SODIUM LAURYL SULFATE (UNII: 368GB5141J) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color white Score no score Shape CAPSULE Size 19mm Flavor Imprint Code SAL726 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60687-427-01 100 in 1 BOX, UNIT-DOSE 05/15/2019 1 NDC:60687-427-11 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090055 05/15/2019

MYCOPHENOLATE MOFETIL mycophenolate mofetil tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60687-438(NDC:64380-725) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MYCOPHENOLATE MOFETIL (UNII: 9242ECW6R0) (MYCOPHENOLIC ACID - UNII:HU9DX48N0T) MYCOPHENOLATE MOFETIL 500 mg

Inactive Ingredients Ingredient Name Strength MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) POVIDONE K30 (UNII: U725QWY32X) MAGNESIUM STEARATE (UNII: 70097M6I30) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C RED NO. 40 (UNII: WZB9127XOA) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) FERRIC OXIDE RED (UNII: 1K09F3G675) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)

Product Characteristics Color brown Score no score Shape CAPSULE Size 18mm Flavor Imprint Code SAL725 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60687-438-01 100 in 1 BOX, UNIT-DOSE 05/15/2019 1 NDC:60687-438-11 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090456 05/15/2019

Labeler - American Health Packaging (929561009)

Establishment
Name	Address	ID/FEI	Business Operations
American Health Packaging		929561009	repack(60687-427, 60687-438)

Revised: 4/2019 Document Id: 87c055d7-31ba-6a83-e053-2a95a90a9035 34391-3 Set id: 8015f042-54fb-4a7a-a10b-6219e1a450c8 Version: 1 Effective Time: 20190430 American Health Packaging

1 Indications And Usage ⮝

Mycophenolate mofetil capsules (MMF) 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 immunosuppressants.

2 Dosage And Administration ⮝

2.1 Important Administration Instructions

Mycophenolate Mofetil Capsules

Mycophenolate 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

Adults

The 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). The recommended dose of mycophenolate mofetil oral suspension for pediatric kidney transplant patients 3 months and older is 600 mg/m2, administered twice daily (maximum daily dose of 2g or 10 mL of the oral suspension). Pediatric patients with BSA 1.25 m2 may be dosed with capsules or tablets as follows:

Table 1. Pediatric Dosing Using Capsules or Tablets 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 or tablets 1 g twice daily (2 g daily dose)

2.3 Dosing for Heart Transplant Patients: Adults

The recommended dose of mycophenolate mofetil 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 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 Impairment

No dose adjustments are needed in kidney transplant patients with delayed graft function postoperatively [see Clinical Pharmacology (12.3)]. In kidney transplant patients with severechronic impairment of the graft (GFR <25 mL/min/1.73 m2), do not administer doses of mycophenolate mofetil greater than 1 g twice a day. These patients should be carefully monitored [see Clinical Pharmacology (12.3)].

Neutropenia

If neutropenia develops (ANC <1.3 x 103/mL), dosing with mycophenolate mofetil 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 Capsules USP are available in the following strength:

250 mg

hard gelatin capsules with a light blue opaque cap and a bright orange opaque body, filled with a white to off-white powder with small agglomerates; imprinted with "TEVA" on the cap and "7334" on the 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 Warnings And Precautions ⮝

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 immunosuppressants, 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)]. The majority of PTLD cases appears to be related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. 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 C

Consider 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 receive 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 x 103/mL] developed in transplant patients receiving mycophenolate mofetil capsules 3 g daily [see Adverse Reactions (6.1)]. Patients receiving mycophenolate mofetil capsules 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 x 103/mL), 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 capsules in combination with other immunosuppressive agents. In some cases, PRCA was found to be reversible with dose reduction or cessation of mycophenolate mofetil capsule 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 capsules are 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)].

5.12 Effect of Concomitant Medications on Mycophenolic Acid Concentrations

A variety of drugs have potential to alter systemic MPA exposure when co-administered with mycophenolate mofetil capsules. Therefore, determination of MPA concentrations in plasma before and after making any changes to immunosuppressive therapy, or when adding or discontinuing concomitant medications, may be appropriate to ensure MPA concentrations remain stable.

5.13 Potential Impairment of Ability to Drive or Operate Machinery

Mycophenolate mofetil capsules may impact the ability to drive and use machines. Patients should avoid driving or using machines if they experience somnolence, confusion, dizziness, tremor, or hypotension during treatment with mycophenolate mofetil capsules [see Adverse Reactions (6.1)].

6 Adverse Reactions ⮝

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)]

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.

An estimated total of 1557 patients received mycophenolate mofetil capsules during pivotal clinical trials in the prevention of acute organ rejection. Of these, 991 were included in the three renal studies, 277 were included in one hepatic study, and 289 were included in one cardiac study. Patients in all study arms also received cyclosporine and corticosteroids.

The data described below primarily derive from five randomized, active-controlled double- blind 12-month trials of mycophenolate mofetil capsules in de novo kidney (3) heart (1) and liver (1) transplant patients [see Clinical Studies (14.1, 14.2 and 14.3)].

Mycophenolate Mofetil Oral

The 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)

Adverse drug reaction	Kidney Studies				Heart Study			Liver Study
	Mycophenolate Mofetil	AZA		Placebo	Mycophenolate Mofetil	AZA		Mycophenolate Mofetil	AZA
(MedDRA) System Organ Class	2g/day (n=501) or 3g/day (n=490)	1 to 2 mg/kg/dayor 100 to 150 mg/day			3g/day	1.5 to 3 mg/kg/day		3g/day	1 to 2 mg/kg/day
	(n=991)	(n=326)		(n=166)	(n=289)	(n=289)		(n=277)	(n=287)
	%	%		%	%	%		%	%
Infections and infestations
Bacterial infections	39.9	33.7	37.3		-		-	27.4		26.5
Viral infections	- a	-	-		31.1		24.9	-		-
Blood and lymphatic system disorders
Anemia	20.0	23.6	2.4		45.0		47.1	43.0		53.0
Ecchymosis	-	-	-		20.1		9.7	-		-
Leukocytosis	-	-	-		42.6		37.4	22.4		21.3
Leukopenia	28.6	24.8	4.2		34.3		43.3	45.8		39.0
Thrombocytopenia	-	-	-		24.2		28.0	38.3		42.2
Metabolism and nutrition disorders
Hypercholesterolemia	-	-	-		46.0		43.9	-		-
Hyperglycemia	-	-	-		48.4		53.3	43.7		48.8
Hyperkalemia	-	-	-		-		-	22.0		23.7
Hypocalcemia	-	-	-		-		-	30.0		30.0
Hypokalemia	-	-	-		32.5		26.3	37.2		41.1
Hypomagnesemia	-	-	-		20.1		14.2	39.0		37.6
Psychiatric disorders
Depression	-	-	-		20.1		15.2	-		-
Insomnia	-	-	-		43.3		39.8	52.3		47.0
Nervous system disorders
Dizziness	-	-	-		34.3		33.9	-		-
Headache	-	-	-		58.5		55.4	53.8		49.1
Tremor	-	-	-		26.3		25.6	33.9		35.5
Cardiac disorders
Tachycardia	-	-	-		22.8		21.8	22.0		15.7
Vascular disorders
Hypertension	27.5	32.2	19.3		78.9		74.0	62.1		59.6
Hypotension	-	-	-		34.3		40.1	-		-
Respiratory, thoracic and mediastinal disorders
Cough	-	-	-		40.5		32.2	-		-
Dyspnea	-	-	-		44.3		44.3	31.0		30.3
Pleural effusion	-	-	-		-		-	34.3		35.9
Gastrointestinal disorders
Abdominal pain	22.4	23.0	11.4		41.9		39.4	62.5		51.2
Constipation	-	-	-		43.6		38.8	37.9		38.3
Decreased appetite	-	-	-		-		-	25.3		17.1
Diarrhea	30.4	20.9	13.9		52.6		39.4	51.3		49.8
Dyspepsia	-	-	-		22.1		22.1	22.4		20.9
Nausea	-	-	-		56.1		60.2	54.5		51.2
Vomiting	-	-	-		39.1		34.6	32.9		33.4
Hepatobiliary disorders
Blood lactate dehydrogenase increased	-	-	-		23.5		18.3	-		-
Hepatic enzyme increased	-	-	-		-		-	24.9		19.2
Skin and subcutaneous tissues disorders
Rash	-	-	-		26.0		20.8	-		-
Renal and urinary disorders
Blood creatinine increased	-	-	-		42.2		39.8	-		-
Blood urea increased	-	-	-		36.7		34.3	-		-
General disorders and administration site conditions
Asthenia	-	-	-		49.1		41.2	35.4		33.8
Edema b	21.0	28.2	8.4		67.5		55.7	48.4		47.7
Pain c	24.8	32.2	9.6		79.2		77.5	74.0		77.5
Pyrexia	-	-	-		56.4		53.6	52.3		56.1

a : - Indicates that the incidence was below the cutoff value of 20% for inclusion in the table.
b : Edema includes peripheral edema, facial edema, scrotal edema.
c : Pain includes musculoskeletal pain (myalgia, neck pain, back pain).

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, pseudolymphoma) 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.

Cytopenias, including leukopenia, anemia, thrombocytopenia and pancytopenia are a known risk associated with mycophenolate and may lead or contribute to the occurrence of infections and hemorrhages [see Warnings and Precautions (5.3)]. Severe neutropenia (ANC <0.5 x 103/ L) developed in up to 2% of kidney transplant patients, up to 2.8% of heart transplant patients and up to 3.6% of liver transplant patients receiving mycophenolate mofetil capsules 3 g daily [see Warnings and Precautions (5.4) and Dosage and Administration (2.5)].

The most common opportunistic infections in patients receiving mycophenolate mofetil capsules with other immunosuppressants were mucocutaneous candida, CMV viremia/syndrome, and herpes simplex. The proportion of patients with CMV viremia/syndrome was 13.5%. In patients receiving mycophenolate mofetil capsules (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 most serious gastrointestinal disorders reported were ulceration and hemorrhage, which are known risks associated with mycophenolate mofetil capsules. Mouth, esophageal, gastric, duodenal, and intestinal ulcers often complicated by hemorrhage, as well as hematemesis, melena, and hemorrhagic forms of gastritis and colitis were commonly reported during the pivotal clinical trials, while the most common gastrointestinal disorders were diarrhea, nausea and vomiting. Endoscopic investigation of patients with mycophenolate mofetil capsules-related diarrhea revealed isolated cases of intestinal villous atrophy [see Warnings and Precautions (5.5)].

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 4. Adverse Reactions in Controlled Studies of De Novo Kidney, Heart or Liver Transplantation Reported in 3% to <20% of Patients Treated with Mycophenolate Mofetil in Combination with Cyclosporine and Corticosteroids

System Organ Class	Adverse Reactions
Body as a Whole	cellulitis, chills, hernia, malaise
Infections and Infestations	fungal infections
Hematologic and Lymphatic	coagulation disorder, ecchymosis, pancytopenia
Urogenital	hematuria
Cardiovascular	hypotension
Metabolic and Nutritional	acidosis, alkaline phosphatase increased, hyperlipemia, hypophosphatemia, weight loss
Digestive	esophagitis, flatulence, gastritis, gastrointestinal hemorrhage, hepatitis, ileus, nausea and vomiting, stomach ulcer, stomatitis
Neoplasm benign, malignant and unspecified	neoplasm
Skin and Appendages	skin benign neoplasm, skin carcinoma
Psychiatric	confusional state
Nervous	hypertonia, paresthesia, somnolence
Musculoskeletal	arthralgia, myasthenia

Pediatric Study

The 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.

Geriatrics

Elderly 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 Intravenous

The 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 orbits

-Abnormalities of the ear and eye: abnormally formed or absent external/middle ear, coloboma, microphthalmos

-Malformations of the fingers: polydactyly, syndactyly, brachydactyly

-Cardiac abnormalities: atrial and ventricular septal defects

-Esophageal malformations: esophageal atresia

-Nervous system malformations: such as spina bifida.

• Digestive:Colitis, pancreatitis

• Hematologic and Lymphatic: Bone marrow failure, 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)].

• Immune: Hypersensitivity, hypogammaglobinemia.

• Infections: Meningitis, infectious endocarditis, tuberculosis, atypical mycobacterial infection, progressive multifocal leukoencephalopathy, BK virus infection, viral reactivation of hepatitis B and hepatitis C, protozoal infections [see Warnings and Precautions (5.3)].

• Respiratory: Bronchiectasis, interstitial lung disease, 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.
  
• Vascular: Lymphocele

7 Drug Interactions ⮝

7.1 Effect of Other Drugs on Mycophenolate Mofetil Capsules

Table 5. Drug Interactions with Mycophenolate Mofetil Capsules that Affect Mycophenolic Acid (MPA) Exposure

Antacids with Magnesium or Aluminum Hydroxide
Clinical 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 capsules 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 capsules.
Examples	Lansoprazole, pantoprazole
Drugs that Interfere with Enterohepatic Recirculation
Clinical 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 capsules.
Examples	Trimethoprim/sulfamethoxazole, bile acid sequestrants (cholestyramine), rifampin as well as aminoglycoside, cephalosporin, fluoroquinolone and penicillin classes of antimicrobials
Drugs Modulating Glucuronidation
Clinical 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 capsules.
Examples	Telmisartan (induces glucuronidation); isavuconazole (inhibits glucuronidation).
Calcium Free Phosphate Binders
Clinical 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 capsules.
Examples	Sevelamer

7.2 Effect of Mycophenolate Mofetil Capsules on Other Drugs

Table 6. Drug Interactions with Mycophenolate Mofetil Capsules that Affect Other Drugs

Drugs that Undergo Renal Tubular Secretion
Clinical Impact	When concomitantly used with mycophenolate mofetil capsules, 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 Contraceptives
Clinical Impact	Concomitant use with mycophenolate mofetil capsules 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 Use In Specific Populations ⮝

8.1 Pregnancy

Pregnancy Exposure Registry

There 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 capsule treatment. To report a pregnancy or obtain information about the registry, visit www.mycophenolateREMS.com or call 1-800-617-8191.

Risk Summary

Use 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.

Data

Human Data

A 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 Data

In 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 Summary

There 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 capsules and any potential adverse effects on the breastfed infant from mycophenolate mofetil capsules or from the underlying maternal condition.

Data

Limited 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 to 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 Planning

For 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 Testing

To 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.

Contraception

Female Patients

Females of reproductive potential taking mycophenolate mofetil capsules must receive contraceptive counseling and use acceptable contraception (see Table 7 for acceptable contraception methods). Patients must use acceptable birth control during the entire mycophenolate mofetil capsule therapy, and for 6 weeks after stopping mycophenolate mofetil capsules, unless the patient chooses abstinence.

Patients should be aware that mycophenolate mofetil capsules reduce blood levels of the hormones from the oral contraceptive pill and could theoretically reduce its effectiveness [see Drug Interactions (7.2)].

Table 7. Acceptable Contraception Methods For Females Of Reproductive Potential

Pick from the following birth control options:

Male Patients

Genotoxic 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 capsules have been established in pediatric patients 3 months and older for the prophylaxis of kidney rejection after allogeneic kidney transplant. Use of mycophenolate mofetil capsules in this population is supported by evidence from adequate and well-controlled studies of mycophenolate mofetil capsules in adults with additional data from one open-label, pharmacokinetic and safety study of mycophenolate mofetil capsules 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 capsules 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 Transplant

No 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 adjustments are necessary; however, doses greater than 1 g administered twice a day should be avoided.

Patients with Heart and Liver Transplant

No 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 Transplant

No 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 Transplant

No 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 Management

MPA and the phenolic glucuronide metabolite of MPA (MPAG) are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 mcg/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, USP is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor.

The chemical name for mycophenolate mofetil, USP (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 the following structural formula:

C23H31NO7 M.W. 433.50

Mycophenolate mofetil, USP is a white to almost white crystalline powder. It is slightly soluble in water (43 mcg/mL at pH 7.4), freely soluble in acetone, soluble in methanol, sparingly soluble in anhydrous ethanol, and practically insoluble in water. No polymorphic form was found. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for mycophenolate mofetil, USP are 5.6 for the morpholino group and 8.5 for the phenolic group.

Mycophenolate mofetil, USP is available for oral administration as capsules containing 250 mg of mycophenolate mofetil, USP.

Inactive ingredients in Mycophenolate Mofetil Capsules USP, 250 mg include: black iron oxide, croscarmellose sodium, D&C red #28, D&C yellow #10, FD&C blue #1, FD&C red #40, gelatin, magnesium stearate, povidone, pregelatinized corn starch, propylene glycol, shellac glaze, and titanium dioxide.

12 Clinical Pharmacology ⮝

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

Absorption

Following 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 shown in Table 8. 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 (1.5g twice daily) (see Table 8).

Table 8. 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	24.5	63.9
		( 0.36)	( 9.5)	( 16.2)
		(n=129)	(n=129)	(n=117)
Kidney Transplant Patients (twice daily dosing) Time After Transplantation	Dose/Route	Tmax(h)	Cmax(mcg/mL)	Interdosing Interval AUC(0- 12h) (mcg h/mL)
5 days	1 g/iv	1.58	12.0	40.8
		( 0.46)	( 3.82)	( 11.4)
		(n=31)	(n=31)	(n=31)
6 days	1 g/oral	1.33	10.7	32.9
		( 1.05)	( 4.83)	( 15.0)
		(n=31)	(n=31)	(n=31)
Early (Less than 40 days)	1 g/oral	1.31	8.16	27.3
		( 0.76)	( 4.50)	( 10.9)
		(n=25)	(n=25)	(n=25)
Early (Less than 40 days)	1.5 g/oral	1.21	13.5	38.4
		( 0.81)	( 8.18)	( 15.4)
		(n=27)	(n=27)	(n=27)
Late (Greater than 3	1.5 g/oral	0.90	24.1	65.3
months)		( 0.24)	( 12.1)	( 35.4)
		(n=23)	(n=23)	(n=23)
Heart transplant Patients (twice daily dosing) Time After Transplantation	Dose/Route	Tmax(h)	Cmax(mcg/mL)	Interdosing Interval AUC(0- 12h) (mcg h/mL)
Early	1.5 g/oral	1.8	11.5	43.3
(Day before discharge)		( 1.3)	( 6.8)	( 20.8)
		(n=11)	(n=11)	(n=9)
Late (Greater than 6	1.5 g/oral	1.1	20.0	54.1a
months)		( 0.7)	( 9.4)	( 20.4)
		(n=52)	(n=52)	(n=49)
Liver transplant Patients (twice daily dosing) Time After Transplantation	Dose/Route	Tmax(h)	Cmax(mcg/mL)	Interdosing Interval AUC(0- 12h) (mcg h/mL)
4 to 9 days	1 g/iv	1.50	17.0	34.0
		( 0.517)	( 12.7)	( 17.4)
		(n=22)	(n=22)	(n=22)
Early (5 to 8 days)	1.5 g/oral	1.15	13.1	29.2
		( 0.432)	( 6.76)	( 11.9)
		(n=20)	(n=20)	(n=20)
Late (Greater than 6	1.5 g/oral	1.54	19.3	49.3
months)		( 0.51)	( 11.7)	( 14.8)
		(n=6)	(n=6)	(n=6)

aAUC(0-12h) values quoted are extrapolated from data from samples collected over 4 hours.

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 Food

Food (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)].

Distribution

The mean ( SD) apparent volume of distribution of MPA in 12 healthy volunteers was 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%.

Elimination

Mean ( 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.

Metabolism

The 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 below].

Excretion

Negligible 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 Populations

Patients with Renal Impairment

The 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 9.

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 Nonfunction

In 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 Impairment

The 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 9.

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).

Table 9. 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	1 g	0.75	25.3	45.0
GFR greater than 80 mL/min/1.73 m2		( 0.27)	( 7.99)	( 22.6)
(n=6)
Mild Renal Impairment	1 g	0.75	26.0	59.9
GFR 50 to 80 mL/min/1.73 m2		( 0.27)	( 3.82)	( 12.9)
(n=6)
Moderate Renal Impairment	1 g	0.75	19.0	52.9
GFR 25 to 49 mL/min/1.73 m2		( 0.27)	( 13.2)	( 25.5)
(n=6)
Severe Renal Impairment	1 g	1.00	16.3	78.6
GFR less than 25 mL/min/1.73 m2		( 0.41)	( 10.8)	( 46.4)
(n=7)
Pharmacokinetic Parameters for Hepatic Impairment
	Dose	Tmax(h)	Cmax(mcg/mL)	AUC(0-48h) (mcg h/mL)
Healthy Volunteers	1 g	0.63	24.3	29.0
(n=6)		( 0.14)	( 5.73)	( 5.78)
Alcoholic Cirrhosis	1 g	0.85	22.4	29.8
(n=18)		( 0.58)	( 10.1)	( 10.7)

Pediatric Patients

The 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 10.

Table 10. Mean ( SD) Computed Pharmacokinetic Parameters for MPA by Age and Time after Allogeneic Kidney Transplantation

a adjusted to a dose of 600 mg/m2
b n=20
c n=16
d a subset of 1 to <6 yr

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 Patients

Data 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 Patients

The 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 Interaction Studies

Acyclovir

Coadministration 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 Hydroxides

Absorption 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 capsules 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.

Cholestyramine

Following 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.

Cyclosporine

Cyclosporine (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 to 50% greater when MMF was administered without cyclosporine compared with when MMF was 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 Glucuronidation

Concomitant 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 capsules 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.

Ganciclovir

Following 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) mg h/mL and 30.9 ( 11.2) mcg/mL, respectively, after administration of MMF alone.

Oral Contraceptives

A 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.

Sevelamer

Concomitant administration of sevelamer and MMF in adult and pediatric patients decreased the mean MPA Cmax and AUC(0-12h) by 36% and 26% respectively.

Antimicrobials

Antimicrobials 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 Cmax of MPA after concomitant administration were 75.2 ( 19.8) mcg h/mL and 34.0 ( 6.6) mg/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 capsule-treated kidney transplant recipients received either oral ciprofloxacin 500 mg twice daily or amoxicillin plus clavulanic acid 375 mg three times 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 Nonclinical Toxicology ⮝

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 Clinical Studies ⮝

14.1 Kidney Transplantation

Adults

The 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 11.

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

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

Table 11. Treatment Failure in De Novo Kidney Transplantation Studies

USA Study (N=499 patients)	Mycophenolate Mofetil 2 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 rejection	9.6%	12.7%	6.0%
Biopsy-proven rejection episode on treatment	19.8%	17.5%	38.0%
Europe/Canada/Australia Study (N=503 patients)	Mycophenolate Mofetil 2 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%

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

No advantage of mycophenolate mofetil at 12 months with respect to graft loss or patient death (combined) was established (Table 12). Numerically, patients receiving mycophenolate mofetil 2 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 12. 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-Up

One 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 kidney 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 13).

Table 13. 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 monthsa	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%)

a Hemodynamic 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.

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 14).

Table 14. De Novo Liver Transplantation Study Rejection at 6 Months/Death or Retransplantation 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%)