Cellcept

• 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)].

  ,

  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 CELLCEPT 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 (0.01 to 0.05 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 CELLCEPT 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 0.015 and 0.01 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 0.05 and 0.03 times the recommended human doses for renal and cardiac transplant patients, respectively, when corrected for 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 patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity whenever possible. Risks and benefits of CELLCEPT 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 CELLCEPT. 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 CELLCEPT must receive contraceptive counseling and use acceptable contraception (see

  Table 9

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

  Patients should be aware that CELLCEPT 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 CELLCEPT 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)]

  .

  ]

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

  [see

  5.2 Lymphoma and Other Malignancies

  Patients receiving immunosuppressants, including CELLCEPT, 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 CELLCEPT (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 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

  5.3 Serious Infections

  Patients receiving immunosuppressants, including CELLCEPT, 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 CELLCEPT 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.

  ]

  .

CELLCEPT [mycophenolate mofetil (MMF)] is indicated for the prophylaxis of organ rejection, in adult and pediatric recipients 3 months of age and older of allogeneic kidney

• CELLCEPT 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

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

  CELLCEPT Capsules, Tablets and Oral Suspension

  CELLCEPT oral dosage forms (capsules, tablets or oral suspension)

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

  CELLCEPT tablets should not be crushed and CELLCEPT capsules should not be opened or crushed. Patients should avoid inhalation or contact of the skin or mucous membranes with the powder contained in CELLCEPT capsules and oral suspension. 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 CELLCEPT should be given as soon as possible following kidney, heart or liver transplant. It is recommended that CELLCEPT be administered on an empty stomach. In stable transplant patients, however, CELLCEPT may be administered with food if necessary

  [see Clinical Pharmacology (12.3)].

  Once reconstituted, CELLCEPT Oral Suspension must not be mixed with any liquids prior to dose administration. If needed, CELLCEPT Oral Suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).

  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 CELLCEPT at the usual times.

  CELLCEPT Intravenous

  CELLCEPT Intravenous is recommended for patients unable to take oral CELLCEPT. CELLCEPT Intravenous should be administered within 24 hours following transplant. CELLCEPT Intravenous can be administered for up to 14 days; however, patients should be switched to oral CELLCEPT as soon as they can tolerate oral medication.

  CELLCEPT Intravenous must be reconstituted before use

  [see Dosage and Administration (2.6)]

  . CELLCEPT Intravenous is incompatible with other intravenous infusion solutions and should not be mixed or administered concurrently via the same infusion catheter with other intravenous drugs or infusion admixtures.

  CELLCEPT Intravenous must not be administered as a bolus. Following reconstitution, CELLCEPT Intravenous must be administered by slow intravenous infusion over a period of no less than 2 hours by either peripheral or central vein, as rapid infusion increases the risk of local adverse reactions such as phlebitis and thrombosis

  [see Adverse Reactions (6.1)]

  .
  )
• 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 CELLCEPT 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 CELLCEPT 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 CELLCEPT 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 CELLCEPT 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)].
  ), preparation of oral suspension and IV solution. (
  2.6 Preparation Instructions of Oral Suspension and Intravenous for Pharmacists

  General Preparation Instructions Before Handling the Formulations

  Mycophenolate mofetil (MMF) has demonstrated teratogenic effects in humans. Follow applicable special handling and disposal procedures¹

  [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Use in Specific Populations (8.1, 8.3), How Supplied/Storage and Handling (16.1)].

  Care should be taken to avoid inhalation or direct contact with skin or mucous membranes of the dry powder or the constituted suspension because MMF has demonstrated teratogenic effects in humans

  .

  Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table surface after reconstitution. If such contact occurs, wash hands thoroughly with soap and water; rinse eyes with water.

  Alert patients that they and others should also avoid inhalation or contact of the skin or mucous membranes with the oral suspension. Advise them to wash the area thoroughly with soap and water if such contact occurs; if ocular contact occurs, rinse eyes with plain water.

  CELLCEPT Oral Suspension

  CELLCEPT Oral Suspension must be reconstituted by the pharmacist prior to dispensing to the patient. CELLCEPT Oral Suspension should not be mixed with any other medication. After reconstitution, the oral suspension contains 200 mg/mL MMF.

  Before proceeding with the reconstitution steps read the general preparation instructions above

  [see General Preparation Instructions Before Handling the Formulations].

  The following are the steps for reconstitution:

  • Tap the closed bottle several times to loosen the powder.
  • Measure 94 mL of water in a graduated cylinder.
  • Add approximately half the total amount of water for reconstitution to the bottle and shake the closed bottle well for about 1 minute.
  • Add the remainder of water and shake the closed bottle well for about 1 minute.
  • Remove the child-resistant cap and push bottle adapter into neck of bottle.
  • Close bottle with child-resistant cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child-resistant status of the cap.
  • Write the date of expiration of the constituted suspension on the bottle label. (The shelf-life of the constituted suspension is 60 days.)
  • Dispense with the "Instruction for Use" and oral dispensers. Alert patients to read the important handling information described in the instructions for use.

  Store reconstituted suspension at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Storage in a refrigerator at 2°C to 8°C (36°F to 46°F) is acceptable. Do not freeze. Discard any unused portion 60 days after constitution.

  CELLCEPT Intravenous

  Before proceeding with the preparation steps for CELLCEPT Intravenous read the general preparation instructions

  [see General Preparation Instructions Before Handling the Formulations]

  and note the following:

  • CELLCEPT Intravenous does not contain an antibacterial preservative; therefore, reconstitution and dilution of the product must be performed under aseptic conditions.
  • This product is sealed under vacuum and should retain a vacuum throughout its shelf life. If a lack of vacuum in the vial is noted while adding the diluent, the vial should not be used.

  CELLCEPT Intravenous must be reconstituted and further diluted. A detailed description of the preparation is given below.

  Table 4 Preparation Instructions of CELLCEPT Intravenous for Pharmacists

  Preparation of the 1g dose

  Reconstitute two (2) vials of CELLCEPT Intravenous by injecting 14 mL of 5% Dextrose Injection USP into each vial. Gently shake the vial to dissolve the drug. Inspect the resulting slightly yellow solution for particulate matter and discoloration prior to further dilution. Discard the vials if particulate matter or discoloration is observed. Dilute the contents of the two reconstituted vials (approximately 2 × 15 mL) into 140 mL of 5% Dextrose Injection USP. Inspect the resulting infusion solution and discard if particulate matter or discoloration is observed.

  Preparation of the 1.5 g dose

  Reconstitute three (3) vials of CELLCEPT Intravenous by injecting 14 mL of 5% Dextrose Injection USP into each vial. Gently shake the vial to dissolve the drug. Inspect the resulting slightly yellow solution for particulate matter and discoloration prior to further dilution. Discard the vials if particulate matter or discoloration is observed. Dilute the contents of the three reconstituted vials (approximately 3 × 15 mL) into 210 mL of 5% Dextrose Injection USP. Inspect the resulting infusion solution and discard if particulate matter or discoloration is observed.

  The administration of the infusion should be initiated within 4 hours of reconstitution and dilution of the drug product. Keep solutions at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Discard unused portion of the reconstituted solutions.

  CELLCEPT Injection should not be mixed or administered concurrently via the same infusion catheter with other intravenous drugs or infusion admixtures.
  )

CELLCEPT is available in the following dosage forms and strengths:

• 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 CELLCEPT 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 CELLCEPT. 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 CELLCEPT must receive contraceptive counseling and use acceptable contraception (see

  Table 9

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

  Patients should be aware that CELLCEPT 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 CELLCEPT 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)]

  .
  )