These Highlights Do Not Include All The Information Needed To Use Cellcept®

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.

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 CELLCEPT 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)].

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

CELLCEPT (mycophenolate mofetil) is an antimetabolite immunosuppressant. It is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor.

The chemical name for mycophenolate mofetil (MMF) is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has an empirical formula of C₂₃H₃₁NO₇, a molecular weight of 433.50, and the following structural formula:

MMF is a white to off-white crystalline powder. It is slightly soluble in water (43 µg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for MMF are 5.6 for the morpholino group and 8.5 for the phenolic group.

MMF hydrochloride has a solubility of 65.8 mg/mL in 5% Dextrose Injection USP (D5W). The pH of the reconstituted solution is 2.4 to 4.1.

CELLCEPT is available for oral administration as capsules containing 250 mg of MMF, tablets containing 500 mg of MMF, and as a powder for oral suspension which, when reconstituted, contains 200 mg/mL of MMF.

Inactive ingredients in CELLCEPT 250 mg capsules include croscarmellose sodium, magnesium stearate, povidone (K-90) and pregelatinized starch. The capsule shells contain black iron oxide, FD&C blue #2, gelatin, red iron oxide, silicon dioxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.

Inactive ingredients in CELLCEPT 500 mg tablets include croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone (K-90), and Opadry^® lavender Y-5R-10272-A (hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol 400, FD&C Blue No. 2 aluminum lake [indigo carmine aluminum lake], and red iron oxide).

Inactive ingredients in CELLCEPT Oral Suspension include aspartame, citric acid anhydrous, colloidal silicon dioxide, methylparaben, mixed fruit flavor, sodium citrate dihydrate, sorbitol, soybean lecithin, and xanthan gum.

CELLCEPT Intravenous is the hydrochloride salt of MMF. The chemical name for the hydrochloride salt of MMF is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate hydrochloride. It has an empirical formula of C₂₃H₃₁NO₇ HCl and a molecular weight of 469.96.

CELLCEPT Intravenous is available as a sterile white to off-white lyophilized powder in single-dose vials containing MMF hydrochloride for administration by intravenous infusion only. Each vial contains 500 mg of mycophenolate mofetil equivalent to 542 mg of mycophenolate mofetil hydrochloride. The inactive ingredients are polysorbate 80, 25 mg, and citric acid, 5 mg. Sodium hydroxide or hydrochloric acid may have been used in the manufacture of CELLCEPT Intravenous to adjust the pH. Reconstitution and dilution with 5% Dextrose Injection USP yields a slightly yellow solution of MMF, 6 mg/mL [see Dosage and Administration (2.6)].

During treatment with CELLCEPT, the use of live attenuated vaccines should be avoided (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines) and patients should be advised that vaccinations may be less effective. Advise patients to discuss with the physician before seeking any immunizations.

Safety and effectiveness have been established in pediatric patients 3 months and older for the prophylaxis of organ rejection of allogenic kidney, heart or liver transplants.

Clinical studies of CELLCEPT 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 geriatric and younger patients. In general, dose selection for a geriatric 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)].

Inform patients that CELLCEPT 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 (5.9)].

Advise males of childbearing potential not to donate semen during therapy and for 90 days following discontinuation of CELLCEPT [see Warnings and Precautions (5.13)].

CELLCEPT is contraindicated in patients with a history of hypersensitivity, including anaphylaxis, to mycophenolate mofetil (MMF), mycophenolic acid (MPA) or any component of the drug product [see Warnings and Precautions (5.8)]. CELLCEPT Intravenous is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN).

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

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

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)]
• Acute Inflammatory Syndrome Associated with Mycophenolate Products [see Warnings and Precautions (5.7)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.8)]

• See FPI for drugs that may interfere with systemic exposure and reduce CELLCEPT efficacy: antacids with magnesium or aluminum hydroxide, proton pump inhibitors, drugs that interfere with enterohepatic recirculation, telmisartan, calcium-free phosphate binders. (7.1)
• CELLCEPT may reduce effectiveness of oral contraceptives. Use of additional barrier contraceptive methods is recommended. (7.2)
• See FPI for other important drug interactions. (7)

Advise patients not to donate blood during therapy and for at least 6 weeks following discontinuation of CELLCEPT [see Warnings and Precautions (5.12)].

Read this Instructions for Use before you take or give CELLCEPT for the first time and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

Important:

• Always use the oral dispenser provided with CELLCEPT Oral Suspension to make sure you measure the right amount of medicine. If your CELLCEPT Oral Suspension does not come with the oral dispenser, contact your pharmacist.
• Call your pharmacist if your oral dispenser is lost or damaged.
• Your pharmacist will write the expiration date on your CELLCEPT Oral Suspension bottle label. Do not use CELLCEPT after the expiration date.
• Ask your doctor or pharmacist if you have any questions or are unsure about how to take or give the right amount of medicine.
• The CELLCEPT Oral Suspension should not be mixed with any type of liquids before taking or giving the dose.
• Do not let the CELLCEPT Oral Suspension come in contact with the skin. If this happens, wash the skin well with soap and water. If the CELLCEPT Oral Suspension gets in the eyes, rinse the eyes with plain water.
• If you spill any CELLCEPT Oral Suspension, wipe it up using paper towels wet with water. Put the child-resistant bottle cap back on the bottle and wipe the outside of the bottle with wet paper towels.

Supplies needed to take or give a dose of CELLCEPT Oral Suspension:

To take or give a dose of CELLCEPT Oral Suspension, you will need the bottle of medicine and the oral dispenser provided with the medicine (See Figure 1 ). Your pharmacist will insert the bottle adapter in the CELLCEPT Oral Suspension bottle. Do not remove the bottle adapter from the bottle.

Taking or giving a dose of CELLCEPT Oral Suspension:

How should I store CELLCEPT Oral Suspension?

• Store the CELLCEPT Oral Suspension at room temperature between 59°F to 86°F (15°C to 30°C), for up to 60 days. You can also store the CELLCEPT Oral Suspension in the refrigerator between 36°F to 46°F (2°C to 8°C). )
• Do not freeze.

Keep CELLCEPT Oral Suspension and all medicines out of the reach of children.

Distributed by:

Genentech USA, Inc.

A Member of the Roche Group

1 DNA Way

South San Francisco, CA 94080-4990

^©2022 Genentech, Inc. All rights reserved.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Revised: August 2022

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

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)].

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 [see Clinical Studies (14.1)], heart [see Clinical Studies (14.2)] or liver transplants [see Clinical Studies (14.3)], in combination with other immunosuppressants.

Mycophenolate mofetil (MMF) is absorbed following oral administration and hydrolyzed to mycophenolic acid (MPA), the active metabolite. MPA is a selective uncompetitive inhibitor of the two isoforms (type I and type II) of inosine monophosphate dehydrogenase (IMPDH) leading to inhibition of the de novo pathway of guanosine nucleotide synthesis and blocks DNA synthesis. The mechanism of action of MPA is multifaceted and includes effects on cellular checkpoints responsible for metabolic programming of lymphocytes. MPA shifts transcriptional activities in lymphocytes from a proliferative state to catabolic processes. In vitro studies suggest that MPA modulates transcriptional activities in human CD4⁺ T-lymphocytes by suppressing the Akt/mTOR and STAT5 pathways that are relevant to metabolism and survival, leading to an anergic state of T-cells whereby the cells become less responsive to antigenic stimulation. Additionally, MPA enhanced the expression of negative co-stimulators such as CD70, PD-1, CTLA-4, and transcription factor FoxP3 as well as decreased the expression of positive co-stimulators CD27 and CD28.

MPA decreases proliferative responses of T- and B-lymphocytes to both mitogenic and allo-antigenic stimulation, antibody responses, as well as the production of cytokines from lymphocytes and monocytes such as GM-CSF, IFN-ɣ, IL-17, and TNF-α. Additionally, 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.

Overall, the effect of MPA is cytostatic and reversible.

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)].

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 CELLCEPT 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 CELLCEPT and AZA with respect to biopsy-proven rejection with hemodynamic compromise.
• Survival: CELLCEPT was shown to be at least as effective as AZA in preventing death or re-transplantation at 1 year (see Table 15 ).

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 CELLCEPT 1 g twice daily intravenously for up to 14 days followed by CELLCEPT 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, CELLCEPT 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 16 ).

Mycophenolate mofetil (MMF) has demonstrated teratogenic effects in humans [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. CELLCEPT tablets should not be crushed and CELLCEPT capsules should not be opened or crushed. Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in CELLCEPT capsules, CELLCEPT Oral Suspension (before or after constitution), or CELLCEPT Intravenous (during or after preparation) [see Dosage and Administration (2.6)]. Follow applicable special handling and disposal procedures ¹.

• Blood Dyscrasias (Neutropenia, Red Blood Cell Aplasia): Monitor with blood tests; consider treatment interruption or dose reduction. (5.4)
• Gastrointestinal Complications: Monitor for complications such as bleeding, ulceration and perforations, particularly in patients with underlying gastrointestinal disorders. (5.5)
• Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency: Avoid use of CELLCEPT. (5.6)
• Acute Inflammatory Syndrome Associated with Mycophenolate Products: Monitor for this paradoxical inflammatory reaction. (5.7)
• Hypersensitivity Reactions: Discontinue CELLCEPT; treat and monitor until signs and symptoms resolve. (5.8)
• Immunizations: Avoid live attenuated vaccines. (5.9)
• Local Reactions with Rapid Intravenous Administration: CELLCEPT Intravenous must not be administered by rapid or bolus intravenous injection. (5.10)
• Phenylketonurics: Oral suspension contains aspartame. (5.11)
• Blood Donation: Avoid during therapy and for 6 weeks thereafter. (5.12)
• Semen Donation: Avoid during therapy and for 90 days thereafter. (5.13)
• Potential Impairment on Driving and Use of Machinery: CELLCEPT may affect ability to drive or operate machinery. (5.15)

• 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)
• Reduce or interrupt dosing in the event of neutropenia. (2.5)
• See full prescribing information (FPI) for: adjustments for renal impairment and neutropenia (2.5), preparation of oral suspension and IV solution. (2.6)

CELLCEPT is available in the following dosage forms and strengths:

The following adverse reactions have been identified during post-approval use of CELLCEPT. 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.
• Cardiovascular: Venous thrombosis has been reported in patients treated with CELLCEPT administered intravenously.
• 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 CELLCEPT in combination with other immunosuppressive agents [see Warnings and Precautions (5.4)].
• Immune: Hypersensitivity reactions, including anaphylaxis and angioedema [see Warnings and Precautions (5.8)], 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 CELLCEPT.
• Vascular: Lymphocele

• 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)

Postmarketing cases of hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with CELLCEPT. These reactions generally occurred within hours to the next day after initiating CELLCEPT. If signs or symptoms of hypersensitivity reaction occur, discontinue CELLCEPT; treat and monitor until symptoms resolve [see Contraindications (4)].

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 adult patients received CELLCEPT 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 CELLCEPT in de novo kidney (3) heart (1) and liver (1) transplant patients [see Clinical Studies (14.1, 14.2, and 14.3)].

Inform patients of the potential risk of hypersensitivity reactions. Advise patients to stop taking CELLCEPT and seek immediate medical attention if signs or symptoms of hypersensitivity reaction occur (such as swelling of face, lips, tongue, or throat; difficulty breathing or swallowing) [see Warnings and Precautions (5.8)].

Inform patients that acute inflammatory reactions have been reported in some patients who received CELLCEPT. Some reactions were severe, requiring hospitalization. Advise patients to contact their physician if they develop fever, joint stiffness, joint pain or muscle pains [see Warnings and Precautions (5.7)].

• Advise patients not to crush CELLCEPT tablets and not to open CELLCEPT capsules.
• Advise patients to avoid inhalation or contact of the skin or mucous membranes with the powder contained in CELLCEPT capsules and with the 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.
• 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 CELLCEPT at the usual times.

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

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)].

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 [see Warnings and Precautions (5.3)].

Inform patients that CELLCEPT 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)].

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

Phenylalanine can be harmful to patients with phenylketonuria (PKU). CELLCEPT Oral Suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine/mL suspension). Before prescribing CELLCEPT Oral Suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including CELLCEPT.

NDC 0004-0298-09

CellCept^® Intravenous

(mycophenolate mofetil for injection)

500 mg

FOR INTRAVENOUS INFUSION ONLY.

Each single-dose vial contains the equivalent of 500 mg mycophenolate mofetil (equivalent to 542 mg of

mycophenolate mofetil hydrochloride), 25 mg polysorbate 80 and 5 mg citric acid. Sodium hydroxide or

hydrochloric acid may have been used to adjust pH.

Attention Pharmacist: Dispense the accompanying Medication Guide to each patient. For additional

Medication Guides, call 1-800-617-8191 or visit www.gene.com/gene/products/information/cellcept.

Rx only

4 Single-Dose Vials

Genentech

10215811

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.

NDC 0004-0261-29

CellCept^®

Oral Suspension

(mycophenolate

mofetil for oral

suspension)

200 mg/mL

Each mL contains 200 mg mycophenolate

mofetil after constitution.

Attention Pharmacist: Dispense the accompanying

Medication Guide to each patient. For additional

Medication Guides, call 1-800-617-8191 or visit

www.gene.com/gene/products/information/cellcept.

Rx only

Genentech

10225425

• 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 broad-spectrum sunscreen with high protection factor.

NDC 0004-0260-43

CellCept^®

(mycophenolate

mofetil tablets)

500 mg

Each tablet contains

500 mg mycophenolate mofetil.

Rx only

Attention Pharmacist: Dispense the

accompanying Medication Guide to each

patient. For additional Medication Guides call

1-800-617-8191 or visit www.gene.com/gene/

products/information/cellcept.

500 tablets

Genentech

10235320

Advise patients that CELLCEPT 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 CELLCEPT [see Warnings and Precautions (5.15)].

NDC 0004-0259-43

CellCept^®

(mycophenolate

mofetil capsules)

250 mg

Each capsule contains

250 mg mycophenolate mofetil.

Rx only

Attention Pharmacist: Dispense the

accompanying Medication Guide to each

patient. For additional Medication Guides call

1-800-617-8191 or visit www.gene.com/gene/

products/information/cellcept.

500 capsules

Genentech

10235316

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 0.2 times the recommended clinical dose (2 g/day) in renal transplant patients and 0.15 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 0.035 times the recommended clinical dose in kidney transplant patients and 0.025 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 0.05 times the recommended clinical dose in renal transplant patients and 0.03 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 0.01 times the recommended clinical dose in renal transplant patients and 0.005 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.

CELLCEPT Intravenous solution must not be administered by rapid or bolus intravenous injection as rapid infusion increases the risk of local adverse reactions such as phlebitis and thrombosis [see Adverse Reactions (6.1)].

CELLCEPT 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 CELLCEPT [see Adverse Reactions (6.1)].

Severe neutropenia [absolute neutrophil count (ANC) <0.5 × 10³/µL] developed in transplant patients receiving CELLCEPT 3 g daily [see Adverse Reactions (6.1)]. Patients receiving CELLCEPT 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 CELLCEPT itself, concomitant medications, viral infections, or a combination of these causes. If neutropenia develops (ANC <1.3 × 10³/µL), dosing with CELLCEPT should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately [see Dosage and Administration (2.5)].

Patients receiving CELLCEPT 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 CELLCEPT in combination with other immunosuppressive agents. In some cases, PRCA was found to be reversible with dose reduction or cessation of CELLCEPT therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk.

• 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)].

Acute inflammatory syndrome (AIS) has been reported with the use of MMF and mycophenolate products, and some cases have resulted in hospitalization. AIS is a paradoxical pro-inflammatory reaction characterized by fever, arthralgias, arthritis, muscle pain and elevated inflammatory markers including, C-reactive protein and erythrocyte sedimentation rate, without evidence of infection or underlying disease recurrence. Symptoms occur within weeks to months of initiation of treatment or a dose increase. After discontinuation, improvement of symptoms and inflammatory markers are usually observed within 24 to 48 hours.

Monitor patients for symptoms and laboratory parameters of AIS when starting treatment with mycophenolate products or when increasing the dosage. Discontinue treatment and consider other treatment alternatives based on the risk and benefit for the patient.

A variety of drugs have potential to alter systemic MPA exposure when co-administered with CELLCEPT. 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.

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

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.

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 CELLCEPT 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)].

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

CELLCEPT (mycophenolate mofetil) is an antimetabolite immunosuppressant. It is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor.

The chemical name for mycophenolate mofetil (MMF) is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has an empirical formula of C₂₃H₃₁NO₇, a molecular weight of 433.50, and the following structural formula:

MMF is a white to off-white crystalline powder. It is slightly soluble in water (43 µg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for MMF are 5.6 for the morpholino group and 8.5 for the phenolic group.

MMF hydrochloride has a solubility of 65.8 mg/mL in 5% Dextrose Injection USP (D5W). The pH of the reconstituted solution is 2.4 to 4.1.

CELLCEPT is available for oral administration as capsules containing 250 mg of MMF, tablets containing 500 mg of MMF, and as a powder for oral suspension which, when reconstituted, contains 200 mg/mL of MMF.

Inactive ingredients in CELLCEPT 250 mg capsules include croscarmellose sodium, magnesium stearate, povidone (K-90) and pregelatinized starch. The capsule shells contain black iron oxide, FD&C blue #2, gelatin, red iron oxide, silicon dioxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.

Inactive ingredients in CELLCEPT 500 mg tablets include croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone (K-90), and Opadry^® lavender Y-5R-10272-A (hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol 400, FD&C Blue No. 2 aluminum lake [indigo carmine aluminum lake], and red iron oxide).

Inactive ingredients in CELLCEPT Oral Suspension include aspartame, citric acid anhydrous, colloidal silicon dioxide, methylparaben, mixed fruit flavor, sodium citrate dihydrate, sorbitol, soybean lecithin, and xanthan gum.

CELLCEPT Intravenous is the hydrochloride salt of MMF. The chemical name for the hydrochloride salt of MMF is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate hydrochloride. It has an empirical formula of C₂₃H₃₁NO₇ HCl and a molecular weight of 469.96.

CELLCEPT Intravenous is available as a sterile white to off-white lyophilized powder in single-dose vials containing MMF hydrochloride for administration by intravenous infusion only. Each vial contains 500 mg of mycophenolate mofetil equivalent to 542 mg of mycophenolate mofetil hydrochloride. The inactive ingredients are polysorbate 80, 25 mg, and citric acid, 5 mg. Sodium hydroxide or hydrochloric acid may have been used in the manufacture of CELLCEPT Intravenous to adjust the pH. Reconstitution and dilution with 5% Dextrose Injection USP yields a slightly yellow solution of MMF, 6 mg/mL [see Dosage and Administration (2.6)].

During treatment with CELLCEPT, the use of live attenuated vaccines should be avoided (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines) and patients should be advised that vaccinations may be less effective. Advise patients to discuss with the physician before seeking any immunizations.

Safety and effectiveness have been established in pediatric patients 3 months and older for the prophylaxis of organ rejection of allogenic kidney, heart or liver transplants.

Clinical studies of CELLCEPT 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 geriatric and younger patients. In general, dose selection for a geriatric 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)].

Inform patients that CELLCEPT 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 (5.9)].

Advise males of childbearing potential not to donate semen during therapy and for 90 days following discontinuation of CELLCEPT [see Warnings and Precautions (5.13)].

CELLCEPT is contraindicated in patients with a history of hypersensitivity, including anaphylaxis, to mycophenolate mofetil (MMF), mycophenolic acid (MPA) or any component of the drug product [see Warnings and Precautions (5.8)]. CELLCEPT Intravenous is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN).

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

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

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)]
• Acute Inflammatory Syndrome Associated with Mycophenolate Products [see Warnings and Precautions (5.7)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.8)]

• See FPI for drugs that may interfere with systemic exposure and reduce CELLCEPT efficacy: antacids with magnesium or aluminum hydroxide, proton pump inhibitors, drugs that interfere with enterohepatic recirculation, telmisartan, calcium-free phosphate binders. (7.1)
• CELLCEPT may reduce effectiveness of oral contraceptives. Use of additional barrier contraceptive methods is recommended. (7.2)
• See FPI for other important drug interactions. (7)

Advise patients not to donate blood during therapy and for at least 6 weeks following discontinuation of CELLCEPT [see Warnings and Precautions (5.12)].

Read this Instructions for Use before you take or give CELLCEPT for the first time and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

Important:

• Always use the oral dispenser provided with CELLCEPT Oral Suspension to make sure you measure the right amount of medicine. If your CELLCEPT Oral Suspension does not come with the oral dispenser, contact your pharmacist.
• Call your pharmacist if your oral dispenser is lost or damaged.
• Your pharmacist will write the expiration date on your CELLCEPT Oral Suspension bottle label. Do not use CELLCEPT after the expiration date.
• Ask your doctor or pharmacist if you have any questions or are unsure about how to take or give the right amount of medicine.
• The CELLCEPT Oral Suspension should not be mixed with any type of liquids before taking or giving the dose.
• Do not let the CELLCEPT Oral Suspension come in contact with the skin. If this happens, wash the skin well with soap and water. If the CELLCEPT Oral Suspension gets in the eyes, rinse the eyes with plain water.
• If you spill any CELLCEPT Oral Suspension, wipe it up using paper towels wet with water. Put the child-resistant bottle cap back on the bottle and wipe the outside of the bottle with wet paper towels.

Supplies needed to take or give a dose of CELLCEPT Oral Suspension:

To take or give a dose of CELLCEPT Oral Suspension, you will need the bottle of medicine and the oral dispenser provided with the medicine (See Figure 1 ). Your pharmacist will insert the bottle adapter in the CELLCEPT Oral Suspension bottle. Do not remove the bottle adapter from the bottle.

Taking or giving a dose of CELLCEPT Oral Suspension:

How should I store CELLCEPT Oral Suspension?

• Store the CELLCEPT Oral Suspension at room temperature between 59°F to 86°F (15°C to 30°C), for up to 60 days. You can also store the CELLCEPT Oral Suspension in the refrigerator between 36°F to 46°F (2°C to 8°C). )
• Do not freeze.

Keep CELLCEPT Oral Suspension and all medicines out of the reach of children.

Distributed by:

Genentech USA, Inc.

A Member of the Roche Group

1 DNA Way

South San Francisco, CA 94080-4990

^©2022 Genentech, Inc. All rights reserved.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Revised: August 2022

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

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)].

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 [see Clinical Studies (14.1)], heart [see Clinical Studies (14.2)] or liver transplants [see Clinical Studies (14.3)], in combination with other immunosuppressants.

Mycophenolate mofetil (MMF) is absorbed following oral administration and hydrolyzed to mycophenolic acid (MPA), the active metabolite. MPA is a selective uncompetitive inhibitor of the two isoforms (type I and type II) of inosine monophosphate dehydrogenase (IMPDH) leading to inhibition of the de novo pathway of guanosine nucleotide synthesis and blocks DNA synthesis. The mechanism of action of MPA is multifaceted and includes effects on cellular checkpoints responsible for metabolic programming of lymphocytes. MPA shifts transcriptional activities in lymphocytes from a proliferative state to catabolic processes. In vitro studies suggest that MPA modulates transcriptional activities in human CD4⁺ T-lymphocytes by suppressing the Akt/mTOR and STAT5 pathways that are relevant to metabolism and survival, leading to an anergic state of T-cells whereby the cells become less responsive to antigenic stimulation. Additionally, MPA enhanced the expression of negative co-stimulators such as CD70, PD-1, CTLA-4, and transcription factor FoxP3 as well as decreased the expression of positive co-stimulators CD27 and CD28.

MPA decreases proliferative responses of T- and B-lymphocytes to both mitogenic and allo-antigenic stimulation, antibody responses, as well as the production of cytokines from lymphocytes and monocytes such as GM-CSF, IFN-ɣ, IL-17, and TNF-α. Additionally, 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.

Overall, the effect of MPA is cytostatic and reversible.

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)].

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 CELLCEPT 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 CELLCEPT and AZA with respect to biopsy-proven rejection with hemodynamic compromise.
• Survival: CELLCEPT was shown to be at least as effective as AZA in preventing death or re-transplantation at 1 year (see Table 15 ).

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 CELLCEPT 1 g twice daily intravenously for up to 14 days followed by CELLCEPT 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, CELLCEPT 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 16 ).

Mycophenolate mofetil (MMF) has demonstrated teratogenic effects in humans [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. CELLCEPT tablets should not be crushed and CELLCEPT capsules should not be opened or crushed. Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in CELLCEPT capsules, CELLCEPT Oral Suspension (before or after constitution), or CELLCEPT Intravenous (during or after preparation) [see Dosage and Administration (2.6)]. Follow applicable special handling and disposal procedures ¹.

• Blood Dyscrasias (Neutropenia, Red Blood Cell Aplasia): Monitor with blood tests; consider treatment interruption or dose reduction. (5.4)
• Gastrointestinal Complications: Monitor for complications such as bleeding, ulceration and perforations, particularly in patients with underlying gastrointestinal disorders. (5.5)
• Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency: Avoid use of CELLCEPT. (5.6)
• Acute Inflammatory Syndrome Associated with Mycophenolate Products: Monitor for this paradoxical inflammatory reaction. (5.7)
• Hypersensitivity Reactions: Discontinue CELLCEPT; treat and monitor until signs and symptoms resolve. (5.8)
• Immunizations: Avoid live attenuated vaccines. (5.9)
• Local Reactions with Rapid Intravenous Administration: CELLCEPT Intravenous must not be administered by rapid or bolus intravenous injection. (5.10)
• Phenylketonurics: Oral suspension contains aspartame. (5.11)
• Blood Donation: Avoid during therapy and for 6 weeks thereafter. (5.12)
• Semen Donation: Avoid during therapy and for 90 days thereafter. (5.13)
• Potential Impairment on Driving and Use of Machinery: CELLCEPT may affect ability to drive or operate machinery. (5.15)

• 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)
• Reduce or interrupt dosing in the event of neutropenia. (2.5)
• See full prescribing information (FPI) for: adjustments for renal impairment and neutropenia (2.5), preparation of oral suspension and IV solution. (2.6)

CELLCEPT is available in the following dosage forms and strengths:

The following adverse reactions have been identified during post-approval use of CELLCEPT. 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.
• Cardiovascular: Venous thrombosis has been reported in patients treated with CELLCEPT administered intravenously.
• 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 CELLCEPT in combination with other immunosuppressive agents [see Warnings and Precautions (5.4)].
• Immune: Hypersensitivity reactions, including anaphylaxis and angioedema [see Warnings and Precautions (5.8)], 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 CELLCEPT.
• Vascular: Lymphocele

• 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)

Postmarketing cases of hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with CELLCEPT. These reactions generally occurred within hours to the next day after initiating CELLCEPT. If signs or symptoms of hypersensitivity reaction occur, discontinue CELLCEPT; treat and monitor until symptoms resolve [see Contraindications (4)].

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 adult patients received CELLCEPT 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 CELLCEPT in de novo kidney (3) heart (1) and liver (1) transplant patients [see Clinical Studies (14.1, 14.2, and 14.3)].

Inform patients of the potential risk of hypersensitivity reactions. Advise patients to stop taking CELLCEPT and seek immediate medical attention if signs or symptoms of hypersensitivity reaction occur (such as swelling of face, lips, tongue, or throat; difficulty breathing or swallowing) [see Warnings and Precautions (5.8)].

Inform patients that acute inflammatory reactions have been reported in some patients who received CELLCEPT. Some reactions were severe, requiring hospitalization. Advise patients to contact their physician if they develop fever, joint stiffness, joint pain or muscle pains [see Warnings and Precautions (5.7)].

• Advise patients not to crush CELLCEPT tablets and not to open CELLCEPT capsules.
• Advise patients to avoid inhalation or contact of the skin or mucous membranes with the powder contained in CELLCEPT capsules and with the 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.
• 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 CELLCEPT at the usual times.

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

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)].

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 [see Warnings and Precautions (5.3)].

Inform patients that CELLCEPT 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)].

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

Phenylalanine can be harmful to patients with phenylketonuria (PKU). CELLCEPT Oral Suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine/mL suspension). Before prescribing CELLCEPT Oral Suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including CELLCEPT.

NDC 0004-0298-09

CellCept^® Intravenous

(mycophenolate mofetil for injection)

500 mg

FOR INTRAVENOUS INFUSION ONLY.

Each single-dose vial contains the equivalent of 500 mg mycophenolate mofetil (equivalent to 542 mg of

mycophenolate mofetil hydrochloride), 25 mg polysorbate 80 and 5 mg citric acid. Sodium hydroxide or

hydrochloric acid may have been used to adjust pH.

Attention Pharmacist: Dispense the accompanying Medication Guide to each patient. For additional

Medication Guides, call 1-800-617-8191 or visit www.gene.com/gene/products/information/cellcept.

Rx only

4 Single-Dose Vials

Genentech

10215811

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.

NDC 0004-0261-29

CellCept^®

Oral Suspension

(mycophenolate

mofetil for oral

suspension)

200 mg/mL

Each mL contains 200 mg mycophenolate

mofetil after constitution.

Attention Pharmacist: Dispense the accompanying

Medication Guide to each patient. For additional

Medication Guides, call 1-800-617-8191 or visit

www.gene.com/gene/products/information/cellcept.

Rx only

Genentech

10225425

• 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 broad-spectrum sunscreen with high protection factor.

NDC 0004-0260-43

CellCept^®

(mycophenolate

mofetil tablets)

500 mg

Each tablet contains

500 mg mycophenolate mofetil.

Rx only

Attention Pharmacist: Dispense the

accompanying Medication Guide to each

patient. For additional Medication Guides call

1-800-617-8191 or visit www.gene.com/gene/

products/information/cellcept.

500 tablets

Genentech

10235320

Advise patients that CELLCEPT 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 CELLCEPT [see Warnings and Precautions (5.15)].

NDC 0004-0259-43

CellCept^®

(mycophenolate

mofetil capsules)

250 mg

Each capsule contains

250 mg mycophenolate mofetil.

Rx only

Attention Pharmacist: Dispense the

accompanying Medication Guide to each

patient. For additional Medication Guides call

1-800-617-8191 or visit www.gene.com/gene/

products/information/cellcept.

500 capsules

Genentech

10235316

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 0.2 times the recommended clinical dose (2 g/day) in renal transplant patients and 0.15 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 0.035 times the recommended clinical dose in kidney transplant patients and 0.025 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 0.05 times the recommended clinical dose in renal transplant patients and 0.03 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 0.01 times the recommended clinical dose in renal transplant patients and 0.005 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.

CELLCEPT Intravenous solution must not be administered by rapid or bolus intravenous injection as rapid infusion increases the risk of local adverse reactions such as phlebitis and thrombosis [see Adverse Reactions (6.1)].

CELLCEPT 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 CELLCEPT [see Adverse Reactions (6.1)].

Severe neutropenia [absolute neutrophil count (ANC) <0.5 × 10³/µL] developed in transplant patients receiving CELLCEPT 3 g daily [see Adverse Reactions (6.1)]. Patients receiving CELLCEPT 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 CELLCEPT itself, concomitant medications, viral infections, or a combination of these causes. If neutropenia develops (ANC <1.3 × 10³/µL), dosing with CELLCEPT should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately [see Dosage and Administration (2.5)].

Patients receiving CELLCEPT 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 CELLCEPT in combination with other immunosuppressive agents. In some cases, PRCA was found to be reversible with dose reduction or cessation of CELLCEPT therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk.

• 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)].

Acute inflammatory syndrome (AIS) has been reported with the use of MMF and mycophenolate products, and some cases have resulted in hospitalization. AIS is a paradoxical pro-inflammatory reaction characterized by fever, arthralgias, arthritis, muscle pain and elevated inflammatory markers including, C-reactive protein and erythrocyte sedimentation rate, without evidence of infection or underlying disease recurrence. Symptoms occur within weeks to months of initiation of treatment or a dose increase. After discontinuation, improvement of symptoms and inflammatory markers are usually observed within 24 to 48 hours.

Monitor patients for symptoms and laboratory parameters of AIS when starting treatment with mycophenolate products or when increasing the dosage. Discontinue treatment and consider other treatment alternatives based on the risk and benefit for the patient.

A variety of drugs have potential to alter systemic MPA exposure when co-administered with CELLCEPT. 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.

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