CellCept

CellCept

mycophenolic acid

Manufacturer:

Roche

Marketer:

DKSH
Full Prescribing Info
Contents
Mycophenolate mofetil.
Description
Active ingredient: mycophenolate mofetil.
Oral administration: Each capsule contains 250 mg mycophenolate mofetil; each tablet contains 500 mg mycophenolate mofetil.
Intravenous administration: Each vial contain the equivalent to 500mg mycophenolate mofetil (as the hydrochloride salt).
Action
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 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 utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.
Clinical/Efficacy Studies: 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. CellCept has also been administered in combination with cyclosporin and corticosteroids for the treatment of refractory renal rejection episodes. Prior to treatment with CellCept, patients may have also received antilymphocyte globulin, antithymocyte globulin and OKT3. CellCept has further been used in clinical trials together with daclizumab and tacrolimus.
Prevention of organ rejection: The safety and efficacy of CellCept in combination with corticosteroids and ciclosporin for the prevention of organ rejection were assessed in renal transplant patients in three randomised, double-blind, multicentre trials, in cardiac patients in one randomised double-blind, multicentre trial, and in hepatic patients in one randomised, double-blind, multicentre trial.
Renal transplant: The three studies compared two dose levels of oral 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). 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.
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 summarise 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 summarised separately. Patients who prematurely discontinued treatment were not followed for the occurrence of acute rejection after termination. More patients receiving CellCept discontinued (without prior biopsy-proven rejection, death or graft loss) than discontinued in the control groups, with the highest rate in the CellCept 3 g/day group. Therefore, the acute rejection rates may be underestimates, particularly in the CellCept 3 g/day group. (See Table 1.)

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

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Cardiac transplant: A double-blind, randomised, comparative, parallel-group, multicentre 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 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 haemodynamic 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 3 prematurely discontinued treatment were followed for the occurrence of allograft rejection for up to 6 months and for the occurrence of death for 1 year.
1. Rejection: No difference was established between CellCept and azathioprine (AZA) with respect to biopsy-proven rejection with haemodynamic compromise, presented as follows. (See Table 3.)

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2. Survival: In the enrolled patients, there were no statistically significant differences between patients randomised to MMF and patients randomised 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, presented as follows. (See Table 4.)

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Hepatic transplant: A double-blind, randomised, comparative, parallel-group, multicentre study in primary hepatic transplant recipients was performed at 16 centres 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 CellCept 1g twice daily intravenously for up to 14 days followed by 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 posttransplantation, 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 posttransplantation. 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 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 randomised, 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-Haenzel 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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Pharmacokinetics: The pharmacokinetics of MMF have been studied in renal, cardiac and hepatic transplant patients.
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 1.5g oral MMF dose or 1g i.v. MMF dose have similar MPA levels compared to renal transplant patients receiving 1g oral or i.v. MMF.
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 quantification (0.4 μg/mL).
Immediately post-transplant period (<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). MPA AUC values obtained following administration of 1g twice daily intravenous CellCept at the recommended infusion rate to renal transplant patients in the immediate post-transplant phase are comparable to those observed following oral dosing. In hepatic transplant patients, administration of 1g twice daily intravenous CellCept followed by 1.5g twice daily. Oral CellCept resulted in MPA AUC values similar to those found in renal transplant patients administered 1g 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 Cmax was decreased by 40% in the presence of food.
Equivalence of oral dosage forms: Bioequivalence of CellCept oral dosage forms have been evaluated. Two 500 mg tablets have been shown to be bioequivalent to four 250mg capsules.
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 co-administration of cholestyramine (4 g three times daily), consistent with interruption of enterohepatic recirculation. At clinically relevant concentrations, MPA is 97% bound to plasma albumin.
Metabolism: MPA is metabolized principally by glucuronyl transferase (isoform UGT1A9) to form the inactive phenolic glucoronide 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 (diarrhoea, leucopenia).
Elimination: Oral administration of radiolabelled mycophenolate mofetil resulted in complete recovery of the administered dose, with 93% of the administered dose recovered in the urine and 6% recovered in the feces. Most (about 87%) of the administered dose is excreted in the urine as MPAG. A negligible amount of drug (<1% of dose) is excreted as MPA in the urine.
At clinically encountered concentrations, MPA and MPAG are not removed by hemodialysis. However, at high MPAG concentrations (>100μg/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: Patients with severe 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/1.73m2) were 28-75% higher than those observed in normal healthy subjects or subjects with lesser degrees of renal impairment. However, 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 or 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.
Patients with delayed renal graft function post-transplant: In patients with delayed graft function post-transplant, mean MPA AUC0-12 was comparable to that seen in post-transplant patients without delayed graft function. There may be a transient increase in the freefraction and concentration of plasma MPA in patients with delayed renal graft function. Dose adjustment of Cellcept does not appear to be necessary (see Special Dosage Instructions under Dosage & Administration). Mean plasma MPAG AUC0-12 was 2- to 3-fold higher than in post-transplant patients without delayed 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.
Patients with 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.
Elderly (≥ 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: Preclinical 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 non-clinical 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).
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 patients. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation. Teratogenicity: In teratology studies in rats and rabbits, foetal 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 Use in Pregnancy & Lactation.
Other: In experimental models, mycophenolate mofetil was not tumourigenic. The highest dose tested in the animal carcinogenicity studies resulted in approximately 2-3 times the systemic exposure (AUC or Cmax) observed in renal transplant patients at the recommended clinical dose of 2g/day and 1.3-2 times the systemic exposure (AUC or Cmax) observed in cardiac transplant patients at the recommended clinical dose of 3 g/day. 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.
Indications/Uses
CellCept is indicated for: prophylaxis of acute organ rejection and treatment of refractory organ rejection in patients receiving allogeneic renal transplants.
Prophylaxis of acute organ rejection and increased graft and patient survival in patients receiving allogeneic cardiac transplants.
Prophylaxis of acute organ rejection in patients receiving allogeneic hepatic transplants.
CellCept should be used concomitantly with cyclosporin and corticosteroids.
Dosage/Direction for Use
Standard Dosage for prophylaxis of renal rejection: A dose of 1 g administered orally or intravenously (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 1.5g administered twice daily (daily dose of 3g) 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 2g per day of CellCept demonstrated an overall better safety profile compared to patients receiving 3g per day of CellCept.
Standard Dosage for prophylaxis of cardiac rejection: A dose of 1.5g administered orally or intravenously (over NO LESS THAN 2 HOURS) twice a day (daily dose of 3g) is recommended for use in cardiac transplant patients.
Standard Dosage for prophylaxis of hepatic rejection: A dose of 1.0g administred intravenousely (over NO LESS THAN 2 HOURS) twice a day (daily dose of 2g) or 1.5g orally twice a day (daily dose of 3g) is recommended for use in hepatic transplant patients.
For Oral Administration only: Standard dosage for treatment of refractory renal rejection: A dose of 1.5 g administered twice a day (daily dose of 3g) is recommended for management of refractory rejection.
Oral administration (see Pharmacology: Pharmacokinetics: Absorption under Actions): The initial dose of CellCept should be given as soon as possible following renal, cardiac or hepatic transplantation.
Intravenous administration: Caution: CellCept i.v. solution must not be administered by rapid or bolus intravenous injection.
CellCept i.v. is an alternative dosage form to CellCept capsules and tablets recommended for patients unable to take oral CellCept. CellCept i.v. should be administered within 24 hours following transplantation. CellCept i.v. can be administered for up to 14 days. Patients should be switched to oral CellCept as soon as they can tolerate oral medication.
Following reconstitution and dilution with 5% Dextrose intravenous infusion to a concentration of 6 mg/mL, CellCept i.v. must be administered by slow intravenous infusion over a period of NO LESS THAN 2 HOURS by either a peripheral or a central vein.
Special dosage instructions: Patients with neutropenia: If neutropenia develops (absolute neutrophil count <1.3 x 103/μl), dosing with CellCept should be interrupted or the dose should be reduced and the patient carefully observed (see Precautions).
For dosage instructions in special population, please refer to Renal Impairment, Hepatic Impairment and Use in the Elderly under Precautions.
Overdosage
Reports of overdoses with mycophenolate mofetil have been received from clinical trials and during postmarketing 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 CellCept should be interrupted or the dose reduced (see Precautions).
MPA cannot be removed by haemodialysis. 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).
Contraindications
Allergic reactions to CellCept have been observed. Therefore, CellCept is contraindicated in patients with hypersensitivity to mycophenolate mofetil or mycophenolic acid. CellCept i.v. is contraindicated in patients who are allergic to polysorbate 80.
CellCept is contraindicated during pregnancy due to its mutagenic and teratogenic potential (see Use in Pregnancy & Lactation).
CellCept is contraindicated in women of childbearing potential not using highly effective contraceptive methods (see Females and Males of Reproductive Potential under Precautions).
CellCept is contraindicated in women who are breastfeeding (see Use in Pregnancy & Lactation).
Special Precautions
General: Neoplasms: As in all patients receiving immunosuppressive regimens involving combinations of drugs, patients receiving CellCept as part of an immunosuppressive regimen are at an 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 by heptatitis 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 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 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. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy.
There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving mycophenolate mofetil in combination with other immunosuppressants. In some of these cases switching mycophenolate mofetil to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on mycophenolate mofetil who develop recurrent infections should have their serum immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobulinaemia, appropriate clinical action should be considered taking into account the potent cytostatic effects that mycophenolic acid has on T- and B-lymphocytes.
There have been published reports of bronchiectasis in adults and children who received mycophenolate mofetil in combination with other immunosuppressants. In some of these cases switching mycophenolate mofetil to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinaemia or to a direct effect on the lung. There have also been isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal (see Adverse Reactions). It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.
Blood and immune system: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with 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 CellCept therapy. In transplant patients however reduced immunosuppression may place the graft at risk.
Patients receiving CellCept should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients on 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 CellCept should be monitored for neutropenia. The development of neutropenia may be related to 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 CellCept should be interrupted or the dose should be reduced and the patient carefully observed (see Special Dosage Instructions under Dosage & Administration).
Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of CellCept.
Patients should be advised that during treatment with 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: CellCept has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hemorrhage, and perforation. CellCept should be administered with caution in patients with active digestive system disease.
CellCept is an IMPDH (inosine monophosphate dehydrogenase) inhibitor therefore it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
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. Drugs which interfere with MPA's enterohepatic cycle (e.g. cholestyramine, antibiotics) should be used with caution due to their potential to reduce the plasma levels and efficacy of CellCept (see Interactions). Some degree of enterohepatic recirculation is anticipated following i.v. administration of CellCept. 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). It is recommended that 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: Elderly patients may be at an increased risk of adverse events such as certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared with younger individuals (see Adverse Reactions).
CellCept is contraindicated in pregnancy and during breastfeeding (see Use in Pregnancy & Lactation).
Men should not donate semen during therapy and for 90 days following discontinuation of CellCept.
Administration of doses greater than 1 g twice daily. to renal transplant patients with severe chronic renal impairment should be avoided (see Pharmacology: Pharmacokinetics under Actions and Special Dosage Instructions under Dosage & Administration).
No dose adjustment is recommended for post-transplant patients with delayed renal graft function, but patients should be carefully monitored (see Pharmacology: Pharmacokinetics under Actions and Special Dosage Instructions under Dosage & Administration). No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
Ability to Drive and Use Machines: 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 CellCept (see Adverse Reactions).
Renal Impairment: Patients with severe renal impairment: In renal transplant patients with severe chronic renal impairment (glomerular filtration rate <25 mL/min/1.73m2), outside of the immediate post-transplant period or after treatment of acute of refractory rejection, doses greater than 1 g administered twice a day should be avoided. (see Precautions).
No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
Patients with delayed renal graft function post-transplant: No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively. (See Pharmacology: Pharmacokinetics under Actions.)
Hepatic Impairment: No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease. (see Pharmacology: Pharmacokinetics under Actions). No data are available for cardiac transplant patients with severe hepatic parenchymal disease.
Use in the Elderly:
The recommended oral doses of 1 g twice daily for renal transplant patients, 1.5 g twice daily. For cardiac or hepatic transplant patients is appropriate for elderly patients (see Precautions, Adverse Reactions, and Pharmacology: Pharmacokinetics: Pharmacokinetics in special populations under Actions).
Use In Pregnancy & Lactation
Females And Males Of Reproductive Potential: Fertility: 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: Preclinical 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 CellCept, female patients of childbearing potential must have two negative serum or urine pregnancy tests with a sensitivity of at least 25mIU/mL. A second test should be performed 8-10 days later. If it is not possible to perform two tests 8-10 days apart before treatment starts (because of the timing of transplant organ availability), a pregnancy test must be performed immediately before starting treatment and a second test performed 8-10 days later.
Contraception: Females: Cellcept is contraindicated in women of childbearing potential not using highly effective contraceptive methods (see Contraindications).
Before the start of treatment, female and male 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 child bearing potential should use two reliable forms of contraception simultaneously, including at least one of which must be highly effective before beginning 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 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:
CellCept is contraindicated during pregnancy due to its mutagenic and teratogenic potential (see Contraindications). 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 immunosupressants 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; Oesophageal malformations (e.g. oesophageal 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: Preclinical Safety: Teratogenicity under Actios).
Labor and delivery: The safe use of CellCept during labor and delivery has not been established.
Lactation: It is not known whether the drug is excreted in human milk. Due to the potential for serious adverse reactions in nursing infants, CellCept is contraindicated during breastfeeding (see Contraindication).
Although the relevance to humans is unknown, tudies in rats have shown mycophenolate mofetil to be excreted in milk.
Adverse Reactions
The adverse event profile associated with the use of immunosuppressive drugs is often difficult to establish owing to patients' underlying diseases and the concurrent use of many other medications.
Clinical trials: An estimated total of 1557 patients received 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 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 CellCept demonstrated an overall better safety profile than patients receiving 3 g CellCept. The safety profile of 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 CellCept in comparison to patients receiving i.v. corticosteroids.
Tabulated summary of adverse drug reactions from clinical trials: Adverse drug reactions from clinical trials (Table 7) 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 Table 7.)

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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 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 CellCept as part of an immunosuppressive regime 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 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 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 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. The safety and efficacy of Cellcept in children below the age of 18 years have not been established.
Elderly patients (≥ 65 years): Elderly patients, particularly those who are receiving 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 CellCept treated patients (see Precautions).
Congenital disorders and Pregnancy, puerperium, and perinatal conditions: See Use in Pregnancy & Lactation.
Drug Interactions
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 prodrug, e.g. valacyclovir to compete for tubular secretion, further increasing the concentrations of both drugs.
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 CellCept. When comparing rates of transplant rejection or rates of graft loss between CellCept patients taking PPIs vs. CellCept patients not taking PPIs, no significant differences were seen. This data support extrapolation of this finding to all antacids because the reduction in exposure when CellCept was co-administered with magnesium and aluminium hydroxides is considerably lower than when CellCept was co-administered with PPIs.
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).
Cyclosporin A: Cyclosporin 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 CellCept and CsA compared with patients receiving sirolimus or belatacept and similar doses of 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).
Drugs affecting glucuronidation: Concomitant administration of drugs inhibiting glucuronidation of MPA may increase MPA exposure (e.g., increase of MPA AUC0-∞ by 35% was observed with concomitant administration of isavuconazole). Caution is therefore recommended when administering these drugs concomitantly with CellCept.
Telmisartan: Concomitant administration of telmisartan and 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. When comparing rates of transplant rejection, rates of graft loss or adverse event profiles between CellCept patients with and without concomitant telmisartan medication, no clinical consequences of the pharmacokinetic DDI were seen. However, caution should be exercised when CellCept is co-administered with telmisartan and monitoring of CellCept levels may be considered.
Ganciclovir: Based on the results of a single-dose administration study of recommended doses of oral mycophenolate and iv ganciclovir and the known effects of renal impairment on the pharmacokinetics of mycophenolate mofetil (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 mycophenolate mofetil dose adjustment is not required. In patients with renal impairment in which mycophenolate mofetil and ganciclovir or its prodrugs, e.g. valganciclovir are coadministered, patients should be monitored carefully.
Oral contraceptives: A study of coadministration of CellCept (1g 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 CellCept on serum levels of progesterone, LH and FSH, thus indicating no influence of 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 CellCept (see Females and Males of Reproductive Potential under Precautions).
Rifampicin: After correction for dose a 70% decrease in MPA exposure (AUC0-12h) 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 CellCept doses accordingly to maintain clinical efficacy when the drugs are administered concomitantly.
Tacrolimus: Exposure to tacrolimus concomitantly administered with CellCept had no effect on the AUC or Cmax 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 CellCept.
However, in hepatic transplant patients, there was an increase of approximately 20% in tacrolimus AUC when multiple doses of CellCept (1.5 g twice daily.) were administered to patients taking tacrolimus.
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 predose 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 AUC0- 48 by 30% following a single dose of CellCept. No such effect on the systemic exposure of MPA with either of these antibiotics occurred when they were administered separately.
Other interactions: Co-administration 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.
Concomitant administration of sevelamer and CellCept in adults and pediatric patients decreased the MPA Cmax and AUC0-12 by 30% and 25 %, respectively. This data suggest that sevelamer and other calcium free phosphate binders preferentially should be given 2 hours after CellCept intake to minimise the impact on the absorption of MPA.
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).
Caution For Usage
Special Instructions for Use, Handling and Disposal: CellCept oral administration: Mycophenolate mofetil has demonstrated teratogenic effects (see Use in Pregnancy & Lactation), therefore CellCept tablets and capsules should not be crushed or opened. Patients should also avoid inhalation or contact of the skin or mucous membranes with the powder contained in CellCept capsules and oral suspension (before reconstitution). If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.
CellCept intravenous administration: Because mycophenolate mofetil has demonstrated teratogenic effects, caution should be exercised in the handling and preparation of solutions of Cellcept i.v. Avoid direct contact of prepared solutions of Cellcept i.v. with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.
Preparation of infusion solution (6mg/mL): CellCept i.v. does not contain an antibacterial preservative; therefore, reconstitution and dilution of the product must be performed under aseptic conditions.
CellCept i.v.infusion solution must be prepared in two steps; the first step is a reconstitution step with 5% Dextrose Intravenous Infusion and the second step is a dilution step with 5% Dextrose Intravenous Infusion. A detailed description of the preparation is given as follows: Step 1: Two vials of CellCept i.v. are used for preparing each 1g dose, three vials are needed for each 1.5g dose. Reconstitute the contents of each vial by injecting 14ml of 5% Dextrose Intravenous Infusion.
Gently shake the vial to dissolve the drug yielding a slightly yellow solution.
Inspect the resulting solution for particulate matter and discolouration prior to further dilution. Discard the vial(s) if particulate matter or discolouration is observed.
Step 2: To prepare a 1 g dose, further dilute the contents of the two reconstituted vials (approx. 2 x15 mL) into 140mL of 5% Dextrose Intravenous Infusion. To prepare a 1.5 g dose, further dilute the contents of the three reconstituted vials (approx. 3 x 15 mL) into 210 ml of 5% Dextrose intravenous infusion. The final concentration of both solutions is approximately 6 mg mycophenolate mofetil per mL.
Inspect the infusion solution for particulate matter or discolouration. Discard the infusion solution if particulate matter or discolouration is observed.
Caution: Cellcept i.v. solution must not be administered by rapid or bolus intravenous injection (see Precautions).
If the infusion solution is not prepared immediately prior to administration, the commencement of administration of the infusion solution should be within 4 hours from reconstitution and dilution of the drug product. Keep solutions at 15-30°C.
Any unused product or waste materials should be disposed of in accordance with local requirements.
Incompatibilities: CellCept i.v. is incompatible with i.v. infusion solutions other than Dextrose Intravenous Infusion. CellCept i.v. should not be mixed with or administered concurrently via the same infusion catheter as other i.v. drugs or infusion admixtures.
Storage
CellCept capsules and tablets: Do not store above 25°C, store in the original package.
CellCept powder for solution for infusion: Do not store above 30°C.
Reconstituted solution and infusion solution: Stored at 15-30°C.
MIMS Class
ATC Classification
L04AA06 - mycophenolic acid ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.
Presentation/Packing
Cap 250 mg x 100's. Tab 500 mg x 50's. Powd for soln for infusion (vial) 500 mg x 4's.
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