CellCept

Mycophenolate mofetil.

Active ingredient: Mycophenolate mofetil.
Oral administration: Each tablet contains 500 mg mycophenolate mofetil. Mycophenolate mofetil (CellCept) film-coated tablets are caplet shaped, lavender tablets, with "Roche" engraved on one side and "CellCept 500" on the other.
Route of Administration: Oral administration.
Sterile/Radioactive Statement: Not applicable.
Excipients/Inactive Ingredients: As registered locally.

Therapeutic/Pharmacologic Class of Drug: Selective Immunosuppressive agent (immunosuppressant) - Mycophenolic acid. ATC Code: L04AA06.
Pharmacology: Pharmacodynamics: Mechanism of Action: Mycophenolate mofetil (MMF) is the 2-morpholinoethyl ester of mycophenolic acid (MPA). 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. The mechanism by which MPA inhibits the enzymatic activity of IMPDH appears to be related to the ability of MPA to structurally mimic both nicotinamide adenine dinucleotide cofactor and a catalytic water molecule. This prevents the oxidation of IMP to xanthose-5'-monophosphate which is the committed step in de novo guanosine nucleotide biosynthesis. Two IMPDH isoforms have been identified, isoform type I, which is present in most known cells (including resting human lymphocytes) and isoform type II, which is strongly and predominantly expressed in activated human B- and T-lymphocytes. The type II isoform is nearly five times more sensitive to inhibition by MPA than is the type I isoform. MPA has more potent cytostatic effects on lymphocytes than on other cells 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.
In addition to its inhibition of IMPDH and the resulting deprivation of lymphocytes, MPA also influences cellular checkpoints responsible for metabolic programming of lymphocytes [198]. It has been shown, using human CD4+ T-cells, that MPA shifts transcriptional activities in lymphocytes from a proliferative state to catabolic processes relevant to metabolism and survival leading to an anergic state of T-cells, whereby the cells become unresponsive to their specific antigen.
Clinical/Efficacy Studies: Transplant studies: Mycophenolate mofetil (CellCept) has been administered in combination with the following agents in clinical trials for the prevention of renal, cardiac and hepatic rejection episodes: antithymocyte globulin, OKT3, ciclosporin and corticosteroids. Mycophenolate mofetil (CellCept) has also been administered in combination with ciclosporin and corticosteroids for the treatment of refractory renal rejection episodes. Prior to treatment with Mycophenolate mofetil (CellCept), patients may have also received antilymphocyte globulin, antithymocyte globulin and OKT3. Mycophenolate mofetil (CellCept) has further been used in clinical trials together with daclizumab and tacrolimus.
Prevention of organ rejection: Adults: The safety and efficacy of Mycophenolate mofetil (CellCept) in combination with corticosteroids and ciclosporin for the prevention of organ rejection were assessed in renal transplant patients in three randomized, double-blind, multicenter trials, in cardiac patients in one randomized double-blind, multicenter trial, and in hepatic patients in one randomized, double-blind, multicenter trial.
Children: The safety, pharmacokinetics and efficacy of Mycophenolate mofetil (CellCept) in combination with corticosteroids and ciclosporin for the prevention of organ rejection in pediatric renal transplant patients were assessed in an open-label, multicenter study in 100 patients (aged 3 months to 18 years).
Renal transplant: Adults: The three studies compared two dose levels of oral Mycophenolate mofetil (CellCept) (1 g twice daily and 1.5 g twice daily) with azathioprine (2 studies) or placebo (1 study) when administered in combination with ciclosporin and corticosteroids to prevent acute rejection episodes.
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). Mycophenolate mofetil (CellCept) was studied in the following three therapeutic regimens: (1) antithymocyte globulin induction/MMF or azathioprine/ciclosporin/corticosteroids, (2) MMF or azathioprine/ciclosporin/corticosteroids, and (3) MMF or placebo/ciclosporin/corticosteroids.
Mycophenolate mofetil (CellCept), in combination with corticosteroids and ciclosporin reduced (statistically significant at the <0.05 level) the incidence of treatment failure within the first 6 months following transplantation. The following tables summarize the results of these studies. 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 (CellCept) discontinued (without prior biopsy-proven rejection, death or graft loss) than discontinued in the control groups, with the highest rate in the Mycophenolate mofetil (CellCept) 3 g/day group. Therefore, the acute rejection rates may be underestimates, particularly in the Mycophenolate mofetil (CellCept) 3 g/day group. (See Table 1.)

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Cumulative incidence of 12-month graft loss and patient death are presented as follows. No advantage of Mycophenolate mofetil (CellCept) with respect to graft loss and patient death was established. Numerically, patients receiving Mycophenolate mofetil (CellCept) 2 g/day and 3 g/day experienced a better outcome than controls in all three studies; patients receiving Mycophenolate mofetil (CellCept) 2 g/day experienced a better outcome than Mycophenolate mofetil (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 and patient death at 1 year. (See Table 2.)

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Children (aged 3 months to 18 years): One open-label, safety, pharmacokinetics and efficacy study of Mycophenolate mofetil (CellCept) powder for oral suspension in combination with ciclosporin and corticosteroids for the prevention of renal allograft rejection was performed in 100 pediatric patients (aged 3 months to 18 years) at centers in the US (9), Europe (5) and Australia (1). Mycophenolate mofetil (CellCept) was dosed at 600 mg/m² twice daily (up to 1 g twice daily) in all age groups.
The primary efficacy endpoint was the proportion of patients experiencing an acute rejection episode in the first 6 months post-transplant. 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 post-transplant was similar to that observed in adult renal transplant patients.
Cardiac transplant: A double-blind, randomized, comparative, parallel-group, multicenter study was performed in primary cardiac transplant recipients. The total number of patients enrolled was 650; 72 never received study drug and 578 received study drug. Patients received Mycophenolate mofetil (CellCept) 1.5 g twice daily (n=289) or azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with ciclosporin 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 transplanted during the first 12 months following transplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection for up to 6 months and for the occurrence of death for 1 year.
1. Rejection: No difference was established between Mycophenolate mofetil (CellCept) and azathioprine (AZA) with respect to biopsy-proven rejection with hemodynamic compromise, as presented as follows. (See Table 3.)

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2. Survival: In the enrolled patients, there were no statistically significant differences between patients randomized to MMF and patients randomized to AZA for death and retransplantation. In patients who received study drug, the lower limit of the 97.5% confidence interval of the difference of death and retransplantation was 0.9 at 1 year, indicating that MMF was superior to AZA in these patients, as presented as follows. (See Table 4.)

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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 and 564 received study drug. Patients either received Mycophenolate mofetil (CellCept) 1g twice daily intravenously for up to 14 days followed by Mycophenolate mofetil (CellCept) 1.5 g twice daily orally or azathioprine 1-2 mg/kg/day intravenously followed by azathioprine 1-2 mg/kg/day orally, in combination with ciclosporin and corticosteroids as maintenance immunosuppressive therapy. The two primary endpoints were: (1) the proportion of patients who experienced, in the first 6 months post transplantation, one or more episodes of biopsy-proven and treated rejection or death/retransplantation, and (2) the proportion of patients who experienced graft loss (death/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/retransplantation) for 1 year.
Results: In the primary (intent-to-treat) analyses Mycophenolate mofetil (CellCept) in combination with corticosteroids and ciclosporin was superior to azathioprine for prevention of acute rejection (p = 0.025) and equivalent to azathioprine for survival. (See Table 5.)

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Treatment of refractory organ rejection: A randomized, open-label comparison study of MMF 3g per day against intravenous corticosteroids was conducted in 150 renal transplant recipients with refractory, acute, cellular allograft rejection. The primary endpoint was the proportion of patients who were still alive with a functioning graft at 6 months after study entry.
Results: The incidence of graft loss in the control group was unexpectedly low and the primary analysis, based on the sequential probability ratio test showed a trend toward improved graft survival in the MMF group (p=0.081). A secondary analysis, using the Cochran-Mantel-Haenszel test (not adjusted for sequential monitoring) suggested a 45% reduction in the incidence of graft loss or death at 6 months after study entry in the MMF arm (p=0.062). (See Table 6.)

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Lupus nephritis studies: Many studies have investigated the use of Mycophenolate mofetil (CellCept) for induction and maintenance therapy of lupus nephritis. Two large meta-analyses provide the most robust evidence to support the use of MMF in the management of lupus nephritis: The Cochrane Collaboration reviewed 50 randomized controlled trials including 2846 adults and children with biopsy-proven lupus nephritis Class III-V receiving immunosuppressive therapy. MMF with corticosteroids was found to be as effective as IV cyclophosphamide with corticosteroids in preventing death, inducing complete remission in proteinuria and achieving stable kidney function at six months with lower rates of toxicity. In maintenance therapy, MMF with corticosteroids was more effective than AZA with corticosteroids at preventing relapse with no difference in clinically important side effects.
The National Kidney Foundation reviewed 53 randomized trials including 4,222 adults and children (from 10 years of age) with proliferative lupus nephritis receiving immunosuppressive therapy. Thirty-eight of the trials in the Cochrane review were also included in this meta-analysis. MMF with corticosteroids was as effective as IV cyclophosphamide with corticosteroids for inducing remission in lupus nephritis with improved tolerability. MMF with corticosteroids was superior to AZA with corticosteroids for maintaining disease remission.
The results of these meta-analyses are in line with the results of the largest randomized controlled study in lupus nephritis, the Aspreva Lupus Management Study (ALMS), which was a two-phase study investigating the efficacy of Mycophenolate mofetil (CellCept) in induction and maintenance therapy of patients with Class III-V lupus nephritis. In the induction phase of the study, patients were randomly assigned to a target dose of 3 g/day Mycophenolate mofetil (CellCept) or 0.5 to 1.0 g/m²/month IV cyclophosphamide for 6 months. Both groups received prednisone, tapered from a maximum starting dose of 60 mg/day. There was no significant difference in the number of patients who met the primary endpoint of a pre-specified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine, supporting the finding of the meta-analyses that Mycophenolate mofetil (CellCept) is as effective as IV cyclophosphamide for induction therapy. In the 36-month maintenance phase of the study, the primary endpoint was the time to treatment failure measured as the time until the first event which was defined as death, end-stage renal disease, sustained doubling of the serum creatinine level, renal flare, or the need for rescue therapy. Mycophenolate mofetil (CellCept) (2 g/day) was superior to AZA (2 mg/kg/day) in time to treatment failure (hazard ratio, 0.44; 95% confidence interval, 0.25 to 0.77; P = 0.003), supporting the finding of the meta-analyses that MMF is more effective than azathioprine at preventing relapse.
Immunogenicity: No data available.
Pharmacokinetics: The pharmacokinetics of MMF have been studied in renal, cardiac and hepatic transplant patients and in patients with lupus nephritis.
In general, the pharmacokinetic profile of MPA is similar in renal and in cardiac transplant patients. In the early transplant period, hepatic transplant patients receiving a 1.5 g oral MMF dose or 1 g i.v. MMF dose have similar MPA levels compared to renal transplant patients receiving 1 g oral or i.v. MMF. The pharmacokinetic profile of MPA in lupus nephritis is similar to that reported in transplantation (including the high variability in exposure to active drug observed) but is complicated by more unpredictable changes in renal function in lupus nephritis patients.
Absorption: Following oral and intravenous administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94% relative to i.v. mycophenolate mofetil. Mycophenolate mofetil can be measured systemically during intravenous infusion; however, after oral administration it is below the limit of quantitation (0.4 μg/mL).
Immediately post-transplant (<40 days) renal, cardiac and hepatic transplant patients had mean MPA AUCs approximately 30% lower and Cmax approximately 40% lower compared to the late transplant period (3-6 months post transplant). This is referred to as non-stationarity of MPA pharmacokinetics. MPA AUC values obtained following administration of 1 g twice daily intravenous Mycophenolate mofetil (CellCept) at the recommended infusion rate to renal patients in the immediate post-transplant phase are comparable to those observed following oral dosing. In hepatic transplant patients, administration of 1 g twice daily intravenous Mycophenolate mofetil (CellCept) followed by 1.5 g twice daily oral Mycophenolate mofetil (CellCept) resulted in MPA AUC values similar to those found in renal transplant patients administered 1 g Mycophenolate mofetil (CellCept) twice daily.
Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil administered at doses of 1.5 g twice daily to renal transplant patients. However, MPA C_max was decreased by 40% in the presence of food.
Equivalence of oral dosage forms: Bioequivalence of Mycophenolate mofetil (CellCept) oral dosage forms have been evaluated. Two 500 mg tablets have been shown to be bioequivalent to four 250 mg capsules. Likewise, 1 g/5 mL of Mycophenolate mofetil (CellCept) constituted powder for oral suspension has been shown to be bioequivalent to four 250 mg capsules (see Dosage & Administration).
Distribution: Secondary increases in plasma MPA concentrations are usually observed at approximately 6-12 hours post-dose, consistent with enterohepatic recirculation. A reduction of approximately 40% in the AUC of MPA is associated with coadministration of cholestyramine (4 g three times daily), consistent with interruption of enterohepatic recirculation.
At clinically relevant concentrations, MPA is 97% bound to plasma albumin. This value is dependent on renal function; changes in albumin binding after initiating therapy may explain the non-stationarity in the pharmacokinetics of MPA.
Metabolism: MPA is conjugated primarily by glucuronyltransferase (isoform UGT1A9) to form the inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted back to free MPA 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 (diarrhea, leucopenia).
Elimination: Oral administration of radiolabelled mycophenolate mofetil resulted in complete recovery of the administered dose, with 93% of the dose recovered in the urine and 6% recovered in the feces. Most (about 87%) of a dose is excreted in the urine as MPAG. A negligible amount of drug (<1% of dose) is excreted as MPA in the urine.
Enterohepatic recirculation interferes with accurate determination of MPA's disposition parameters; only apparent values can be indicated. In healthy volunteers and patients with autoimmune disease approximate clearance values of 10.6 L/h and 8.27 L/h respectively and half-life values of 17 h were observed. In transplant patients mean clearance values were higher (range 11.9-34.9 L/h) and mean half-life values shorter (5-11 h) with little difference between renal, hepatic or cardiac transplant patients. In the individual patients, these elimination parameters vary based on type of co-treatment with other immunosuppressants, time post-transplantation, plasma albumin concentration and renal function. These factors explain why reduced exposure is seen when Mycophenolate mofetil (CellCept) is co-administered with cyclosporine (see Interactions) and why plasma concentrations tend to increase over time compared to what is observed immediately after transplantation (see non-stationarity in Absorption and Distribution as previously mentioned).
At clinically encountered concentrations, MPA and MPAG are not removed by hemodialysis. However, at high MPAG concentrations (>100 μg/mL), small amounts of MPAG are removed. By interfering with enterohepatic circulation of the drug, bile acid sequestrants, such as cholestyramine, reduce MPA AUC (see Overdosage).
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 potently interact with renal organic anion transporters.
Pharmacokinetics in Special Populations: Renal impairment: In a single-dose study (6 subjects per group), mean plasma MPA AUCs observed after oral dosing in subjects with severe chronic renal impairment (glomerular filtration rate <25 mL/min/1.73 m²) were 28-75% higher than those observed in normal healthy subjects or subjects with lesser degrees of renal impairment. The mean single-dose MPAG AUC was 3- to 6-fold higher in subjects with severe renal impairment than in subjects with mild renal impairment and normal healthy subjects, consistent with the known renal elimination of MPAG.
Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied.
There is also a paucity of information available for lupus nephritis patients with severe renal impairment. Therapeutic drug monitoring in lupus nephritis patients with GFR <30 mL/min is advisable.
Patients with delayed renal graft function post-transplant: In patients with delayed renal graft function post-transplant, mean MPA AUC_0-12 was comparable to that seen in post-transplant patients without delayed renal graft function. There may be a transient increase in the free-fraction and concentration of plasma MPA in patients with delayed renal graft function. Dose adjustment of Mycophenolate mofetil (CellCept) does not appear to be necessary (see Special Dosage Instructions under Dosage & Administration). Mean plasma MPAG AUC_0-12 was 2- to 3-fold higher than in post-transplant patients without delayed renal graft function.
In patients with primary non-functioning graft following renal transplantation, plasma concentrations of MPAG accumulated; accumulation of MPA, if any, was much smaller.
Hepatic impairment: Overall, the pharmacokinetics of MPA and MPAG were relatively unaffected by hepatic parenchymal disease in volunteers with alcoholic cirrhosis dosed with oral or intravenous MMF. 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.
Pediatric Population (aged ≤18 years): Pharmacokinetic parameters were evaluated in 55 pediatric renal transplant patients (ranging from 1 year to 18 years of age) given 600 mg/m² mycophenolate mofetil orally twice daily (up to a maximum of 1 g twice daily). This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving Mycophenolate mofetil (CellCept) at a dose of 1 g twice daily in the early and late post-transplant period. MPA AUC values across age groups were similar in the early and late post-transplant period.
Pharmacokinetics have not been formally evaluated in pediatric lupus nephritis patients. However, in patients with systemic lupus erythematosus (some with renal involvement), similar typical MPA AUC_0-12 values following MMF administration were observed in children, adolescent, and adult patients.
Geriatric Population (≥ 65 years): The pharmacokinetics of mycophenolate mofetil and its metabolites have not been found to be altered in geriatric transplant patients when compared to younger transplant patients.
Toxicology: Nonclinical Safety: The hematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred at systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day for renal transplant recipients. Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended doses. Gastrointestinal and renal effects consistent with dehydration were also observed in the monkey at the highest dose (systemic exposure levels equivalent to or greater than clinical exposure). The nonclinical toxicity profile of mycophenolate mofetil appears to be consistent with adverse events observed in human clinical trials which now provide safety data of more relevance to the patient population (see Adverse Reactions).
Carcinogenicity: In experimental models, mycophenolate mofetil was not tumorigenic. The highest dose tested in the animal carcinogenicity studies resulted in approximately 2-3 times the systemic exposure (AUC or C_max) observed in renal transplant patients at the recommended clinical dose of 2 g/day and 1.3-2 times the systemic exposure (AUC or C_max) observed in cardiac transplant patients at the recommended clinical dose of 3 g/day.
Genotoxicity: Two genotoxicity assays (the mouse lymphoma/thymidine kinase assay and the mouse micronucleus aberration assay) indicated a potential of mycophenolate mofetil to cause chromosomal instability at severely cytotoxic dose levels. Other genotoxicity tests (the bacterial mutation assay, the yeast mitotic gene conversion assay or the Chinese hamster ovary cell chromosomal aberration assay) did not demonstrate mutagenic activity.
Impairment of Fertility: Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. The systemic exposure at this dose represents 2 to 3 times the clinical exposure at the recommended clinical dose of 2 g/day in renal transplant patients and 1.3-2 times the clinical exposure at the recommended clinical dose of 3 g/day in cardiac transplant patients. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (including anophthalmia, agnathia, and hydrocephaly) in the first generation offspring in the absence of maternal toxicity. The systemic exposure at this dose was approximately 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.
Reproductive Toxicity: In teratology studies in rats and rabbits, fetal resorptions and malformations occurred in rats at 6 mg/kg/day (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg/kg/day (including cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels are approximately equivalent to or less than 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients.
Refer to Pregnancy under Use in Pregnancy & Lactation.

Mycophenolate mofetil (CellCept) in combination with corticosteroids and either ciclosporin or tacrolimus is indicated for: prophylaxis of acute organ rejection and treatment of first or refractory organ rejection in patients receiving allogeneic renal transplants; prophylaxis of acute organ rejection in patients receiving allogeneic cardiac transplants. (In the treated population, MMF improved survival in the first year after transplantation); prophylaxis of acute organ rejection in patients receiving allogeneic hepatic transplants.
Mycophenolate mofetil (CellCept) is indicated for induction and maintenance therapy of patients with Class III-V lupus nephritis (diagnosed according to International Society of Nephrology/Renal Pathology Society classification).

Refer to full prescribing information for corticosteroids and either ciclosporin or tacrolimus, which are used in combination with Mycophenolate mofetil (CellCept).
Transplant patients: Standard dosage for prophylaxis of renal rejection: Adults: A dose of 1 g administered orally (over NO LESS THAN 2 HOURS) twice a day (daily dose of 2 g) is recommended for use in renal transplant patients. Although a dose of 1.5 g administered twice daily (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving 2 g/day of Mycophenolate mofetil (CellCept) demonstrated an overall better safety profile compared to patients receiving 3 g/day of Mycophenolate mofetil (CellCept).
Children (aged 3 months to 18 years): Patients with a body surface area > 1.5 m² may be prescribed Mycophenolate mofetil (CellCept) tablets at a dose of 1 g twice daily (2 g daily dose).
Standard dosage for prophylaxis of cardiac rejection: Adults: A dose of 1.5 g administered orally (over NO LESS THAN 2 HOURS) twice a day (daily dose of 3 g) is recommended for use in cardiac transplant patients.
Children: No data are available for pediatric cardiac transplant patients.
Standard dosage for prophylaxis of hepatic rejection: Adults: A dose of 1.5 g orally twice a day (daily dose of 3 g) is recommended for use in hepatic transplant patients.
Children: No data are available for pediatric hepatic transplant patients.
Standard dosage for treatment of first or refractory renal rejection: Adults: A dose of 1.5 g administered orally (over NO LESS THAN 2 HOURS) twice a day (daily dose of 3 g) is recommended for management of first or refractory rejection.
Children: No data are available for treatment of first or refractory renal rejection in pediatric renal transplant patients.
Oral administration (see Pharmacology: Pharmacokinetics: Absorption under Actions): The initial dose of Mycophenolate mofetil (CellCept) should be given as soon as possible following renal, cardiac or hepatic transplantation.
Lupus nephritis patients: Standard Dosage for Induction Therapy: Adults: A dose of 750 mg-1.5 g administered orally twice a day (daily dose of up to 3 g) is recommended.
Children: A dose of 600 mg/m² administered orally twice a day (up to a maximum of 2 g daily) is recommended.
Standard Dosage for Maintenance Therapy: Adults: A dose of 500 mg-1 g administered orally twice a day is recommended.
Children: A dose of 300 mg/m² administered orally twice a day is recommended.
Mycophenolate mofetil (CellCept) should be used in combination with corticosteroids. Doses should be introduced gradually and adjusted according to clinical response. Therapeutic drug monitoring could help prevent sub-therapeutic exposure (C_min ≥3.0 mg/L or inter-dose AUC ≥35 h*mg/L).
Special Dosage Instructions: Pediatric use: See previous text and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Geriatric use: For transplant patients, no oral dosage adjustment is recommended (see Precautions).
For lupus nephritis patients, no recommendation is available.
For IV administration of Mycophenolate mofetil (CellCept), no recommendation is available.
Renal impairment: For renal transplant patients with severe chronic renal impairment (glomerular filtration rate <25 mL/min/1.73 m²) outside of the immediate post-transplant period or after treatment of acute or refractory rejection, administration of doses greater than 1 g twice daily should be avoided (see Pharmacology: Pharmacokinetics under Actions).
For post-transplant patients with delayed renal graft function, no dose adjustment is recommended but patients should be carefully monitored (see Pharmacology: Pharmacokinetics under Actions).
For cardiac or hepatic transplant patients with severe renal impairment, no data are available.
For lupus nephritis patients with GFR <30 mL/min, therapeutic drug monitoring is advised.
Hepatic impairment: For renal transplant patients with severe hepatic parenchymal disease, no dose adjustments are recommended (see Pharmacology: Pharmacokinetics under Actions).
For cardiac transplant and lupus nephritis patients with severe hepatic parenchymal disease, no data are available.
Patients with neutropenia: For patients that develop neutropenia (absolute neutrophil count <1.3 x 10³/μL), dosing with Mycophenolate mofetil (CellCept) should be interrupted or the dose should be reduced (see Precautions).

Reports of overdoses with mycophenolate mofetil have been received from clinical trials and during post-marketing experience. In many of these cases no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the drug.
It is expected that an overdose of mycophenolate mofetil could possibly result in oversuppression of the immune system and increase susceptibility to infections and bone marrow suppression (see Precautions). If neutropenia develops, dosing with Mycophenolate mofetil (CellCept) should be interrupted or the dose reduced (see Precautions).
MPA cannot be removed by hemodialysis. However, at high MPAG plasma concentrations (>100 μg/mL), small amounts of MPAG are removed. Bile acid sequestrants, such as cholestyramine, can remove MPA by increasing excretion of the drug (see Pharmacology: Pharmacokinetics under Actions).

Allergic reactions to Mycophenolate mofetil (CellCept) have been observed. Therefore, Mycophenolate mofetil (CellCept) is contraindicated in patients with a known hypersensitivity to mycophenolate mofetil or mycophenolic acid (MPA). Mycophenolate mofetil (CellCept) i.v. is also contraindicated in patients with known hypersensitivity to polysorbate 80.
Mycophenolate mofetil (CellCept) is contraindicated during pregnancy due to its mutagenic and teratogenic potential (see Pregnancy under Use in Pregnancy & Lactation).
Mycophenolate mofetil (CellCept) is contraindicated in women of childbearing potential not using highly effective contraceptive methods (see Females and Males of Reproductive Potential under Use in Pregnancy & Lactation).
Mycophenolate mofetil (CellCept) is contraindicated in women who are breastfeeding (see Lactation under Use in Pregnancy & Lactation).

General: Neoplasms: As in all patients receiving immunosuppressive regimens involving combinations of drugs, patients receiving Mycophenolate mofetil (CellCept) 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 with all patients at an 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.
Infections: Oversuppression of the immune system can also increase susceptibility to infection including opportunistic infections, fatal infections and sepsis (see Adverse Reactions). Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation, or infections caused by polyomaviruses. Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. Cases of Progressive Multifocal Leukoencephalopathy (PML) associated with the JC virus, sometimes fatal, have been reported in Mycophenolate mofetil (CellCept) treated patients. The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a Neurologist should be considered as clinically indicated.
BK virus-associated nephropathy has been observed during the use of Mycophenolate mofetil (CellCept) in patients post renal transplant. This infection can be associated with serious outcomes, sometimes leading to renal graft loss. Patient monitoring may help detect patients at risk for BK virus-associated nephropathy. Due to the cytostatic effect of Mycophenolate mofetil (CellCept) on B- and T-lymphocytes, increased severity of COVID-19 may occur. Dose reduction or discontinuation of Mycophenolate mofetil (CellCept) should be considered for patients who develop evidence of BK virus-associated nephropathy, or in cases of clinically significant COVID-19.
Blood and immune system: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Mycophenolate mofetil (CellCept) in combination with other immunosuppressive agents. The mechanism for mycophenolate mofetil induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppression regimen are also unknown. In some cases PRCA was found to be reversible with dose reduction or cessation of Mycophenolate mofetil (CellCept) therapy. In transplant patients however reduced immunosuppression may place the graft at risk.
Patients receiving Mycophenolate mofetil (CellCept) should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients on Mycophenolate mofetil (CellCept) should have complete blood counts weekly during the first month of treatment, twice monthly for the second and third months, then monthly through the first year. In particular, patients receiving Mycophenolate mofetil (CellCept) should be monitored for neutropenia. The development of neutropenia may be related to Mycophenolate mofetil (CellCept), concomitant medications, viral infection or some combination of these causes (see Special Dosage Instructions under Dosage & Administration). If neutropenia develops (absolute neutrophil count <1.3 x 10³/μL), dosing with Mycophenolate mofetil (CellCept) should be interrupted or the dose should be reduced and the patient carefully observed (see Special Dosage Instructions under Dosage & Administration).
Blood Donation: Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of Mycophenolate mofetil (CellCept).
Vaccination: Patients should be advised that during treatment with Mycophenolate mofetil (CellCept) vaccinations may be less effective and the use of live attenuated vaccines should be avoided (see Interactions). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
Gastro-intestinal: Mycophenolate mofetil (CellCept) has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hemorrhage, and perforation. Mycophenolate mofetil (CellCept) should be administered with caution in patients with active digestive system disease.
Mycophenolate mofetil (CellCept) is an inosine monophosphate dehydrogenase (IMPDH) inhibitor; therefore it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
Interactions: Caution should be exercised when switching combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation e.g. ciclosporin to others devoid of this effect e.g. tacrolimus, sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure (see Interactions). Therapeutic drug monitoring of MPA may be appropriate when switching combination therapy (e.g. from ciclosporin to tacrolimus or vice versa) or to ensure adequate immunosuppression in patients with high immunological risk (e.g. risk of rejection, treatment with antibiotics, addition or removal of an interacting medication).
Drugs which interfere with MPA's enterohepatic cycle (e.g. cholestyramine, sevelamer, antibiotics) should be used with caution due to their potential to reduce the plasma levels and efficacy of Mycophenolate mofetil (CellCept) (see Interactions). Sevelamer and other calcium free phosphate binders should be taken 2 hours after Mycophenolate mofetil (CellCept) intake to minimize the impact on the absorption of MPA.
It is recommended that Mycophenolate mofetil (CellCept) should not be administered concomitantly with azathioprine because both have the potential to cause bone marrow suppression and such concomitant administration has not been studied.
Special Populations: Semen Donation: Men should not donate semen during therapy and for 90 days following discontinuation of Mycophenolate mofetil (CellCept).
Drug Abuse and Dependence: There is no data available to show that Mycophenolate mofetil (CellCept) has the potential for drug abuse or dependence.
Ability to Drive and Use Machines: Mycophenolate mofetil (CellCept) may have a moderate influence on the ability to drive and use machines.
Patients should be advised to use caution when driving or using machines if they experience adverse drug reactions such as somnolence, confusion, dizziness, tremor, or hypotension during treatment with Mycophenolate mofetil (CellCept) (see Adverse Reactions).
Renal Impairment: See Dosage & Administration and Pharmacology: Pharmacokinetics under Actions.
Hepatic Impairment: See Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Use in Pregnancy & Lactation: Mycophenolate mofetil (CellCept) is contraindicated in pregnancy and during breastfeeding (see Pregnancy and Lactation under Use in Pregnancy & Lactation).
Use in Children: See Dosage & Administration, Adverse Reactions, and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Use in the Elderly: Geriatric patients may be at an increased risk of adverse events such as certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema, compared with younger individuals (see Adverse Reactions).
See Dosage & Administration, previous text, Adverse Reactions, and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.

Females and Males of Reproductive Potential: Fertility: Mycophenolate mofetil (CellCept) is contraindicated in women of childbearing potential not using highly effective contraceptive methods (see Contraindications). Malformations (including anophthalmia, agnathia, and hydrocephaly) occurred in the first generation offspring of female rats treated with oral doses of mycophenolate mofetil in the absence of maternal toxicity (see Pharmacology: Toxicology: Nonclinical Safety: Impairment of Fertility under Actions). No effect was seen on the fertility of male rats treated with mycophenolate mofetil.
Pregnancy Testing: Prior to starting therapy with Mycophenolate mofetil (CellCept), female patients of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mlU/mL. A second test should be performed 8-10 days later. Repeat pregnancy tests should be performed during routine follow-up visits. Results of all pregnancy tests should be discussed with the patient. Patients should be instructed to consult their physician immediately should pregnancy occur.
Contraception: Females: Mycophenolate mofetil (CellCept) is contraindicated in women of childbearing potential not using highly effective contraceptive methods (see Contraindications).
Before the start of treatment, female patients of reproductive potential must be made aware of the increased risk of pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention, and planning. Women of childbearing potential should use two reliable forms of contraception simultaneously, at least one of which must be highly effective, before beginning Mycophenolate mofetil (CellCept) therapy, during therapy, and for six weeks following discontinuation of therapy, unless abstinence is the chosen method of contraception.
Males: Limited clinical evidence is currently available on paternal exposure to Mycophenolate mofetil (CellCept). This evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to mycophenolate.
Non-clinical evidence shows that the dose of mycophenolate that could be transferred via the seminal fluid to a potentially pregnant partner is 30-fold lower than the concentration without teratogenic effects in animals, and 200-fold lower than the lowest teratogenic concentration in animals. Therefore, the risk of harm mediated via seminal fluid is considered negligible. However, genotoxic effects have been observed in animal studies at exposures exceeding the human therapeutic exposures by approximately 2.5-times. Thus, the risk of genotoxic effects on sperm cells cannot completely be excluded.
In absence of sufficient data to exclude a risk of harm to the fetus conceived during or directly after the treatment of the father, the following precautionary measure is recommended: sexually active male patients and/or their female partners are recommended to use effective contraception during treatment of the male patient and for at least 90 days after cessation of treatment.
Pregnancy: Mycophenolate mofetil (CellCept) is contraindicated during pregnancy due to its mutagenic and teratogenic potential (see Contraindications). Mycophenolate mofetil (CellCept) is a human teratogen, with an increased risk of spontaneous abortions (mainly in the first trimester) and congenital malformations in case of maternal exposure during pregnancy (see Post Marketing under Adverse Reactions). In the medical literature, the risk of spontaneous abortions has been reported as 45 to 49% following mycophenolate mofetil exposure, compared to a reported rate between 12 and 33% in solid organ transplant patients treated with other immunosuppressants.
Congenital malformations (including multiple malformations in individual newborns) have been reported in 23 to 27% of live births in mycophenolate mofetil exposed pregnancies in published literature. For comparison the risk of malformations is estimated at approximately 2% of live births in the overall population and at approximately 4 to 5 % in solid organ transplant patients treated with immunosuppressants other than mycophenolate mofetil.
The following malformations were most frequently reported post-marketing, in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy: Facial malformations such as cleft lip, cleft palate, micrognathia and hypertelorism of the orbits; Abnormalities of the ear (e.g. abnormally formed or absent external/middle ear) and eye (e.g. coloboma, microphthalmos); Malformations of the fingers (e.g. polydactyly, syndactyly, brachydactyly); Cardiac abnormalities such as atrial and ventricular septal defects; Esophageal malformations (e.g. esophageal atresia); Nervous system malformations (such as spina bifida).
These findings were consistent with teratology studies performed in rats and rabbits where fetal resorptions and malformations occurred in absence of maternal toxicity (see Pharmacology: Toxicology: Nonclinical Safety: Reproductive Toxicity under Actions).
Labor and delivery: The safe use of Mycophenolate mofetil (CellCept) during labor and delivery has not been established.
Lactation: It is not known whether the Mycophenolate mofetil (CellCept) is excreted in human breast milk. Due to the potential for serious adverse reactions in nursing infants, Mycophenolate mofetil (CellCept) is contraindicated during breastfeeding (see Contraindications).
Although the relevance to humans is unknown, studies in rats have shown mycophenolate mofetil to be excreted in milk.

The safety profile presented in this section is based on data from both clinical trials and post marketing experience and has been shown to be consistent across transplant and lupus nephritis patient populations.
Clinical Trials: An estimated total of 1557 patients received Mycophenolate mofetil (CellCept) during pivotal clinical trials in the prevention of acute organ rejection. Of these, 991 were included in the pooled renal studies ICM1866, MYC022, MYC023, 277 were included in the hepatic study MYC2646, and 289 were included in the cardiac study MYC1864. Patients in all study arms also received ciclosporin and corticosteroids.
Diarrhea, leukopenia, sepsis, and vomiting were among the most common and/or serious adverse drug reactions associated with the administration of Mycophenolate mofetil (CellCept) in the pivotal trials. There was also evidence of a higher frequency of certain types of infection, e.g. opportunistic infections (see Precautions).
In the three pivotal trials for prevention of renal transplant rejection, patients receiving 2 g per day of Mycophenolate mofetil (CellCept) demonstrated an overall better safety profile than patients receiving 3 g Mycophenolate mofetil (CellCept). The safety profile of Mycophenolate mofetil (CellCept) in patients treated for refractory renal transplant rejection was similar to that observed in the pivotal trials for prevention of renal rejection at doses of 3 g per day. Diarrhea and leukopenia, followed by anemia, nausea, abdominal pain, sepsis, nausea and vomiting, and dyspepsia were the predominant adverse events reported more frequently in patients receiving Mycophenolate mofetil (CellCept) in comparison to patients receiving i.v. corticosteroids.
The adverse event profile associated with the administration of Mycophenolate mofetil (CellCept) i.v. has been shown to be similar to that observed after oral administration.
Tabulated summary of adverse drug reactions from clinical trials: Adverse drug reactions from clinical trials (Tables 7a and 7b) are listed by MedDRA system organ class along with their incidence. The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Due to the large differences observed in the frequency of certain ADRs across the different transplant indications, the frequency is presented separately for renal, hepatic and cardiac transplant patients. (See Tables 7a and 7b.)

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Description of selected adverse drug reactions: Infections: All patients treated with immunosuppressants are at increased risk of bacterial, viral, and fungal infections (some of which may lead to a fatal outcome), including those caused by opportunistic agents and latent viral reactivation (see Precautions). The risk increases with total immunosuppressive load (see Precautions). The most serious infections were sepsis and peritonitis. The most common opportunistic infections in patients receiving Mycophenolate mofetil (CellCept) with other immunosuppressants were mucocutaneous candida, CMV viremia/syndrome, and herpes simplex. The proportion of patients with CMV viremia/syndrome was 13.5%.
Malignancies: Patients receiving Mycophenolate mofetil (CellCept) as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see Precautions).
Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in the incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1 year, but less than 3 years. In supportive clinical trials of treatment of refractory renal rejection, the lymphoma rate was 3.9% at an average follow-up of 42 months.
Blood and lymphatic disorders: Cytopenias, including leukopenia, anemia, thrombocytopenia and pancytopenia, are a known risk associated with mycophenolate and may lead or contribute to the occurrence of infections and hemorrhages (see Precautions).
Gastrointestinal: The most serious gastrointestinal disorders were ulceration and hemorrhage which are known risks associated with Mycophenolate mofetil (CellCept). Mouth, esophageal, gastric, duodenal, and intestinal ulcers often complicated by hemorrhage, as well as hematemesis, melena, and hemorrhagic forms of gastritis and colitis were commonly reported during the pivotal clinical trials. The most common gastrointestinal disorders however, were diarrhea, nausea and vomiting. Endoscopic investigation of patients with Mycophenolate mofetil (CellCept)-related diarrhea have revealed isolated cases of intestinal villous atrophy (see Precautions).
General disorders and administration site conditions: Edema, including peripheral, face and scrotal edema, was reported very commonly during the pivotal trials. Musculoskeletal pain such as myalgia, and neck and back pain were also very commonly reported.
Special Populations: Children (aged 3 months to 18 years): The type and frequency of adverse drug reactions in a clinical study of 100 pediatric patients aged 3 months to 18 years given 600 mg/m² mycophenolate mofetil orally twice daily, were generally similar to those observed in adult patients given 1 g Mycophenolate mofetil (CellCept) twice daily. However, the following treatment-related adverse events occurred with a frequency of ≥ 10 % in children and were more frequent in the pediatric population, particularly in children under 6 years of age, when the frequency of treatment-related adverse events were compared to adults: diarrhea, leukopenia, sepsis, infection, and anemia.
Elderly patients (≥65 years): Elderly patients, particularly those who are receiving Mycophenolate mofetil (CellCept) as part of a combination immunosuppressive regimen, may be at greater increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema, compared to younger individuals (see Precautions).
Post Marketing: Adverse drug reactions in Table 8 are listed according to system organ class in MedDRA and the corresponding frequency category estimation for each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 8.)

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Infections: Serious life-threatening infections such as meningitis and infectious endocarditis have been reported occasionally and there is evidence of a higher frequency of certain types of infections such as tuberculosis and atypical mycobacterial infection.
Progressive Multifocal Leukoencephalopathy (PML) and BK virus-associated nephropathy have been reported in Mycophenolate mofetil (CellCept) treated patients (see Precautions).
Congenital disorders and Pregnancy, puerperium, and perinatal conditions: See Pregnancy for further information under Use in Pregnancy & Lactation.
General disorders and administration site conditions: De novo purine synthesis inhibitors-associated acute inflammatory syndrome is a newly described paradoxical pro-inflammatory reaction associated with mycophenolate and other purine synthesis inhibitors, characterized by fever, arthralgias, arthritis, muscle pain and elevated inflammatory markers. Anecdotal literature reports showed rapid improvements following discontinuation of the drug.

DNA Polymerase Inhibitors (acyclovir, ganciclovir): Acyclovir: Higher MPAG (the phenolic glucuronide of MPA) and acyclovir plasma concentrations were observed when mycophenolate mofetil was administered with acyclovir than when the drugs were administered alone. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its prodrugs e.g. valacyclovir to compete for tubular secretion, further increasing the concentrations of both drugs.
Ganciclovir: Based on the results of a single dose administration study of recommended doses of oral mycophenolate and i.v. ganciclovir and the known effects of renal impairment on the pharmacokinetics of MMF (see Pharmacology: Pharmacokinetics under Actions and Precautions) and ganciclovir, it is anticipated that coadministration of these agents (which compete for mechanisms of renal tubular secretion) will result in increases in MPAG and ganciclovir concentration. No substantial alteration of MPA pharmacokinetics is anticipated and MMF dose adjustment is not required. In patients with renal impairment in whom MMF and ganciclovir or its prodrugs valganciclovir are co-administered, patients should be monitored carefully.
Antacids and proton pump inhibitors (PPIs): Decreased mycophenolic acid (MPA) exposure has been observed when antacids, such as magnesium and aluminium hydroxides, and PPIs, including lansoprazole and pantoprazole were administered with Mycophenolate mofetil (CellCept). When comparing rates of transplant rejection or rates of graft loss between Mycophenolate mofetil (CellCept) patients taking PPIs vs. Mycophenolate mofetil (CellCept) patients not taking PPIs, no significant differences were seen. These data support extrapolation of this finding to all antacids because the reduction in exposure when Mycophenolate mofetil (CellCept) was co-administered with magnesium and aluminium hydroxides is considerably lower than when Mycophenolate mofetil (CellCept) was co-administered with PPIs.
Sequestrants: Cholestyramine: Following single-dose administration of 1.5 g of mycophenolate mofetil to normal healthy subjects pretreated with 4 g three times daily of cholestyramine for 4 days, there was a 40% reduction in the AUC of MPA. Caution should be used during concomitant administration of drugs that interfere with enterohepatic circulation (see Precautions).
Sevelamer: Concomitant administration of sevelamer and Mycophenolate mofetil (CellCept) in adults and pediatric patients decreased the MPA C_max and AUC_0-12 by 30% and 25%, respectively (see Interactions under Precautions).
Immunosuppressants: Ciclosporin A: Ciclosporin A (CsA) pharmacokinetics were unaffected by mycophenolate mofetil. However, CsA interferes with MPA enterohepatic recycling, resulting in reduced MPA exposures by 30-50% in renal transplant patients treated with Mycophenolate mofetil (CellCept) and CsA compared with patients receiving sirolimus or belatacept and similar doses of Mycophenolate mofetil (CellCept). Conversely, changes of MPA exposure should be expected when switching patients from CsA to one of the immunosuppressants which do not interfere with MPA's enterohepatic cycle (see Precautions).
Tacrolimus: Exposure to tacrolimus concomitantly administered with Mycophenolate mofetil (CellCept) had no effect on the AUC or C_max of MPA in liver transplant recipients. A similar finding was observed in a recent study in kidney transplant recipients.
In renal transplant patients it was shown that the tacrolimus concentration did not appear to be altered by Mycophenolate mofetil (CellCept).
However, in hepatic transplant patients, there was an increase of approximately 20% in tacrolimus AUC when multiple doses of Mycophenolate mofetil (CellCept) (1.5 g twice daily) were administered to patients taking tacrolimus.
Antibiotics: Rifampicin: After correction for dose a 70% decrease in MPA exposure (AUC_0-12) has been observed with concomitant rifampicin administration in a single heart-lung transplant patient. It is therefore recommended to monitor MPA exposure levels and to adjust Mycophenolate mofetil (CellCept) doses accordingly to maintain clinical efficacy when the drugs are administered concomitantly.
Antibiotics eliminating β-glucuronidase-producing bacteria in the intestine (e.g. aminoglycoside, cephalosporin, fluoroquinolone, and penicillin classes of antibiotics) may interfere with MPAG/MPA enterohepatic recirculation thus leading to reduced systemic MPA exposure (see Interactions under Precautions).
Information concerning the following antibiotics is available: Ciprofloxacin or amoxicillin plus clavulanic acid: Reductions in pre-dose (trough) MPA concentrations of 54% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. Effects tended to diminish with continued antibiotic use and cease after discontinuation. The change in pre-dose level may not accurately represent changes in overall MPA exposure, therefore clinical relevance of these observations is unclear.
Norfloxacin and metronidazole: Norfloxacin in combination with metronidazole reduced the MPA AUC_0-48 by 30% following a single dose of Mycophenolate mofetil (CellCept). No such effect on the systemic exposure of MPA with either of these antibiotics occurred when they were administered separately.
Trimethoprim/sulphamethoxazole: No effect on the systemic exposure of MPA (AUC, C_max) was seen with the combination trimethoprim/sulfamethoxazole.
Oral contraceptives: A study of coadministration of Mycophenolate mofetil (CellCept) (1 g twice daily) and combined oral contraceptives containing ethinylestradiol (0.02-0.04 mg) and levonorgestrel (0.05-0.20 mg), desogestrel (0.15 mg) or gestodene (0.05-0.10 mg) conducted in 18 women with psoriasis over 3 menstrual cycles showed no clinically relevant influence of Mycophenolate mofetil (CellCept) on serum levels of progesterone, LH and FSH, thus indicating no influence of Mycophenolate mofetil (CellCept) on the ovulation-suppressing action of the oral contraceptives. The pharmacokinetics of oral contraceptives were not affected to a clinically relevant degree by coadministration of Mycophenolate mofetil (CellCept) (see Females and Males of Reproductive Potential under Use in Pregnancy & Lactation).
Other interactions: Concomitant administration of drugs inhibiting glucuronidation of MPA may increase MPA exposure (e.g., increase of MPA AUC_0-∞ by 35% was observed with concomitant administration of isavuconazole). Caution is therefore recommended when administering these drugs concomitantly with Mycophenolate mofetil (CellCept).
Concomitant administration of telmisartan and Mycophenolate mofetil (CellCept) resulted in an approximately 30% decrease of mycophenolic acid (MPA) concentrations. Telmisartan changes MPA's elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression which in turn results in an enhanced UGT1A9 expression and activity, enhancing glucuronidation. When comparing rates of transplant rejection, rates of graft loss or adverse event profiles between Mycophenolate mofetil (CellCept) patients with and without concomitant telmisartan medication, no clinical consequences of the pharmacokinetic DDI were seen.
Coadministration of probenecid with mycophenolate mofetil in monkeys raises the plasma AUC of MPAG 3-fold. Thus, other drugs known to undergo renal tubular secretion may compete with MPAG and thereby raise plasma concentrations of MPAG or the other drug undergoing tubular secretion.
Live vaccines: Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see Precautions).

Special Instructions for Use, Handling and Disposal: Mycophenolate mofetil (CellCept) oral administration: Mycophenolate mofetil has demonstrated teratogenic effects (see Pregnancy under Use in Pregnancy & Lactation), therefore Mycophenolate mofetil (CellCept) tablets should not be crushed or opened.

Mycophenolate mofetil (CellCept) tablets: Store at temperatures not exceeding 25°C.

Immunosuppressants

L04AA06 - mycophenolic acid ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.

Rx