Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2021 Publisher: Pharmacor Pty Ltd., Suite 803, Level 8, Tower A, The Zenith, 821 Pacific Highway, Chatswood, NSW 2067, Australia www.pharmacor.com.au Website: www.pharmacor.com.au Phone: 1300 138 805
Mycophenolic acid (MPA) is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) which inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Based on Chinese hamster inosine-5'-monophosphate dehydrongenase (IMPDH) in complex with inosine-5'- monophosphate (IMP) and mycophenolic acid (MPA), the mechanism by which mycophenolic acid (MPA) inhibits the enzymic activity of IMPDH (human type II) appears to be related to the ability of mycophenolic acid (MPA) to structurally mimic both the nicotinamide adenine dinucleotide cofactor and a catalytic water molecule. This prevents the oxidation of inosine-5'-monophosphate (IMP) to xanthos-5'-monophosphate, the committed step in the de novo guanosine nucleotide biosynthesis. Human type II and Chinese hamster inosine-5'-monophosphate dehydrongenase (IMPDH) differ by six amino acids but have similar enzymatic characteristics. Mycophenolic acid (MPA) has more potent cytostatic effects on lymphocytes than on other cells because T and B lymphocytes are dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilise salvage pathways. Depletion of guanosine nucleotides leads to the inhibition of glycosylation of adhesion molecules on lymphocytes, a process also considered an action of mycophenolate mofetil.
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.
In experimental animals, mycophenolate mofetil has been demonstrated to prevent inflammatory responses that are immunologically mediated, and to delay tumour development and prolong survival in models of xenogeneic human to mouse and syngeneic murine tumours in vivo.
Mycophenolate Mofetil, the 2-morpholinoethyl ester of mycophenolic acid (MPA) is rapidly absorbed following oral administration and hydrolysed to form free MPA, which is the active metabolite. Mycophenolic acid (MPA) inhibits proliferative responses of T- and Blymphocytes to both mitogenic and allospecific stimulation.
Addition of guanosine or deoxyguanosine reverses the cytostatic effects of mycophenolic acid (MPA) on lymphocytes, showing the specificity of action of the drug. Mycophenolic acid (MPA) also suppresses antibody formation by B lymphocytes. By depletion of guanosine nucleotides, mycophenolic acid (MPA) prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells. By this mechanism, mycophenolic acid (MPA) may inhibit recruitment of leucocytes 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 (IL2), but did block the coupling of these events to DNA synthesis and proliferation.
Animal studies have shown that mortality in rats with Pneumocystis carinii pneumonia is higher during combined treatment with mycophenolate mofetil and trimethoprim/sulfamethoxazole than with either drug alone. Mycophenolate mofetil did not interfere with the ability of trimethoprim/ sulfamethoxazole to reduce the incidence of P. carinii cysts in surviving animals, and reduced the incidence of cysts when administered by itself.
The safety and efficacy of mycophenolate mofetil as adjunctive therapy for the prevention of organ rejection following allogeneic renal transplants were assessed in three randomised, double-blind, multicentre trials.
These studies compared two dose levels of mycophenolate mofetil (1 g twice daily (bd) and 1.5 g bd) with azathioprine (two studies) or placebo (one study) when administered in combination with ciclosporin and corticosteroids to prevent acute rejection episodes. One study also included antithymocyte globulin (ATGAM ) induction therapy.
The primary efficacy endpoint was the proportion of patients in each treatment group who experienced biopsy-proven acute rejection or treatment failure (defined as early termination from the study for any reason without prior biopsy proven rejection) within the first six months after transplantation. Mycophenolate mofetil, when administered with ATGAM induction (one study) and with ciclosporin and corticosteroids (all three studies) was shown to be superior to the following three therapeutic regimens: (1.) ATGAM induction / azathioprine / ciclosporin / corticosteroids; (2)azathioprine / ciclosporin / corticosteroids; (3)ciclosporin / corticosteroids. The superior efficacy of mycophenolate mofetil as adjunctive therapy, when compared to azathioprine or placebo, was demonstrated by a reduction in the incidence of first biopsy proven acute rejection episode or treatment failure within the first 6 months following transplantation. In addition, mycophenolate mofetil reduced the incidence of first biopsy-proven acute rejection episodes within the first 6 months after transplantation.
In Table 6, the percentages for first biopsy-proven rejection alone have not been adjusted for patients who terminated prematurely before experiencing a biopsy-proven rejection episode.
Table 6. Incidence of Biopsy Proven Rejection or Treatment Failure:
| Induction study Azathioprine-Controlled (n=499 patients) | Azathioprine 1-2 mg/kg/day (n=166 patients) | Mycophenolate Mofetil 2 g/day (n=167) | Mycophenolate Mofetil 3 g/day (n=166) |
|---|---|---|---|
| First biopsy proven rejection episode or treatment failure | 47.6% | 31.1% | 31.3% |
| First biopsy proven rejection episode alone | 38.0% | 19.8% | 17.5% |
| No Induction, Azathioprine-Controlled (n=503 patients) | Azathioprine 100-150 mg/day (n=166 patients) | Mycophenolate Mofetil 2 g/day (n=173) | Mycophenolate Mofetil 3 g/day (n=164) |
|---|---|---|---|
| First biopsy proven rejection episode or treatment failure | 50.0% | 38.2% | 34.8% |
| First biopsy proven rejection episode alone | 35.5% | 19.7% | 15.9% |
| No Induction, Placebo-Controlled (n=491 patients) | Placebo (n=166 patients) | Mycophenolate Mofetil 2 g/day (n=165) | Mycophenolate Mofetil 3 g/day (n=160) |
|---|---|---|---|
| First biopsy proven rejection episode or treatment failure | 56.0% | 30.3% | 38.8% |
| First biopsy proven rejection episode alone | 46.4% | 17.0% | 13.8% |
In these three studies, the proportion of patients requiring antilymphocyte therapy for treatment of rejection during the first six months following transplantation was smaller among patients receiving mycophenolate mofetil 2 g per day (5.5 to 10.3%) or mycophenolate mofetil 3 g per day (3.1 to 5.4%) than among patients receiving azathioprine or placebo (15 to 21%).
6 and 12-month patient survival and graft survival was somewhat higher in the patients receiving mycophenolate mofetil in comparison to either azathioprine or placebo. The cumulative proportions of patients who had died or lost their graft by 6 and 12 months' post-transplant are shown in Table 7.
Table 7. Cumulative incidence of combined graft loss and patient death at 6 (12) Months:
| Study | Control (Azathioprine or Placebo) | Mycophenolate Mofetil 2 g/day | Mycophenolate Mofetil 3 g/day |
|---|---|---|---|
| Induction, Azathioprine Controlled | 10.4% (12.2%) | 5.5% (8.5%) | 8.5% (11.5%) |
| No Induction, Azathioprine Controlled | 11.7% (13.6%) | 8.8% (11.7%) | 6.7% (11.0%) |
| No Induction, Placebo Controlled | 10.2% (11.5%) | 6.7% (8.5%) | 8.8% (10.0%) |
The safety and efficacy of mycophenolate mofetil as adjunctive therapy for the treatment of refractory organ rejection following allogeneic renal transplants was assessed in one randomised, open label, multicentre trial. This study was designed to evaluate whether mycophenolate mofetil at a dose of 1.5 g bd was superior to high dose intravenous steroids. In this study, all patients continued to receive concomitant maintenance oral corticosteroids and ciclosporin. The control group received intravenous methylprednisolone (5 mg/kg/day for five days followed by an oral course with tapered doses of corticosteroids); the control patients also generally received azathioprine. A total of 150 patients were enrolled (73 assigned to receive intravenous steroids; 77 assigned to receive mycophenolate mofetil).
Patients enrolled in this study had recurrent or persistent allograft rejection following treatment with either Orthoclone OKT3 , ATGAM , or antilymphocyte globulin for at least seven days, the last day of which occurred within 28 days prior to entry into the study. In addition, patients showed renal biopsy findings consistent with acute rejection at study entry. Serum creatinine concentrations were 442 μmol/L or lower at study entry.
The primary efficacy endpoint was graft and patient survival at six months post-enrolment. Mycophenolate mofetil was shown to be clinically effective in this study as evidenced by a 45% reduction in the number of patients who died or lost their graft. By 6 months post enrolment, 26% of the intravenous steroid group and 14.3% of the mycophenolate mofetil group had died or experienced graft loss. 18 patients (25%) receiving high dose intravenous steroids and nine patients (12%) receiving mycophenolate mofetil lost their graft in the 6 months after enrolment. One patient (1.4%) receiving high dose intravenous steroids and 2 patients (2.6%) receiving mycophenolate Mofetil died in the six months after enrolment. Fewer patients receiving mycophenolate mofetil (10.4%) required treatment with antilymphocyte preparations in the six months after enrolment, compared to those receiving high dose intravenous steroids (24.7%).
In a randomised, double blind, parallel active controlled multicentre study to compare the safety and efficacy of mycophenolate mofetil 1.5 g bd with azathioprine 1.5-3 mg/kg/day, both in combination with ciclosporin and corticosteroids, 650 patients were randomised to the two arms. The primary endpoints investigated were (1) prevention of biopsy proven acute rejection with haemodynamic compromise during the first six months following transplantation and (2) prevention of death or retransplantation during the first year following cardiac transplantation. 72 patients were withdrawn prior to administration and without knowledge of the assigned therapy, primarily because of perioperative adverse events, inability to take oral medication or death. Therefore, 289 patients received study medication in each arm.
Patients in the mycophenolate mofetil arm had a lower incidence of death or retransplantation, however this difference was within the protocol defined range of equivalence, being a ±10% mortality difference.
Mycophenolate mofetil and azathioprine did not differ significantly at six months in biopsyproven acute rejection with haemodynamic compromise.
Table 8. Survival, acute rejection and composite endpoints:
| Parameter | Azathioprine n=289% | Mycophenolate Mofetil n=289% |
|---|---|---|
| Survival Endpoint | ||
| Death or retransplantation at 12 months post-transplant | 11 | 6 |
| Composite Failures at 12 months | ||
| Death, ejection fraction <30%, coronary stenosis or myocardial infarction | 14 | 8 |
| Acute Rejection Endpoints | ||
| Patients with Rejection at 6 months post-transplant | ||
| -with haemodynamic compromise1 | 35 | 32 |
| -with severe haemodynamic compromise (cardiogenic)2,3 | 17 | 11 |
| By ISHLT Grade | ||
| -grade 1A or greater | 97 | 95 |
| -grade 2A or greater | 69 | 65 |
| -grade 3A or greater | 53 | 45 |
| Including pulse treatment of rejection | ||
| -biopsy proven rejection | ||
| treated with pulse immunosuppressives4 | 71 | 64 |
| -biopsy proven or presumed rejection | ||
| treated with pulse immunosuppressives4 | 74 | 66 |
| treated with OKT3 or ATG | 21 | 15 |
1 Haemodynamic compromise defined as one or more of the following:
Pulmonary capillary wedge pressure ≥20 mm or 25% increase;
Cardiac index <2.0 or 25% decrease;
Ejection fraction ≤30%;
Pulmonary artery saturation ≤60% or 25% decrease;
Presence of S3 gallop;
Fractional shortening ≤20% or 25% decrease
2 Severe defined as requirement for inotropic support to manage any one of the clinical conditions listed above.
3 Amongst patients who reached this acute rejection endpoint, no mycophenolate mofetil-treated patients died during 12 months, versus 8 azathioprine recipients during 6 months and 12 azathioprine recipients who died during 12 months.
4 Pulse immunosuppressives being corticosteroids and if required OKT3 by protocol defined regimen (according to ISHLT biopsy grade and degree of haemodynamic compromise).
The safety and efficacy of mycophenolate mofetil was assessed in a randomised, doubleblind, parallel, active-controlled, multicentre study in hepatic transplant patients. This study compared the use of mycophenolate mofetil 1 g bd intravenously for up to 14 days followed by 1.5 g bd orally against azathioprine 1-2 mg/kg/day intravenously followed by 1-2 mg/kg/day orally, both in combination with ciclosporin and corticosteroids. 565 patients were randomised into the two arms, 278 patients in the mycophenolate mofetil group and 287 patients in the azathioprine group.
The two primary endpoints investigated were (1) the proportion of patients who experienced, in the first six months post-transplantation, (a) one or more episodes of biopsy proven and treated rejection or (b) death/retransplantation, and (2) the proportion of patients with graft loss (death/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/retransplantation) for one year.
In the primary analyses mycophenolate mofetil in combination with corticosteroids and ciclosporin was superior to azathioprine for prevention of acute rejection (p = 0.02) in the 6 months following transplant and equivalent to azathioprine for survival or graft loss in the 12 months following transplant. See table 9.
Table 9. Two primary endpoints investigated:
| Azathioprine N = 287 (%) | Mycophenolate Mofetil N=278 (%) | Difference [95%% CI] | |
|---|---|---|---|
| Biopsy-proven and treated rejection or death/retransplantation at 6 months | 47.7 | 38.1 | p=0.02 |
| Death or retransplantation at 12 Months | 14.6 | 14.0 | 0.51 [-5.1, 6.0] |
1 Weighted point estimate of difference in proportions (azathioprine minus Mycophenolate mofetil). Met non inferiority criterion of a lower bound > -10%.
The superiority of mycophenolate mofetil to azathioprine in the time to biopsy-proven and treated rejection or death/retransplantation in the six months following transplant approached statistical significance (log-rank p=0.06). The time to death/retransplantation in the 12 months following transplant was similar in the two treatment groups (log rank p=0.86).
Following oral and intravenous administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, mycophenolic acid. Mycophenolate mofetil is not measurable systemically in plasma following oral administration. The mean extent of absorption of mycophenolic acid during multiple dosing (as measured by the area under the plasma concentration time curve, AUC) increases in a dose proportionate manner over a daily dose range of 1 to 4 g in renal transplant patients.
The administration of mycophenolate mofetil 1.5 g by the oral routes to healthy volunteers resulted in similar plasma mycophenolic acid and inactive glucuronide of mycophenolic acid total AUC values. Recovery of mycophenolic acid in urine was the same for both routes indicating complete absorption of oral mycophenolate mofetil. The mean bioavailability of orally administered mycophenolate mofetil, based on mycophenolic acid AUC, was 94% relative to IV administration.
In a steady state study, the administration of 1 g twice daily of MMF by the IV and oral routes to renal transplant patients in the immediate post-transplant period, resulted in a MPA AUC that was approximately 29% higher for the IV formulation than achieved by the capsule. Cmax was approximately 20% greater for IV.
The results of a single-dose bioequivalence study in 47 healthy volunteers indicated that the 500 mg tablet (x 2) was equivalent to the 250 mg capsule (x 4) with respect to the extent of absorption (AUC), but not the rate of absorption (Cmax). The Cmax for MPA of the tablet was 28% lower than that for the capsule.
In a two-way, randomised, cross-over, bioequivalence study of MMF oral suspension and capsules, a 1 g dose of MMF suspension was bioequivalent to the 250 mg capsule (x 4) with respect to Cmax, t½ , AUClast, AUC0-∞ and Kel. Tmax was marginally shorter for the oral suspension.
Food had no effect on the extent of absorption (mycophenolic acid AUC) of mycophenolate mofetil when administered as 1.5 g bd doses to renal transplant patients. However, the Cmax for mycophenolic acid was decreased by 40% in the presence of food.
The pharmacokinetic profile of mycophenolic acid in cardiac patients is similar to that in renal patients.
As a result of enterohepatic recirculation, secondary increases in plasma mycophenolic acid concentration are usually observed approximately 6 to 12 hours post-dose. Co-administration of cholestyramine (4 g three times daily) with mycophenolate mofetil is associated with a reduction in the AUC of mycophenolic acid of approximately 40% as a result of decreased enterohepatic recirculation. The majority of the difference in the AUC is in the terminal portion of the mycophenolic acid plasma concentration time profile.
At clinically relevant concentrations, mycophenolic acid is 97% bound to plasma albumin.
Mycophenolic acid is metabolised principally by glucuronyl transferases (predominantly isoform UGT1A9) to form the pharmacologically inactive phenolic glucuronide of mycophenolic acid (MPAG). In vivo, MPAG is converted back to free mycophenolic acid via enterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some of MMF’s side effects (diarrhoea, leucopenia).
After oral administration, 93% of the dose was recovered from the urine and 6% from the faeces. The major metabolite of mycophenolate mofetil excreted in urine is MPAG, which accounts for 87% of the oral mycophenolate mofetil dose. Less than 1% of the dose was excreted as mycophenolic acid in the urine. The following metabolites of the morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil: N-(2-carboxymethyl)morpholine, N(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.
Mean ± SD apparent half-life and plasma clearance of mycophenolic acid are 17.9 ± 6.5 hours and 193 ± 48 mL/minute respectively following oral administration.
MPA’s disposition depends on several transporters. Organic anion-transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are involved in MPA’s disposition; OATP isoforms, MRP2 and breast cancer resistance protein (BCRP) are transporters associated with the glucuronides' biliary excretion. Multidrug resistance protein 1 (MDR1) is also able to transport MPA, but its contribution seems to be confined to the absorption process. In the kidney MPA and its metabolites inhibit renal organic anion transporters, with MPAG also being a substrate for OAT3.
In renal, cardiac and hepatic transplant patients, mean steady state (MPA AUC) and Cmax were up to 40% lower in the early post-transplant period (<40 days post-transplant) compared to the late transplant period (three to six months post-transplant).
In renal transplant patients, in the immediate post-transplant phase, mean steady state (MPA AUC) was 24% higher following mycophenolate mofetil 1 g bd intravenous (over two hours) for five days compared with the same dose orally.
In cardiac transplant patients, administration of mycophenolate mofetil 1.5 g bd oral resulted in mean steady state (MPA AUC) values similar to those found in renal transplant patients administered the same dose.
In hepatic transplant patients, administration of mycophenolate mofetil 1 g bd intravenous followed by 1.5 g bd oral mycophenolate mofetil resulted in mean steady state (MPA AUC) values similar to those found in renal transplant patients administered mycophenolate mofetil 1 g bd oral.
In a single dose study (six subjects per group), plasma (MPA AUCs) were up to 30% higher in subjects with mild to moderate renal impairment (GFR 25-80 mL/minute/1.73m²) and 75% higher in subjects with severe renal impairment (GFR <25 mL/minute/1.73m²) than those subjects with normal renal function (GFR >80 mL/minute/1.73m²). The mean increase in MPA AUC observed in subjects with severe renal impairment was comparable to the increase in MPA AUC seen when the dose of mycophenolate mofetil is increased from a daily dose of 2 to 3 g (see Section 4.2 Dose and method of administration). Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. In addition, the single dose plasma AUC of MPAG, was three to six fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects consistent with the known renal elimination of glucuronide of mycophenolic acid. No data are available on the safety of long-term exposure to this level of MPAG.
In patients with delayed renal graft function post-transplant, mean AUC(0-12) of mycophenolic acid was comparable to that seen in post-transplant patients without delayed graft function. However, mean plasma AUC(0-12) of glucuronide of mycophenolic acid was two- to three-fold higher than post-transplant patients without delayed graft function. Also, with repeated dosing, plasma concentrations of glucuronide of mycophenolic acid accumulated, whereas accumulation of mycophenolic acid occurred to a lesser degree, if at all. High plasma concentrations of glucuronide of mycophenolic acid may displace mycophenolic acid from its protein binding sites resulting in a transient increase in the plasma concentration of free mycophenolic acid in patients with delayed graft function.
No dose adjustment is recommended although close monitoring is advised.
The pharmacokinetics of mycophenolate mofetil during haemodialysis are not altered. Haemodialysis does not remove mycophenolic acid or glucuronide of mycophenolic acid. At high concentrations (>100 μg/mL), haemodialysis removes only small amounts of glucuronide of mycophenolic acid (MPAG).
In volunteers with alcoholic cirrhosis, hepatic glucuronide of mycophenolic acid glucuronidation was relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on these processes probably depend on the particular disease. Hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.
Pharmacokinetics in the elderly have not been formally evaluated.
The pharmacokinetic parameters of the mycophenolic acid and glucuronide of mycophenolic acid were evaluated in 55 paediatric renal transplant patients aged 1 to 18 years given mycophenolate mofetil 600 mg/m². Mycophenolate mofetil orally twice daily (up to a maximum of 1 g bd). This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving mycophenolate mofetil at a dose of 1 g bd in the early and late post-transplant period. MPA AUC levels across age groups were similar in the early post-transplant period out to nine months posttransplant. There is limited pharmacokinetic data available for children aged less than 2 years.
Mycophenolic acid, at clinically relevant concentrations, is 97% bound to plasma albumin. Glucuronide of mycophenolic acid(MPAG) is 82% bound to plasma albumin at glucuronide of mycophenolic acid concentration ranges such as those normally seen in stable renal transplant patients; however at higher concentrations of glucuronide of mycophenolic acid which are seen in patients with delayed graft function or with severe renal insufficiency, the bound fraction in vitro decreases to 62%.
In vitro studies to evaluate the effect of several agents on the binding of mycophenolic acid to human serum albumin (HSA) or plasma proteins showed that salicylate (at 250 μ/mL with HSA) and glucuronide of mycophenolic acid (at greater than or equal to 460 μ/mL with plasma proteins) increased the free fraction of mycophenolic acid At concentrations that exceeded what is encountered clinically, naproxen, digoxin, ciclosporin, theophylline, tacrolimus, tolbutamide, propranolol, warfarin, and prednisone did not increase the free fraction of mycophenolic acid. Mycophenolic acid at concentrations as high as 100 μ/mL had little effect on the binding of warfarin, digoxin or propranolol but decreased the binding of theophylline from 53% to 45% and decreased the binding of phenytoin from 90% to 87%.
Mycophenolate mofetil did not induce point mutations (Ames assay) or primary DNA damage (yeast mitotic gene conversion assay) in the presence or absence of metabolic activation. Mycophenolate mofetil did not cause chromosomal damage in vivo at oral doses up to 3000 mg/kg (mouse micronucleus aberration assay) or in vitro with or without metabolic activation at concentrations up to 5 μg/mL (Chinese hamster ovary cell (CHO) chromosomal aberration assay). Chromosome aberrations were present without metabolic activation in an initial CHO cell assay, but only at concentrations (249 to 300 μ/mL) that cause excessive cytotoxicity.
A 104 week oral carcinogenicity study in mice with mycophenolate mofetil at daily doses of 25, 75 or 180 mg/kg showed an increase above control levels in the incidence of lymphosarcomas in females at the highest two dose levels and in males at the highest dose level (1.1-1.9 times the expected maximum clinical dose based on AUC values). The incidence of lymphosarcomas in all mice remained within the range of that observed historically in this strain of mice. In a 104 week oral carcinogenicity study in rats, mycophenolate mofetil in daily doses up to 15 mg/kg (0.6 times the expected maximum clinical dose based on AUC values) was not tumorigenic.
The incidence of lymphoma/lymphoproliferative disease and other malignancies is also increased in patients on immunosuppressive agents, and this appears to be related to the intensity or duration of immunosuppression rather than any specific immunosuppressant agent (see Section 4.4 Special warnings and precautions for use).
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