CellCept

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if Cellcept is excreted in human breast milk or if it will harm your nursing baby. 

Mycophenolate mofetil is an immunosuppressant. Your body may "reject" an organ transplant when the immune system treats the new organ as an invader. An immunosuppressant helps to prevent this rejection.

Mycophenolate mofetil is used to prevent your body from rejecting a kidney, liver, or heart transplant. This medicine is usually given with cyclosporine and a steroid medicine.

Mycophenolate mofetil may also be used for purposes not listed in this medication guide.

You should not use this medicine if you are allergic to mycophenolate mofetil, mycophenolic acid (Myfortic), or to an ingredient called Polysorbate 80.

Using mycophenolate mofetil may increase your risk of developing serious infections or other types of cancer, such as lymphoma or skin cancer. Ask your doctor about your specific risk.

To make sure mycophenolate mofetil is safe for you, tell your doctor if you have:

• a stomach ulcer or other disorder of your stomach or intestines;

• a viral, bacterial, or fungal infection; or

• a rare inherited enzyme deficiency such as Lesch-Nyhan syndrome or Kelley-Seegmiller syndrome.

This medicine can cause a miscarriage or birth defects, especially during the first 3 months of pregnancy. You will need to have a negative pregnancy test before and during treatment with mycophenolate mofetil. You must prevent pregnancy before and during your treatment with mycophenolate mofetil, and for at least 6 weeks after your treatment ends.

If you are a woman of child-bearing potential, you will be required to use birth control. You have child-bearing potential (even if you are not sexually active) from the age of puberty until you have been in menopause for at least 12 months in a row.

Mycophenolate mofetil can make hormonal birth control (pills, injections, implants, skin patches, or vaginal rings) less effective. If you use hormonal birth control, you must also use a back-up barrier method (such as a cervical sponge, a male or female condom, or a diaphragm or cervical cap used together with spermicide).

You do not need to use additional birth control if you use an intrauterine device (IUD), if you have had a tubal ligation, or if your sexual partner has had a vasectomy.

This medicine comes with patient instructions about the most effective non-hormonal forms of birth control to use. Follow these directions carefully. Ask your doctor if you have any questions.

If a pregnancy occurs during treatment, do not stop using mycophenolate mofetil. Call your doctor for instructions. Also call the Mycophenolate Pregnancy Registry (1-800-617-8191).

Mycophenolate mofetil is sometimes given to pregnant women. Your doctor will decide whether you should use this medicine if you are pregnant or planning to become pregnant. Although this medicine can affect pregnancy or fertility, it is sometimes given to women who are unable to use other needed transplant medications.

It is not known whether mycophenolate mofetil passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

The liquid form may contain phenylalanine. Talk to your doctor before using this form of mycophenolate mofetil if you have phenylketonuria (PKU).

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using mycophenolate mofetil. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Avoid taking an antacid together with mycophenolate mofetil. If you also take sevelamer, take it at least 2 hours after you take oral mycophenolate mofetil.

Avoid exposure to sunlight or tanning beds. Mycophenolate mofetil can increase your risk of developing skin cancer. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with mycophenolate mofetil, especially:

• azathioprine;

• cholestyramine;

• an antiviral medicine--acyclovir, ganciclovir, valacyclovir;

• an antibiotic--amoxicillin, ciprofloxacin, metronidazole, norfloxacin, rifampin;

• stomach acid reducers--lansoprazole (Prevacid), pantoprazole (Protonix), and others; or

• a sulfa drug (Bactrim, Septra, SMX-TMP or SMZ-TMP, and others).

This list is not complete. Other drugs may interact with mycophenolate mofetil, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

A nurse or other trained health professional will give you this medicine in a hospital. This medicine is given through a needle placed in one of your veins.

Your doctor will give you a few doses of this medicine until your condition improves, and then switch you to an oral medicine that works the same way. If you have any questions about this, talk to your doctor.

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

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

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

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

CellCept is available for oral administration as capsules containing 250 mg of mycophenolate mofetil, tablets containing 500 mg of mycophenolate mofetil, and as a powder for oral suspension, which when constituted contains 200 mg/mL mycophenolate mofetil.

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 black iron oxide, croscarmellose sodium, FD&C blue #2 aluminum lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone (K-90), red iron oxide, talc, and titanium dioxide; may also contain ammonium hydroxide, ethyl alcohol, methyl alcohol, n-butyl alcohol, propylene glycol, and shellac.

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 mycophenolate mofetil. The chemical name for the hydrochloride salt of mycophenolate mofetil 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 vials containing mycophenolate mofetil hydrochloride for administration by intravenous infusion only. Each vial of CellCept Intravenous contains the equivalent of 500 mg mycophenolate mofetil as the hydrochloride salt. The inactive ingredients are polysorbate 80, 25 mg, and citric acid, 5 mg. Sodium hydroxide 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 mycophenolate mofetil, 6 mg/mL. (For detailed method of preparation, see DOSAGE AND ADMINISTRATION).

Adults

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

Renal Transplant

The three renal studies compared two dose levels of oral CellCept (1 g bid and 1.5 g bid) with azathioprine (2 studies) or placebo (1 study) when administered in combination with cyclosporine (Sandimmune®) and corticosteroids to prevent acute rejection episodes. One study also included antithymocyte globulin (ATGAM®) induction therapy. These studies are described by geographic location of the investigational sites. One study was conducted in the USA at 14 sites, one study was conducted in Europe at 20 sites, and one study was conducted in Europe, Canada, and Australia at a total of 21 sites.

The primary efficacy endpoint was the proportion of patients in each treatment group who experienced treatment failure within the first 6 months after transplantation (defined as biopsy-proven acute rejection on treatment or the occurrence of death, graft loss or early termination from the study for any reason without prior biopsy-proven rejection). CellCept, when administered with antithymocyte globulin (ATGAM®) induction (one study) and with cyclosporine and corticosteroids (all three studies), was compared to the following three therapeutic regimens: (1) antithymocyte globulin (ATGAM®) induction/azathioprine/cyclosporine/corticosteroids, (2) azathioprine/cyclosporine/corticosteroids, and (3) cyclosporine/corticosteroids.

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

The cumulative incidence of 12-month graft loss or patient death is presented below. No advantage of CellCept with respect to graft loss or patient death was established. Numerically, patients receiving CellCept 2 g/day and 3 g/day experienced a better outcome than controls in all three studies; patients receiving CellCept 2 g/day experienced a better outcome than CellCept 3 g/day in two of the three studies. Patients in all treatment groups who terminated treatment early were found to have a poor outcome with respect to graft loss or patient death at 1 year.

One open-label, safety and pharmacokinetic study of CellCept oral suspension 600 mg/m2 bid (up to 1 g bid) in combination with cyclosporine and corticosteroids was performed at centers in the US (9), Europe (5) and Australia (1) in 100 pediatric patients (3 months to 18 years of age) for the prevention of renal allograft rejection. CellCept was well tolerated in pediatric patients (see ADVERSE REACTIONS), and the pharmacokinetics profile was similar to that seen in adult patients dosed with 1 g bid CellCept capsules (see CLINICAL PHARMACOLOGY: Pharmacokinetics). The rate of biopsy-proven rejection was similar across the age groups (3 months to <6 years, 6 years to <12 years, 12 years to 18 years). The overall biopsy-proven rejection rate at 6 months was comparable to adults. The combined incidence of graft loss (5%) and patient death (2%) at 12 months posttransplant was similar to that observed in adult renal transplant patients.

Cardiac Transplant

A double-blind, randomized, comparative, parallel-group, multicenter study in primary cardiac transplant recipients was performed at 20 centers in the United States, 1 in Canada, 5 in Europe and 2 in Australia. The total number of patients enrolled was 650; 72 never received study drug and 578 received study drug. Patients received CellCept 1.5 g bid (n=289) or azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine (Sandimmune® or Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The two primary efficacy endpoints were: (1) the proportion of patients who, after transplantation, had at least one endomyocardial biopsy-proven rejection with hemodynamic compromise, or were retransplanted or died, within the first 6 months, and (2) the proportion of patients who died or were retransplanted during the first 12 months following transplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection for up to 6 months and for the occurrence of death for 1 year.

(1) Rejection: No difference was established between CellCept and azathioprine (AZA) with respect to biopsy-proven rejection with hemodynamic compromise.

(2) Survival: CellCept was shown to be at least as effective as AZA in preventing death or retransplantation at 1 year (see Table 6).

Hepatic Transplant

A double-blind, randomized, comparative, parallel-group, multicenter study in primary hepatic transplant recipients was performed at 16 centers in the United States, 2 in Canada, 4 in Europe and 1 in Australia. The total number of patients enrolled was 565. Per protocol, patients received CellCept 1 g bid intravenously for up to 14 days followed by CellCept 1.5 g bid orally or azathioprine 1 to 2 mg/kg/day intravenously followed by azathioprine 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The actual median oral dose of azathioprine on study was 1.5 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) initially and 1.26 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) at 12 months. The two primary endpoints were: (1) the proportion of patients who experienced, in the first 6 months posttransplantation, one or more episodes of biopsy-proven and treated rejection or death or retransplantation, and (2) the proportion of patients who experienced graft loss (death or retransplantation) during the first 12 months posttransplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection and for the occurrence of graft loss (death or retransplantation) for 1 year.

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

Pregnancy Exposure Prevention and Planning

Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning.

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

Pregnancy Testing

To prevent unplanned exposure during pregnancy, females of reproductive potential should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL immediately before starting 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, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations.

Contraception

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

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

Pregnancy Planning

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

Gastrointestinal Disorders

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

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

Patients with Renal Impairment

Subjects with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) who have received single doses of CellCept showed higher plasma MPA and MPAG AUCs relative to subjects with lesser degrees of renal impairment or normal healthy volunteers. No data are available on the safety of long-term exposure to these levels of MPAG. Doses of CellCept greater than 1 g administered twice a day to renal transplant patients should be avoided and they should be carefully observed (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).

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

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

Infections in Cardiac Transplant Patients

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

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

Concomitant Medications

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

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

Patients with HGPRT Deficiency

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

Immunizations

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

Phenylketonurics

CellCept Oral Suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine/mL suspension). Therefore, care should be taken if CellCept Oral Suspension is administered to patients with phenylketonuria.

Information for Patients

See Medication Guide

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

Laboratory Tests

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

Drug Interactions

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

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

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

Coadministration of PPIs (e.g., lansoprazole, pantoprazole) in single doses to healthy volunteers and multiple doses to transplant patients receiving CellCept has been reported to reduce the exposure to mycophenolic acid (MPA). An approximate reduction of 30 to 70% in the Cmax and 25% to 35% in the AUC of MPA has been observed, possibly due to a decrease in MPA solubility at an increased gastric pH. The clinical impact of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and CellCept. Because clinical relevance has not been established, PPIs should be used with caution when coadministered to transplant patients being treated with CellCept.

Following single-dose administration of 1.5 g mycophenolate mofetil to 12 healthy volunteers pretreated with 4 g tid of cholestyramine for 4 days, MPA AUC decreased approximately 40%. This decrease is consistent with interruption of enterohepatic recirculation which may be due to binding of recirculating MPAG with cholestyramine in the intestine. Some degree of enterohepatic recirculation is also anticipated following intravenous administration of CellCept. Therefore, CellCept is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation.

Cyclosporine (Sandimmune®) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 g bid of mycophenolate mofetil in 10 stable renal transplant patients. The mean (±SD) AUC(0-12h) and Cmax of cyclosporine after 14 days of multiple doses of mycophenolate mofetil were 3290 (±822) ng∙h/mL and 753 (±161) ng/mL, respectively, compared to 3245 (±1088) ng∙h/mL and 700 (±246) ng/mL, respectively, 1 week before administration of mycophenolate mofetil.

Cyclosporine A interferes with MPA enterohepatic recirculation. In renal transplant patients, mean MPA exposure (AUC0-12h) was approximately 30-50% greater when mycophenolate mofetil is administered without cyclosporine compared with when mycophenolate mofetil is coadministered with cyclosporine. This interaction is due to cyclosporine inhibition of multidrug-resistance-associated protein 2 (MRP-2) transporter in the biliary tract, thereby preventing the excretion of MPAG into the bile that would lead to enterohepatic recirculation of MPA. This information should be taken into consideration when MMF is used without cyclosporine; changes in MPA exposure should be expected when switching patients from cyclosporine A to one of the immunosuppressants which do not interfere with MPA's enterohepatic cycle (e.g., tacrolimus; belatacept).

Concommitant administration of telmisartan and CellCept resulted in an approximately 30% decrease in mycophenolic acid (MPA) concentrations. Telmisartan changes MPA's elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results in an enhanced UGT1A9 expression and activity.

Following single-dose administration to 12 stable renal transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 g) and intravenous ganciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and Cmax (n=10) were 54.3 (±19.0) µg∙h/mL and 11.5 (±1.8) µg/mL, respectively, after coadministration of the two drugs, compared to 51.0 (±17.0) µg∙h/mL and 10.6 (±2.0) µg/mL, respectively, after administration of intravenous ganciclovir alone. The mean (±SD) AUC and Cmax of MPA (n=12) after coadministration were 80.9 (±21.6) µg∙h/mL and 27.8 (±13.9) µg/mL, respectively, compared to values of 80.3 (±16.4) µg∙h/mL and 30.9 (±11.2) µg/mL, respectively, after administration of mycophenolate mofetil alone. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the two drugs will compete for tubular secretion and thus further increases in concentrations of both drugs may occur. In patients with renal impairment in which MMF and ganciclovir or its prodrug (eg, valganciclovir) are coadministered, patients should be monitored carefully.

A study of coadministration of CellCept (1 g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) was conducted in 18 women with psoriasis over 3 consecutive menstrual cycles. Mean AUC(0-24h) was similar for ethinylestradiol and 3-keto desogestrel; however, mean levonorgestrel AUC(0-24h) significantly decreased by about 15%. There was large inter-patient variability (%CV in the range of 60% to 70%) in the data, especially for ethinylestradiol. Mean serum levels of LH, FSH and progesterone were not significantly affected. CellCept may not have any influence on the ovulation-suppressing action of the studied oral contraceptives. It is recommended to coadminister CellCept with hormonal contraceptives (eg, birth control pill, transdermal patch, vaginal ring, injection, and implant) with caution and additional barrier contraceptive methods must be used (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning).

Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA Cmax and AUC0-12h by 36% and 26% respectively. This data suggest that sevelamer and other calcium free phosphate binders should not be administered simultaneously with CellCept. Alternatively, it is recommended that sevelamer and other calcium free phosphate binders preferentially could be given 2 hours after CellCept intake to minimize the impact on the absorption of MPA.

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

Following single-dose administration of mycophenolate mofetil (1 g) to 11 healthy volunteers on day 4 of a 5 day course of a combination of norfloxacin and metronidazole, the mean MPA AUC0-48h was significantly reduced by 33% compared to the administration of mycophenolate mofetil alone (p<0.05). Therefore, CellCept is not recommended to be given with the combination of norfloxacin and metronidazole. There was no significant effect on mean MPA AUC0-48h when mycophenolate mofetil was concomitantly administered with norfloxacin or metronidazole separately. The mean (±SD) MPA AUC0-48h after coadministration of mycophenolate mofetil with norfloxacin or metronidazole separately was 48.3 (±24) µg∙h/mL and 42.7 (±23) µg∙h/mL, respectively, compared with 56.2 (±24) µg∙h/mL after administration of mycophenolate mofetil alone.

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

In a single heart-lung transplant patient, after correction for dose, a 67% decrease in MPA exposure (AUC0-12h) has been observed with concomitant administration of mycophenolate mofetil and rifampin. Therefore, CellCept is not recommended to be given with rifampin concomitantly unless the benefit outweighs the risk.

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

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

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week oral carcinogenicity study in mice, mycophenolate mofetil in daily doses up to 180 mg/kg was not tumorigenic. The highest dose tested was 0.5 times the recommended clinical dose (2 g/day) in renal transplant patients and 0.3 times the recommended clinical dose (3 g/day) in cardiac transplant patients when corrected for differences in body surface area (BSA). In a 104-week oral carcinogenicity study in rats, mycophenolate mofetil in daily doses up to 15 mg/kg was not tumorigenic. The highest dose was 0.08 times the recommended clinical dose in renal transplant patients and 0.05 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. While these animal doses were lower than those given to patients, they were maximal in those species and were considered adequate to evaluate the potential for human risk (see WARNINGS).

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

Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. This dose represents 0.1 times the recommended clinical dose in renal transplant patients and 0.07 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (principally of the head and eyes) in the first generation offspring in the absence of maternal toxicity. This dose was 0.02 times the recommended clinical dose in renal transplant patients and 0.01 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.

Pregnancy

See WARNINGS section.

Use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney, and nervous system. In animal studies, congenital malformations and pregnancy loss occurred when pregnant rats and rabbits received mycophenolic acid at dose multiples similar to and less than clinical doses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

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

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

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

Nursing Mothers

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

Pediatric Use

Based on pharmacokinetic and safety data in pediatric patients after renal transplantation, the recommended dose of CellCept oral suspension is 600 mg/m2 bid (up to a maximum of 1 g bid). Also see CLINICAL PHARMACOLOGY, CLINICAL STUDIES, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION.

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

Geriatric Use

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

CellCept (mycophenolate mofetil capsules) 250 mg

Blue-brown, two-piece hard gelatin capsules, printed in black with "CellCept 250" on the blue cap and "Roche" on the brown body. Supplied in the following presentations:

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

CellCept (mycophenolate mofetil tablets) 500 mg

Lavender-colored, caplet-shaped, film-coated tablets printed in black with "CellCept 500" on one side and "Roche" on the other. Supplied in the following presentations:

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Dispense in light-resistant containers, such as the manufacturer's original containers.

CellCept Oral Suspension (mycophenolate mofetil for oral suspension)

Supplied as a white to off-white powder blend for constitution to a white to off-white mixed-fruit flavor suspension. Supplied in the following presentation:

Store dry powder at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Store constituted suspension at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) for up to 60 days. Storage in a refrigerator at 2° to 8°C (36° to 46°F) is acceptable. Do not freeze.

CellCept Intravenous (mycophenolate mofetil hydrochloride for injection)

Supplied in a 20 mL, sterile vial containing the equivalent of 500 mg mycophenolate mofetil as the hydrochloride salt in cartons of 4 vials:

NDC Number

NDC 0004-0298-09

Store powder and reconstituted/infusion solutions at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

PI Revised: July 2015

Get emergency medical help if you have any of these signs of an allergic reaction to this medication: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

CellCept can lower blood cells that help your body fight infection. This can lead to serious conditions including herpes, shingles, hepatitis, blood or tissue infections, severe brain infection causing disability or death, or a viral infection causing kidney transplant failure. Call your doctor right away if you have:

• diarrhea, stomach pain, nausea, vomiting, weight loss;

• weakness on one side of your body, loss of muscle control;

• confusion, thinking problems, loss of interest in things that normally interest you;

• fever, night sweats, tiredness, painful mouth sores, flu symptoms;

• runny or stuffy nose, cough, sore throat, ear pain, headache;

• pale skin, feeling light-headed or short of breath, easy bruising or bleeding (nosebleeds, bleeding gums);

• bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

• pain or burning when you urinate;

• swelling, warmth, redness, or oozing around a skin wound; or

• a new bump or lesion on your skin, or a mole that has changed in size or color.

Common CellCept side effects may include:

• nausea, vomiting, diarrhea;

• swelling in your ankles or feet; or

• high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, shortness of breath).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

AU: Use is contraindicated. UK, US: Use is not recommended. AU TGA pregnancy category: D US FDA pregnancy category: D Comments: -This drug can harm a fetus. -Females and males of reproductive potential should be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and should be counseled regarding pregnancy prevention and planning. -Prior to starting therapy with this drug, female patients of childbearing potential should have 2 negative serum or urine pregnancy tests with a sensitivity of at least 25 milli-international units per milliliter (mIU/mL). The second test should be performed 8 to 10 days after the first one and immediately before starting therapy. Repeat pregnancy tests should be performed during routine follow-up visits. -Women of child bearing potential should use 2 reliable forms of contraception simultaneously, including at least one highly effective method, before beginning therapy, during therapy, and for 6 weeks following discontinuation of therapy, unless abstinence is the chosen method of contraception. -Sexually active men should use condoms during treatment and for at least 90 days after cessation of treatment. Condom use applies for both reproductively competent and vasectomized men, because the risks associated with the transfer of seminal fluid also apply to men who have had a vasectomy. -Female partners of male patients should use highly effective contraception during treatment and for a total of 90 days after the last dose.

-Use of this drug 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. -If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. -Healthcare professionals and patients should be aware that this drug reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness. AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details. US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.