CellCept^®
(mycophenolate mofetil capsules)
(mycophenolate mofetil tablets)
CellCept^® Oral Suspension
(mycophenolate mofetil for oral suspension)
CellCept^® Intravenous
(mycophenolate mofetil hydrochloride for injection)

This product information is intended for United States residents and on-screen viewing only.
Before prescribing, please refer to printed complete product information.

Complete Product Information

WARNING DESCRIPTION CLINICAL PHARMACOLOGY CLINICAL STUDIES INDICATIONS AND USAGE CONTRAINDICATIONS WARNINGS

PRECAUTIONS ADVERSE REACTIONS OVERDOSAGE DOSAGE AND ADMINISTRATION HANDLING AND DISPOSAL HOW SUPPLIED

 

WARNING: Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal, cardiac or hepatic transplant patients should use CellCept. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

DESCRIPTION: 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 C₂₃H₃₁NO_7, 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.)

 

CLINICAL PHARMACOLOGY:

 

Mechanism of Action: Mycophenolate mofetil has been demonstrated in experimental animal models to prolong the survival of allogeneic transplants (kidney, heart, liver, intestine, limb, small bowel, pancreatic islets, and bone marrow).

Mycophenolate mofetil has also been shown to reverse ongoing acute rejection in the canine renal and rat cardiac allograft models. Mycophenolate mofetil also inhibited proliferative arteriopathy in experimental models of aortic and heart allografts in rats, as well as in primate cardiac xenografts. Mycophenolate mofetil was used alone or in combination with other immunosuppressive agents in these studies. Mycophenolate mofetil has been demonstrated to inhibit immunologically mediated inflammatory responses in animal models and to inhibit tumor development and prolong survival in murine tumor transplant models.

 

Mycophenolate mofetil is rapidly absorbed following oral administration and hydrolyzed to form MPA, which is the active metabolite. MPA is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation. Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes. MPA also suppresses antibody formation by B-lymphocytes. 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. Mycophenolate mofetil did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of these events to DNA synthesis and proliferation.

 

Pharmacokinetics: Following oral and intravenous administration, mycophenolate mofetil undergoes rapid and complete metabolism to MPA, the active metabolite. Oral absorption of the drug is rapid and essentially complete. MPA is metabolized to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. The parent drug, mycophenolate mofetil, can be measured systemically during the intravenous infusion; however, shortly (about 5 minutes) after the infusion is stopped or after oral administration, MMF concentration is below the limit of quantitation (0.4 µg/mL).

Absorption: In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil (based on MPA AUC) was 94%. The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in renal transplant patients receiving multiple doses of mycophenolate mofetil up to a daily dose of 3 g (see table below on pharmacokinetic parameters).

 

Food (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g bid to renal transplant patients. However, MPA C_max was decreased by 40% in the presence of food (see DOSAGE AND ADMINISTRATION).

 

Distribution: The mean (±SD) apparent volume of distribution of MPA in 12 healthy volunteers is approximately 3.6 (±1.5) and 4.0 (±1.2) L/kg following intravenous and oral administration, respectively. MPA, at clinically relevant concentrations, is 97% bound to plasma albumin. MPAG is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable renal transplant patients; however, at higher MPAG concentrations (observed in patients with renal impairment or delayed graft function), the binding of MPA may be reduced as a result of competition between MPAG and MPA for protein binding. Mean blood to plasma ratio of radioactivity concentrations was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into the cellular fractions of blood.

In vitro studies to evaluate the effect of other agents on the binding of MPA to human serum albumin (HSA) or plasma proteins showed that salicylate (at 25 mg/dL with HSA) and MPAG (at > 460 µg/mL with plasma proteins) increased the free fraction of MPA. At concentrations that exceeded what is encountered clinically, cyclosporine, digoxin, naproxen, prednisone, propranolol, tacrolimus, theophylline, tolbutamide, and warfarin did not increase the free fraction of MPA. MPA at concentrations as high as 100 µg/mL had little effect on the binding of warfarin, digoxin or propranolol, but decreased the binding of theophylline from 53% to 45% and phenytoin from 90% to 87%.

 

Metabolism: Following oral and intravenous dosing, mycophenolate mofetil undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo, MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.

Secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to 12 hours postdose. The coadministration of cholestyramine (4 g tid) resulted in approximately a 40% decrease in the MPA AUC (largely as a consequence of lower concentrations in the terminal portion of the profile). These observations suggest that enterohepatic recirculation contributes to MPA plasma concentrations.

 

Increased plasma concentrations of mycophenolate mofetil metabolites (MPA 50% increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal insufficiency (see CLINICAL PHARMACOLOGY: Special Populations).

 

Excretion: Negligible amount of drug is excreted as MPA (<1% of dose) in the urine. Orally administered radiolabeled mycophenolate mofetil resulted in complete recovery of the administered dose, with 93% of the administered dose recovered in the urine and 6% recovered in feces. Most (about 87%) of the administered dose is excreted in the urine as MPAG. At clinically encountered concentrations, MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 µg/mL), small amounts of MPAG are removed. Bile acid sequestrants, such as cholestyramine, reduce MPA AUC by interfering with enterohepatic circulation of the drug (see OVERDOSAGE).

Mean (±SD) apparent half-life and plasma clearance of MPA are 17.9 (±6.5) hours and 193 (±48) mL/min following oral administration and 16.6 (±5.8) hours and 177 (±31) mL/min following intravenous administration, respectively.

Pharmacokinetics in Healthy Volunteers, Renal, Cardiac, and Hepatic Transplant Patients: Shown below are the mean (±SD) pharmacokinetic parameters for MPA following the administration of mycophenolate mofetil given as single doses to healthy volunteers and multiple doses to renal, cardiac, and hepatic transplant patients. In the early posttransplant period (<40 days posttransplant), renal, cardiac, and hepatic transplant patients had mean MPA AUCs approximately 20% to 41% lower and mean C_max approximately 32% to 44% lower compared to the late transplant period (3 to 6 months posttransplant).

 

Mean MPA AUC values following administration of 1 g bid intravenous mycophenolate mofetil over 2 hours to renal transplant patients for 5 days were about 24% higher than those observed after oral administration of a similar dose in the immediate posttransplant phase. In hepatic transplant patients, administration of 1 g bid intravenous CellCept followed by 1.5 g bid oral CellCept resulted in mean MPA AUC values similar to those found in renal transplant patients administered 1 g CellCept bid.

 

Pharmacokinetic Parameters for MPA [mean (±SD)] Following Administration of  Mycophenolate Mofetil to Healthy Volunteers (Single Dose), Renal, Cardiac,  and Hepatic Transplant Patients (Multiple Doses)

 

	Dose/Route	Tmax (h)	Cmax (µg/mL)	Total AUC (µg•h/mL)
Healthy Volunteers (single dose)	1 g/oral	0.80 (±0.36) (n=129)	24.5 (±9.5) (n=129)	63.9 (±16.2) (n=117)
Renal Transplant Patients (bid dosing) Time After Transplantation	Dose/Route	Tmax (h)	Cmax (µg/mL)	Interdosing Interval AUC(0-12h) (µg•h/mL)
5 days	1 g/iv	1.58 (±0.46) (n=31)	12.0 (±3.82) (n=31)	40.8 (±11.4) (n=31)
6 days	1 g/oral	1.33 (±1.05) (n=31)	10.7 (±4.83) (n=31)	32.9 (±15.0) (n=31)
Early (<40 days)	1 g/oral	1.31 (±0.76) (n=25)	8.16 (±4.50) (n=25)	27.3 (±10.9) (n=25)
Early (<40 days)	1.5 g/oral	1.21 (±0.81) (n=27)	13.5 (±8.18) (n=27)	38.4 (±15.4) (n=27)
Late (>3 months)	1.5 g/oral	0.90 (±0.24) (n=23)	24.1 (±12.1) (n=23)	65.3 (±35.4) (n=23)
Cardiac Transplant Patients (bid dosing) Time After Transplantation	Dose/Route	Tmax (h)	Cmax (µg/mL)	Interdosing Interval AUC(0-12h) (µg•h/mL)
Early (Day before discharge)	1.5 g/oral	1.8 (±1.3) (n=11)	11.5 (±6.8) (n=11)	43.3 (±20.8) (n=9)
Late (>6 months)	1.5 g/oral	1.1 (±0.7) (n=52)	20.0 (±9.4) (n=52)	54.1* (±20.4) (n=49)
Hepatic Transplant Patients (bid dosing) Time After Transplantation	Dose/Route	Tmax (h)	Cmax (µg/mL)	Interdosing Interval AUC(0-12h) (µg•h/mL)
4 to 9 days	1.0 g/iv	1.50 (± 0.517) (n=22)	17.0 (± 12.7) (n=22)	34.0 (± 17.4) (n=22)
Early (5 to 8 days)	1.5 g/oral	1.15 (± 0.432) (n=20)	13.1 (± 6.76) (n=20)	29.2 (± 11.9) (n=20)
Late (>6 months)	1.5 g/oral	1.54 (± 0.51) (n=6)	19.3 (± 11.7) (n=6)	49.3 (± 14.8) (n=6)

*AUC(0-12h) values quoted are extrapolated from data from samples collected over 4 hours.

Two 500 mg tablets have been shown to be bioequivalent to four 250 mg capsules. Five mL of the 200 mg/mL constituted oral suspension have been shown to be bioequivalent to four 250 mg capsules.

Special Populations: Shown below are the mean (±SD) pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil given as single doses to non-transplant subjects with renal or hepatic impairment.

 

Pharmacokinetic Parameters for MPA [mean (±SD)] Following Single Doses of  Mycophenolate Mofetil Capsules in Chronic Renal and Hepatic Impairment

 

Renal Impairment (no. of patients)	Dose	Tmax (h)	Cmax (µg/mL)	AUC(0-96h) (µg•h/mL)
Healthy Volunteers   GFR >80 mL/min/1.73 m2   (n=6)	1 g	0.75 (±0.27)	25.3 (±7.99)	45.0 (±22.6)
Mild Renal Impairment   GFR 50 to 80 mL/min/1.73 m2   (n=6)	1 g	0.75 (±0.27)	26.0 (±3.82)	59.9 (±12.9)
Moderate Renal Impairment   GFR 25 to 49 mL/min/1.73 m2   (n=6)	1 g	0.75 (±0.27)	19.0 (±13.2)	52.9 (±25.5)
Severe Renal Impairment   GFR <25 mL/min/1.73 m2   (n=7)	1 g	1.00 (±0.41)	16.3 (±10.8)	78.6 (±46.4)
Hepatic Impairment (no. of patients)	Dose	Tmax (h)	Cmax (µg/mL)	AUC(0-48h) (µg•h/mL)
Healthy Volunteers   (n=6)	1 g	0.63 (±0.14)	24.3 (±5.73)	29.0 (±5.78)
Alcoholic Cirrhosis   (n=18)	1 g	0.85 (±0.58)	22.4 (±10.1)	29.8 (±10.7)

Renal Insufficiency: In a single-dose study, MMF was administered as capsule or intravenous infusion over 40 minutes. Plasma MPA AUC observed after oral dosing to volunteers with severe chronic renal impairment [glomerular filtration rate (GFR) <25 mL/min/1.73 m²] was about 75% higher relative to that observed in healthy volunteers (GFR >80 mL/min/1.73 m²). In addition, the single-dose plasma MPAG AUC was 3-fold to 6-fold higher in volunteers with severe renal impairment than in volunteers with mild renal impairment or healthy volunteers, consistent with the known renal elimination of MPAG. No data are available on the safety of long-term exposure to this level of MPAG.

 

Plasma MPA AUC observed after single-dose (1 g) intravenous dosing to volunteers (n=4) with severe chronic renal impairment (GFR <25 mL/min/1.73 m²) was 62.4 µg•h/mL (±19.3). Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied (see PRECAUTIONS: General and DOSAGE AND ADMINISTRATION).

 

In patients with delayed renal graft function posttransplant, mean MPA AUC(0-12h) was comparable to that seen in posttransplant patients without delayed graft function. There is a potential for a transient increase in the free fraction and concentration of plasma MPA in patients with delayed graft function. However, dose adjustment does not appear to be necessary in patients with delayed graft function. Mean plasma MPAG AUC(0-12h) was 2-fold to 3-fold higher than in posttransplant patients without delayed graft function (see PRECAUTIONS: General and DOSAGE AND ADMINISTRATION).

 

In 8 patients with primary non-function of the organ following renal transplantation, plasma concentrations of MPAG accumulated about 6-fold to 8-fold after multiple dosing for 28 days. Accumulation of MPA was about 1-fold to 2-fold.

The pharmacokinetics of mycophenolate mofetil are not altered by hemodialysis. Hemodialysis usually does not remove MPA or MPAG. At high concentrations of MPAG (>100 µg/mL), hemodialysis removes only small amounts of MPAG.

 

Hepatic Insufficiency: In a single-dose (1 g oral) study of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this study were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this study had about a 50% lower AUC as compared to healthy volunteers in other studies, thus making comparisons between volunteers with alcoholic cirrhosis and healthy volunteers difficult. Effects of hepatic disease on this process probably depend on the particular disease. Hepatic disease with other etiologies, such as primary biliary cirrhosis, may show a different effect. In a single-dose (1 g intravenous) study of 6 volunteers with severe hepatic impairment (aminopyrine breath test less than 0.2% of dose) due to alcoholic cirrhosis, MMF was rapidly converted to MPA. MPA AUC was 44.1 µg•h/mL (±15.5).

Pediatrics: The pharmacokinetic parameters of MPA and MPAG have been evaluated in 55 pediatric patients (ranging from 1 year to 18 years of age) receiving CellCept oral suspension at a dose of 600 mg/m² bid (up to a maximum of 1 g bid) after allogeneic renal transplantation. The pharmacokinetic data for MPA is provided in the following table:

 

Mean (±SD) Computed Pharmacokinetic Parameters for MPA by Age and  Time After Allogeneic Renal Transplantation

 

Age Group (n)	Time	Tmax (h)	Dose Adjusteda Cmax (µg/mL)		Dose Adjusteda AUC0-12 (µg•h/mL)
1 to <2 yr   (6)d     1 to <6 yr   (17)     6 to <12 yr (16)   12 to 18 yr   (21)	Early (Day 7)	3.03     (4.70)   1.63     (2.85)   0.940   (0.546)   1.16     (0.830)	10.3   (5.80)      13.2   (7.16)      13.1   (6.30)      11.7   (10.7)	22.5   (6.66)      27.4   (9.54)      33.2   (12.1)      26.3   (9.14)b
1 to <2 yr   (4)d     1 to <6 yr   (15)     6 to <12 yr (14)   12 to 18 yr   (17)	Late (Month 3)	0.725   (0.276)   0.989   (0.511)   1.21     (0.532)   0.978   (0.484)	23.8   (13.4)      22.7   (10.1)      27.8   (14.3)      17.9   (9.57)	47.4   (14.7)      49.7   (18.2)      61.9   (19.6)      53.6   (20.3)c
1 to <2 yr   (4)d    1 to <6 yr   (12)    6 to <12 yr (11)  12 to 18 yr   (14)	Late (Month 9)	0.604   (0.208)   0.869   (0.479)   1.12     (0.462)   1.09     (0.518)	25.6   (4.25)      30.4   (9.16)      29.2   (12.6)      18.1   (7.29)	55.8   (11.6)      61.0   (10.7)      66.8   (21.2)      56.7   (14.0)

^a adjusted to a dose of 600 mg/m^2
b n=20
^c n=16
^d a subset of 1 to <6 yr

The CellCept oral suspension dose of 600 mg/m² bid (up to a maximum of 1 g bid) achieved mean MPA AUC values in pediatric patients similar to those seen in adult renal transplant patients receiving CellCept capsules at a dose of 1 g bid in the early posttransplant period. There was wide variability in the data. As observed in adults, early posttransplant MPA AUC values were approximately 45% to 53% lower than those observed in the later posttransplant period (>3 months). MPA AUC values were similar in the early and late posttransplant period across the 1 year to 18 year age range.

Gender: Data obtained from several studies were pooled to look at any gender-related differences in the pharmacokinetics of MPA (data were adjusted to 1 g oral dose). Mean (±SD) MPA AUC(0-12h) for males (n=79) was 32.0 (±14.5) and for females (n=41) was 36.5 (±18.8) µg•h/mL while mean (±SD) MPA C_max was 9.96 (±6.19) in the males and 10.6 (±5.64) µg/mL in the females. These differences are not of clinical significance.

Geriatric Use: Pharmacokinetics in the elderly have not been studied.

 

CLINICAL STUDIES: 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.

*Sandimmune is a registered trademark of Novartis Pharmaceuticals Corporation.
^#ATGAM is a registered trademark of Pharmacia and Upjohn Company.

 

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. The following tables 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 discontinued receiving CellCept (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.

 

Renal Transplant Studies — Incidence of Treatment Failure (Biopsy-proven Rejection or Early Termination for Any Reason)

 

USA Study (N=499 patients)	CellCept 2 g/day (n=167 patients)	CellCept 3 g/day (n=166 patients)	Azathioprine 1 to 2 mg/kg/day (n=166 patients)
All treatment failures	31.1%	31.3%	47.6%
Early termination without prior acute rejection*	9.6%	12.7%	6.0%
Biopsy-proven rejection episode on treatment	19.8%	17.5%	38.0%
Europe/Canada/ Australia Study (N=503 patients)	CellCept 2 g/day (n=173 patients)	CellCept 3 g/day (n=164 patients)	Azathioprine 100 to 150 mg/day (n=166 patients)
All treatment failures	38.2%	34.8%	50.0%
Early termination without prior acute rejection*	13.9%	15.2%	10.2%
Biopsy-proven rejection episode on treatment	19.7%	15.9%	35.5%
Europe Study (N=491 patients)	CellCept 2 g/day (n=165 patients)	CellCept 3 g/day (n=160 patients)	Placebo (n=166 patients)
All treatment failures	30.3%	38.8%	56.0%
Early termination without prior acute rejection*	11.5%	22.5%	7.2%
Biopsy-proven rejection episode on treatment	17.0%	13.8%	46.4%

·         Does not include death and graft loss as reason for early termination.

 

 

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.

 

Renal Transplant Studies —  Cumulative Incidence of Combined Graft Loss or Patient Death at 12 Months

 

Study	CellCept 2 g/day	CellCept 3 g/day	Control (Azathioprine or Placebo)
USA	8.5%	11.5%	12.2%
Europe/Canada/Australia	11.7%	11.0%	13.6%
Europe	8.5%	10.0%	11.5%

 

Pediatrics: 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.

*Neoral is a registered trademark of Novartis Pharmaceuticals Corporation.

(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 below).

 

Rejection at 6 Months/ Death or  Retransplantation at 1 Year

 

	All Patients		Treated Patients
	AZA N = 323	CellCept N = 327	AZA N = 289	CellCept N = 289
Biopsy-proven rejection with hemodynamic compromise at  6 months*	121 (38%)	120 (37%)	100 (35%)	92 (32%)
Death or retransplantation at  1 year	49 (15.2%)	42 (12.8%)	33 (11.4%)	18 (6.2%)

 

*

Hemodynamic compromise occurred if any of the following criteria were met: pulmonary capillary wedge pressure >20 mm or a 25% increase; cardiac index <2.0 L/min/m2 or a 25% decrease; ejection fraction <30%; pulmonary artery oxygen saturation <60% or a 25% decrease; presence of new S3 gallop; fractional shortening was <20% or a 25% decrease; inotropic support required to manage the clinical condition.

 

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.

Results: 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.

 

Rejection at 6 Months/Death or  Retransplantation at 1 Year

 

	AZA N = 287	CellCept N = 278
Biopsy proven, treated rejection at 6 months (including death or retransplantation)	137 (47.7%)	107 (38.5%)
Death or retransplantation at  1 year	42 (14.6%)	41 (14.7%)

 

INDICATIONS AND USAGE: Renal, Cardiac, and Hepatic Transplant: CellCept is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. CellCept should be used concomitantly with cyclosporine and corticosteroids.

CellCept Intravenous is an alternative dosage form to CellCept capsules, tablets and oral suspension. CellCept Intravenous should be administered within 24 hours following transplantation. CellCept Intravenous can be administered for up to 14 days; patients should be switched to oral CellCept as soon as they can tolerate oral medication.

 

CONTRAINDICATIONS: Allergic reactions to CellCept have been observed; therefore, CellCept is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product. CellCept Intravenous is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN).

 

WARNINGS (see boxed WARNING): Patients receiving immunosuppressive regimens involving combinations of drugs, including CellCept, as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections, fatal infections, and sepsis.

As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

 

CellCept has been administered in combination with the following agents in clinical trials: antithymocyte globulin (ATGAM^®), OKT3 (Orthoclone OKT^® 3*), cyclosporine (Sandimmune^®, Neoral^®) and corticosteroids. The efficacy and safety of the use of CellCept in combination with other immunosuppressive agents have not been determined.

*Orthoclone OKT is a registered trademark of Ortho Biotech Inc.

 

Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving CellCept (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and hepatic transplant patients (see ADVERSE REACTIONS).

 

In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed (see ADVERSE REACTIONS).

 

Adverse effects on fetal development (including malformations) occurred when pregnant rats and rabbits were dosed during organogenesis. These responses occurred at doses lower than those associated with maternal toxicity, and at doses below the recommended clinical dose for renal or cardiac transplantation. There are no adequate and well-controlled studies in pregnant women. However, as CellCept has been shown to have teratogenic effects in animals, it may cause fetal harm when administered to a pregnant woman. Therefore, CellCept should not be used in pregnant women unless the potential benefit justifies the potential risk to the fetus.

 

Women of childbearing potential should have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 1 week prior to beginning therapy. It is recommended that CellCept therapy should not be initiated by the physician until a report of a negative pregnancy test has been obtained.

 

Effective contraception must be used before beginning CellCept therapy, during therapy, and for 6 weeks following discontinuation of therapy, even where there has been a history of infertility, unless due to hysterectomy. Two reliable forms of contraception must be used simultaneously unless abstinence is the chosen method. If pregnancy does occur during treatment, the physician and patient should discuss the desirability of continuing the pregnancy (see PRECAUTIONS: Pregnancy and Information for Patients).

 

In patients receiving CellCept (2 g or 3 g) in controlled studies for prevention of renal, cardiac or hepatic rejection, fatal infection/sepsis occurred in approximately 2% of renal and cardiac patients and in 5% of hepatic patients (see ADVERSE REACTIONS).

 

Severe neutropenia [absolute neutrophil count (ANC) <0.5 x 10³/µL] developed in up to 2.0% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant patients receiving CellCept 3 g daily (see ADVERSE REACTIONS). Patients receiving CellCept should be monitored for neutropenia (see PRECAUTIONS: Laboratory Tests). The development of neutropenia may be related to CellCept itself, concomitant medications, viral infections, or some combination of these causes. If neutropenia develops (ANC <1.3 x 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). Neutropenia has been observed most frequently in the period from 31 to 180 days posttransplant in patients treated for prevention of renal, cardiac, and hepatic rejection.

 

Patients receiving CellCept should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.

 

PRECAUTIONS: General: 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.

 

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).