Mycophenolate Mofetil

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Mycophenolate Mofetil Capsules, 250 mg, Mycophenolate Mofetil Tablets 500 mg
Warning

Immunosuppression may lead to increased susceptibility to infection and possible development of lymphoma. Only physicians experienced in immunosuppressive therapy and management of renal, cardiac or hepatic transplant patients should use Mycophenolate Mofetil. 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.

Female users of childbearing potential must use contraception. Use of Mycophenolate Mofetil during pregnancy is associated with increased risk of pregnancy loss and congenital malformations.

Mycophenolate Mofetil Description

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 mcg/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 is available for oral administration as capsules containing 250 mg of Mycophenolate Mofetil and as tablets containing 500 mg of Mycophenolate Mofetil.

Inactive ingredients in Mycophenolate Mofetil 250 mg capsules include croscarmellose sodium, magnesium stearate. The capsule shells contain gelatin, sodium lauryl sulfate, red iron oxide, titanium dioxide, indigo carmine and edible ink; may also contain shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide and purified water.

Inactive ingredients in Mycophenolate Mofetil 500 mg tablets include microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, hypromellose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol, black iron oxide and red iron oxide.

Mycophenolate Mofetil - 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 cardiac 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 five minutes) after the infusion is stopped or after oral administration, MMF concentration is below the limit of quantitation (0.4 mcg/mL).

Absorption

In 12 healthy volunteers, the mean absolute bioavailability of oral Mycophenolate Mofetil relative to intravenous mycophenolatemofetil (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 1).

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 b.i.d. to renal transplant patients. However, MPA Cmax 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 renal 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 mcg/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 mcg/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 six to twelve hours postdose. The coadministration of cholestyramine (4 g t.i.d.) 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 three-fold to six-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 mcg/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 Cmax approximately 32% to 44% lower compared to the late transplant period (three to six months posttransplant).

Mean MPA AUC values following administration of 1 g b.i.d. intravenous Mycophenolate Mofetil over two hours to renal transplant patients for five 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 b.i.d. intravenous Mycophenolate Mofetil followed by 1.5 g b.i.d. oral Mycophenolate Mofetil resulted in mean MPA AUC values similar to those found in renal transplant patients administered 1 g Mycophenolate Mofetil b.i.d.

Table 1 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
(mcg/mL) Total AUC (mcg?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 (b.i.d. dosing) Time After Transplantation Dose/Route Tmax
(h) Cmax
(mcg/mL) Interdosing Interval AUC(0–12h) (mcg?h/mL) 5 days 1 g/i.v. 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 (b.i.d. dosing) Time After Transplantation Dose/Route Tmax
(h) Cmax
(mcg/mL) Interdosing Interval AUC(0–12h) (mcg?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) 54.1a
(±20.4)
(n=49) Hepatic Transplant Patients (b.i.d. dosing) Time After Transplantation Dose/Route Tmax
(h) Cmax
(mcg/mL) Interdosing Interval AUC(0–12h) (mcg?h/mL) 4 to 9 days 1 g/i.v. 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)

a 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.

Table 2 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
(mcg/mL) AUC(0–96h)
(mcg?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
(mcg/mL) AUC(0–48h)
(mcg?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 three-fold to six-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 mcg?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 to 12h) was comparable to that seen in posttransplant patients without delayed renal graft function. There is a potential for a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. However, dose adjustment does not appear to be necessary in patients with delayed renal graft function. Mean plasma MPAG AUC(0–12h) was two-fold to three-fold higher than in posttransplant patients without delayed renal graft function. (See PRECAUTIONS: General and DOSAGE AND ADMINISTRATION.)

In eight patients with primary graft non-function following renal transplantation, plasma concentrations of MPAG accumulated about six-fold to eight-fold after multiple dosing for 28 days. Accumulation of MPA was about one-fold to two-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 mcg/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 six 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 six 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 mcg•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 Mycophenolate Mofetil oral suspension at a dose of 600 mg/m2 b.i.d (up to a maximum of 1 g b.i.d) after allogeneic renal transplantation. The pharmacokinetic data for MPA is provided in Table 3.

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

a adjusted to a dose of 600 mg/m2

b n=20

c n=16

d a subset of 1 to < 6 yr

The Mycophenolate Mofetil oral suspension dose of 600 mg/m2 b.i.d (up to a maximum of 1 g b.i.d) achieved mean MPA AUC values in pediatric patients similar to those seen in adult renal transplant patients receiving Mycophenolate Mofetil capsules at a dose of 1 g b.i.d 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) mcg?h/mL while mean (±SD) MPA Cmax was 9.96 (±6.19) in the males and 10.6 (±5.64)mcg/mL in the females. These differences are not of clinical significance.

Geriatrics

Pharmacokinetics in the elderly have not been studied.

Clinical Studies Adults

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

Renal Transplant Adults

The three renal studies compared two dose levels of oral Mycophenolate Mofetil (1 g b.i.d and 1.5 g b.i.d.) with azathioprine (two studies) or placebo (one 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 six 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). Mycophenolate Mofetil, 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.

Mycophenolate Mofetil, in combination with corticosteroids and cyclosporine reduced (statistically significant at 0.05 level) the incidence of treatment failure within the first six 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 Mycophenolate Mofetil discontinued without prior biopsy-proven rejection, death or graft loss than discontinued in the control groups, with the highest rate in the Mycophenolate Mofetil 3 g/day group. Therefore, the acute rejection rates may be underestimates, particularly in the Mycophenolate Mofetil 3 g/day group.

Table 4 Renal Transplant Studies Incidence of Treatment Failure (Biopsy-proven Rejection or Early Termination for Any Reason) USA Studya
(N=499 patients) Mycophenolate Mofetil
2 g/day
(n=167 patients) Mycophenolate Mofetil
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 rejectionb 9.6% 12.7% 6.0% Biopsy-proven rejection episode on treatment 19.8% 17.5% 38.0% Europe/Canada/Australia Studyc
(N=503 patients) Mycophenolate Mofetil
2 g/day
(n=173 patients) Mycophenolate Mofetil
3 g/day
(n=164 patients) Azathioprine
100 to 150 mg/kg/day
(n=166 patients) All treatment failures 38.2% 34.8% 50.0% Early termination without prior acute rejectionb 13.9% 15.2% 10.2% Biopsy-proven rejection episode on treatment 19.7% 15.9% 35.5% Europe Studyd
(N=491 patients) Mycophenolate Mofetil
2 g/day
(n=165 patients) Mycophenolate Mofetil
3 g/day
(n=160 patients) Placebo
(n=166 patients) All treatment failures 30.3% 38.8% 56.0% Early termination without prior acute rejectionb 11.5% 22.5% 7.2% Biopsy-proven rejection episode on treatment 17.0% 13.8% 46.4%

a Antithymocyte globulin induction/MMF or azathioprine/cyclosporine/corticosteroids.

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

c MMF or azathioprine/cyclosporine/corticosteroids.

d MMF or placebo/cyclosporine/corticosteroids.

The cumulative incidence of 12-month graft loss or patient death is presented below. No advantage of Mycophenolate Mofetil with respect to graft loss or patient death was established. Numerically, patients receiving Mycophenolate Mofetil 2 g/day and 3 g/day experienced a better outcome than controls in all three studies; patients receiving Mycophenolate Mofetil 2 g/day experienced a better outcome than Mycophenolate Mofetil 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 one year.

Table 5 Renal Transplant Studies Cumulative Incidence of Combined Graft Loss or Patient Death at 12 Months Study Mycophenolate Mofetil
2 g/day Mycophenolate Mofetil
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 Mycophenolate Mofetil oral suspension 600 mg/m2 b.i.d (up to 1 g b.i.d) 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. Mycophenolate Mofetil 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 b.i.d Mycophenolate Mofetil 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, one in Canada, five in Europe and two in Australia. The total number of patients enrolled was 650; 72 never received study drug and 578 received study drug. Patients received Mycophenolate Mofetil 1.5 g b.i.d. (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 six 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 six months and for the occurrence of death for one year.

Rejection: No difference was established between Mycophenolate Mofetil and azathioprine (AZA) with respect to biopsy-proven rejection with hemodynamic compromise. Survival: Mycophenolate Mofetil was shown to be at least as effective as AZA in preventing death or retransplantation at one year. (See Table 6.) Table 6 Rejection at Six Months/Death or Retransplantation at One Year All Patients Treated Patients AZA
N = 323 Mycophenolate Mofetil
N = 327 AZA
N = 289 Mycophenolate Mofetil
N = 289 Biopsy-proven rejection with hemodynamic compromise at six monthsa 121 (38%) 120 (37%) 100 (35%) 92 (32%) Death or retransplantation at one year 49 (15.2%) 42 (12.8%) 33 (11.4%) 18 (6.2%)

a 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, two in Canada, four in Europe and one in Australia. The total number of patients enrolled was 565. Per protocol, patients received Mycophenolate Mofetil 1 g b.i.d. intravenously for up to 14 days followed by Mycophenolate Mofetil 1.5 g b.i.d. 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 six months post-transplantation, 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 post-transplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection and for the occurrence of graft loss (death or retransplantation) for one year.

Results

In combination with corticosteroids and cyclosporine, Mycophenolate Mofetil obtained a lower rate of acute rejection at six months and a similar rate of death or retransplantation at one year compared to azathioprine.

Table 7 Rejection at Six Months/Death or Retransplantation at One Year AZA
N = 287 Mycophenolate Mofetil
N = 278 Biopsy-proven, treated rejection at six months (includes death or retransplantation) 137 (47.7%) 107 (38.5%) Death or retransplantation at one year 42 (14.6%) 41 (14.7%) Indications and Usage for Mycophenolate Mofetil Renal, Cardiac, and Hepatic Transplant

Mycophenolate Mofetil is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. Mycophenolate Mofetil should be used concomitantly with cyclosporine and corticosteroids.

Contraindications

Allergic reactions to Mycophenolate Mofetil have been observed; therefore, Mycophenolate Mofetil is contraindicated in patients with a hypersensitivity to Mycophenolate Mofetil, mycophenolic acid or any component of the drug product.

Warnings

(See boxed WARNING)

Lymphoma and Malignancy

Patients receiving immunosuppressive regimens involving combinations of drugs, including Mycophenolate Mofetil, as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin. (See ADVERSE REACTIONS.) The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

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.

Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving Mycophenolate Mofetil (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of 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.)

Combination with Other Immunosuppressive Agents

Mycophenolate Mofetil has been administered in combination with the following agents in clinical trials: antithymoc

Mycophenolate Mofetil

.