Mycophenolate Mofetil

• 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

  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)].

  (

  5.1 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)].

  )]

  .
• Increased risk of development of lymphoma and other malignancies, particularly of the skin

  [see

  5.2 Lymphoma and Other Malignancies

  Patients receiving immunosuppressants, including Mycophenolate mofetil, 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 broad-spectrum sunscreen with a high protection factor.

  Post-transplant lymphoproliferative disorder (PTLD) 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 kidney, heart and liver transplant patients

  [see Adverse Reactions (6.1)]

  . The majority of PTLD cases appear 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)].

  (

  5.2 Lymphoma and Other Malignancies

  Patients receiving immunosuppressants, including Mycophenolate mofetil, 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 broad-spectrum sunscreen with a high protection factor.

  Post-transplant lymphoproliferative disorder (PTLD) 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 kidney, heart and liver transplant patients

  [see Adverse Reactions (6.1)]

  . The majority of PTLD cases appear 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)].

  )]

  .
• Increased susceptibility to infections, including opportunistic infections and severe infections with fatal outcomes

  [see

  5.3 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. 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
  • COVID-19

  Consider dose reduction or discontinuation of Mycophenolate mofetil 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

  ]. 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

  ]. 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.

  (

  5.3 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. 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
  • COVID-19

  Consider dose reduction or discontinuation of Mycophenolate mofetil 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

  ]. 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

  ]. 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.

  )]

  .

Warnings and Precautions (

Mycophenolate mofetil is an antimetabolite immunosuppressant indicated for the prophylaxis of organ rejection in adult and pediatric recipients 3 months of age and older of allogeneic kidney, heart or liver transplants, in combination with other immunosuppressants. (

•   MYCOPHENOLATE MOFETIL Intravenous is an alternative when patients cannot tolerate oral medication. Administer within 24 hours following transplantation, until patients can tolerate oral medication, up to 14 days. (
  2.1 Important Administration Instructions

  Mycophenolate mofetil should not be used without the supervision of a physician with experience in immunosuppressive therapy.

  Mycophenolate mofetil capsules and tablets

  Mycophenolate mofetil oral dosage forms (capsules or tablets)

  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 oral dosage forms and mycophenolic acid delayed-release tablets are not equivalent.

  Mycophenolate mofetil tablets should not be crushed and 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 should be given as soon as possible following kidney, heart or liver transplant. It is recommended that Mycophenolate mofetil be administered on an empty stomach. In stable transplant patients, however Mycophenolate mofetil 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 at the usual times.
  )
•   Reduce or interrupt dosing in the event of neutropenia. (
  2.5 Dosage Modifications: Patients with Renal Impairment, Neutropenia

  Renal Impairment

  No dosage modifications are needed in kidney transplant patients with delayed graft function postoperatively

  [see Clinical Pharmacology (12.3)]

  . In

  kidney transplant patients with severe chronic impairment of the graft

  (GFR <25 mL/min/1.73 m²), do not administer doses of Mycophenolate mofetil 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 × 10³/µL), 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)]

  .
  )
•   See full prescribing information (FPI) for: adjustments for renal impairment and neutropenia (
  2.5 Dosage Modifications: Patients with Renal Impairment, Neutropenia

  Renal Impairment

  No dosage modifications are needed in kidney transplant patients with delayed graft function postoperatively

  [see Clinical Pharmacology (12.3)]

  . In

  kidney transplant patients with severe chronic impairment of the graft

  (GFR <25 mL/min/1.73 m²), do not administer doses of Mycophenolate mofetil 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 × 10³/µL), 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)]

  .
  ).

Mycophenolate Mofetil, USP is available in the following dosage form and strength:

• 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 patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity whenever possible. Risks and benefits of Mycophenolate mofetil 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. 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 must receive contraceptive counseling and use acceptable contraception (see

  Table 9

  for acceptable contraception methods). Patients must use acceptable birth control during the entire Mycophenolate mofetil therapy, and for 6 weeks after stopping Mycophenolate mofetil, unless the patient chooses abstinence.

  Patients should be aware that Mycophenolate mofetil reduces blood levels of the hormones from the oral contraceptive pill and could theoretically reduce its effectiveness

  [see Drug Interactions (7.2)]

  .

  Table 9 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 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 1.25 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 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)].
  )