Mycophenolic Acid

• Use during pregnancy is associated with increased risks of 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

  5.1 Embryo-Fetal Toxicity

  Use of mycophenolic acid delayed-release tablets 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 aware of these risks and must be counseled regarding pregnancy prevention and planning. Avoid use of mycophenolic acid delayed-release tablets during pregnancy if safer treatment options are available

  [see Use in Specific Populations (8.1, 8.3)]

  ,
  
  
  

  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 mycophenolic acid delayed-release tablets treatment. To report a pregnancy or obtain information about the registry, visit www.mycophenolateREMS.com or call 1-800-617-8191.

  Risk Summary

  Following oral or intravenous (IV) administration, MMF is metabolized to mycophenolic acid (MPA), the active ingredient in mycophenolic acid delayed-release tablets and the active form of the drug. Use of 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 (0.05 and 1.1 times exposure at the recommended clinical doses in kidney transplant patients for rats and rabbits, respectively)

  [see Animal Data]

  .

  Risks and benefits of mycophenolic acid delayed-release tablets should be discussed with the patient. When appropriate, consider alternative immunosuppressants with less potential for embryo-fetal toxicity.

  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, congenital malformations and pregnancy loss occurred when pregnant rats and rabbits received mycophenolate at dose multiples equivalent to and less than the recommended human dose. Oral administration of mycophenolate sodium to pregnant rats from Gestational Day 7 to Day 16 at a dose as low as 1 mg per kg resulted in malformations including anophthalmia, exencephaly, and umbilical hernia. The systemic exposure at this dose represents 0.05 times the clinical exposure at the human dose of 1440 mg per day mycophenolic acid delayed-release tablets. Oral administration of mycophenolate to pregnant rabbits from Gestational Day 7 to Day 19 resulted in embryofetal lethality and malformations including ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia at doses equal to or greater than 80 mg per kg per day, in the absence of maternal toxicity. This corresponds to about 1.1 times the recommended clinical dose based on BSA.

  ,
  
  
  

  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 female patients taking mycophenolic acid delayed-release tablets who are considering pregnancy, consider alternative immunosuppressants with less potential for embryo-fetal toxicity. Risks and benefits of mycophenolic acid delayed-release tablets should be discussed with the patient.

  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 mycophenolic acid delayed-release tablets. 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 embryo-fetal toxicity whenever possible.

  Contraception

  Female Patients

  Females of reproductive potential taking mycophenolic acid delayed-release tablets must receive contraceptive counseling and use acceptable contraception (see Table 5 for Acceptable Contraception Methods). Patients must use acceptable birth control during entire mycophenolic acid delayed-release tablets therapy, and for 6 weeks after stopping mycophenolic acid delayed-release tablets, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely).

  Patients should be aware that mycophenolic acid delayed-release tablets reduce blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness

  [see

  Patient Counseling Information (17), Drug Interactions (7.8)]

  .

  Table 5: 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

  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 mycophenolic acid delayed-release tablets and for at least 90 days after cessation of treatment

  [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1), Patient Counseling Information (17)]

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  ]

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• Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression
  
  
  

  [see 

  5.3 Lymphoma and Other Malignancies

  Patients receiving immunosuppressants, including mycophenolic acid delayed-release tablets, are at increased risk of developing lymphomas and other malignancies, particularly of the skin

  [see

  Adverse Reactions (6)]

  . 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 broad-spectrum sunscreen with a high protection factor.

  Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear 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.

  ]
  
  
  

  .
  
  
  
• Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections
  
  
  

  [see 

  5.4 Serious Infections

  Patients receiving immunosuppressants, including mycophenolic acid delayed-release tablets, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, and new or reactivated viral infections, including opportunistic infections

  [see

  Warnings and Precautions (5.5)]

  . 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.

  ,
  
  
  

  5.5 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 the mycophenolic acid (MPA) derivatives mycophenolic acid delayed-release tablets and MMF. 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. 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. 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

  [see

  Adverse Reactions (6.1)]

  .

  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.

  ]
  
  
  

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• Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe mycophenolic acid delayed-release tablets. Patients receiving mycophenolic acid delayed-release tablets 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 

  5.2 Management of Immunosuppression

  Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe mycophenolic acid delayed-release tablets. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physicians responsible for maintenance therapy should have complete information requisite for the follow-up of the patient

  [see

  Boxed Warning]

  .

  ]
  
  
  

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Warnings and Precautions, Embryo-Fetal Toxicity (

Warnings and Precautions, Lymphoma and Other Malignancies (

Warnings and Precautions, Immunizations (

Warnings and Precautions, Blood Donation (

Warnings and Precautions, Semen Donation (

• Mycophenolic acid delayed-release tablets are an antimetabolite immunosuppressant indicated for prophylaxis of organ rejection in adult patients receiving kidney transplants and in pediatric patients at least 5 years of age and older who are at least 6 months post kidney transplant. (
  
  
  
  
  
  
  1.1 Prophylaxis of Organ Rejection in Kidney Transplant

  Mycophenolic acid delayed-release tablets are indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant.

  Mycophenolic acid delayed-release tablets are indicated for the prophylaxis of organ rejection in pediatric patients 5 years of age and older who are at least 6 months post kidney transplant.

  Mycophenolic acid delayed-release tablets are to be used in combination with cyclosporine and corticosteroids.
  )
  
  
  
  
• Use in combination with cyclosporine and corticosteroids. (
  
  
  
  
  
  
  1.1 Prophylaxis of Organ Rejection in Kidney Transplant

  Mycophenolic acid delayed-release tablets are indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant.

  Mycophenolic acid delayed-release tablets are indicated for the prophylaxis of organ rejection in pediatric patients 5 years of age and older who are at least 6 months post kidney transplant.

  Mycophenolic acid delayed-release tablets are to be used in combination with cyclosporine and corticosteroids.
  )
  
  
  
  

• Mycophenolic acid delayed release tablets and mycophenolate mofetil tablets and capsules should not be used interchangeably. (
  
  
  
  
  
  
  1.2 Limitations of Use

  Mycophenolic acid delayed-release tablets and mycophenolate mofetil (MMF) tablets and capsules should not be used interchangeably without physician supervision because the rate of absorption following the administration of these two products is not equivalent.
  )
  
  
  
  

• In adults: 720 mg by mouth, twice daily (1440 mg total daily dose) on an empty stomach, 1 hour before or 2 hours after food intake. (
  
  
  
  
  
  
  2.1 Dosage in Adult Kidney Transplant Patients

  The recommended dose of mycophenolic acid delayed-release tablets is 720 mg administered twice daily (1440 mg total daily dose).
  )
  
  
  
  
• In children: 5 years of age and older (who are at least 6 months post kidney transplant), 400 mg/m
  
  
  
  
  
  ² by mouth, twice daily (up to a maximum of 720 mg twice daily). (
  
  
  
  
  
  
  2.2 Dosage in Pediatric Kidney Transplant Patients

  The recommended dose of mycophenolic acid delayed-release tablets in conversion (at least 6 months post-transplant) pediatric patients age 5 years and older is 400 mg/m²body surface area (BSA) administered twice daily (up to a maximum dose of 720 mg administered twice daily).
  )
  
  
  
  
• Do not crush, chew, or cut tablet prior to ingestion. (
  
  
  
  
  
  
  2.3 Administration

  Mycophenolic acid delayed-release tablets should be taken on an empty stomach, 1 hour before or 2 hours after food intake

  [see

  Clinical Pharmacology (12.3)]

  .

  Mycophenolic acid delayed-release tablets should not be crushed, chewed, or cut prior to ingesting. The tablets should be swallowed whole in order to maintain the integrity of the enteric coating.

  Pediatric patients with a BSA of 1.19 m²to 1.58 m²may be dosed either with three mycophenolic acid delayed-release 180 mg tablets, or one 180 mg tablet plus one 360 mg tablet twice daily (1080 mg daily dose). Patients with a BSA of > 1.58 m²may be dosed either with four mycophenolic acid delayed-release 180 mg tablets, or two mycophenolic acid delayed-release 360 mg tablets twice daily (1440 mg daily dose). Pediatric doses for patients with BSA < 1.19 m²cannot be accurately administered using currently available formulations of mycophenolic acid delayed-release tablets.
  )
  
  
  
  

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

• The 180 mg tablets are sage green, film-coated, round, unscored tablets with
  
  
  
  
  
  
  M
  over
  
  
  
  
  
  
  MC1
  imprinted in black ink on one side of the tablet and blank on the other side.
  
  
  
  
• The 360 mg tablets are reddish-orange, film-coated, modified capsule-shaped, unscored tablets with
  
  
  
  
  
  
  M MC2
  imprinted in black ink on one side of the tablet and blank on the other side.
  
  
  
  

• Male Patients: 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. (
  
  
  
  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 female patients taking mycophenolic acid delayed-release tablets who are considering pregnancy, consider alternative immunosuppressants with less potential for embryo-fetal toxicity. Risks and benefits of mycophenolic acid delayed-release tablets should be discussed with the patient.

  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 mycophenolic acid delayed-release tablets. 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 embryo-fetal toxicity whenever possible.

  Contraception

  Female Patients

  Females of reproductive potential taking mycophenolic acid delayed-release tablets must receive contraceptive counseling and use acceptable contraception (see Table 5 for Acceptable Contraception Methods). Patients must use acceptable birth control during entire mycophenolic acid delayed-release tablets therapy, and for 6 weeks after stopping mycophenolic acid delayed-release tablets, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely).

  Patients should be aware that mycophenolic acid delayed-release tablets reduce blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness

  [see

  Patient Counseling Information (17), Drug Interactions (7.8)]

  .

  Table 5: 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

  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 mycophenolic acid delayed-release tablets and for at least 90 days after cessation of treatment

  [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1), Patient Counseling Information (17)]

  .
  )