Myfortic

Myfortic

mycophenolic acid

Manufacturer:

Novartis

Distributor:

DKSH
Full Prescribing Info
Contents
Mycophenolate sodium.
Description
Excipients/Inactive Ingredients: Maize starch, povidone (K-30), crospovidone, lactose, colloidal silicon dioxide, magnesium stearate. Coating: Hypromellose phthalate/hydroxypropylmethylcellulose phthalate, titanium dioxide, yellow iron oxide and indigotin.
Action
Pharmacotherapeutic Group: Immunosuppressant.
Pharmacology: Pharmacodynamics: Mechanism of Action: Mycophenolic acid (MPA) inhibits the proliferation of T- and B-lymphocytes more potent than other cells because in contrast to other cell types that can utilize purine salvage pathways, the lymphocyte proliferation is critically dependent on de novo synthesis. Thus, the mode of action is complementary to calcineurin inhibitors, which interfere with cytokine transcription and resting T-lymphocytes.
Pharmacokinetics: Absorption: Following oral administration, mycophenolate sodium is extensively absorbed. Consistent with its enteric-coated design, the time to maximal concentration of MPA was approximately 1.5-2 hrs. In vitro studies demonstrated that the enteric-coated formulation of Myfortic prevents the release of MPA under acidic conditions, as in the stomach.
In stable renal transplant patients on ciclosporin for microemulsion-based immunosuppression, the gastrointestinal absorption of MPA was 93% and the absolute bioavailability was 72%. Myfortic pharmacokinetics are dose-proportional and linear over the studied dose range of 180-2160 mg. Compared to the fasting state, administration of Myfortic 720 mg with a high-fat meal (55 g fat, 1,000 calories) had no effect on the systemic exposure of MPA (AUC) which is the most relevant pharmacokinetic parameter linked to efficacy. However, there was a 33% decrease in the maximal concentration of MPA (Cmax).
Distribution: The volume of distribution at steady state for MPA is 50 L. Both mycophenolic acid and mycophenolic acid glucuronide are highly protein bound, 97% and 82%, respectively. The free MPA concentration may increase under conditions of decreased protein-binding sites (uraemia, hepatic failure, hypoalbuminemia, concomitant use of drugs with high protein-binding). This may put patients at increased risk of MPA-related adverse effects.
Biotransformation: The half-life of MPA is 11.7 hrs and the clearance is 8.6 L/hrs. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA, mycophenolic acid glucuronide (MPAG). It is the predominant metabolite of MPA and does not manifest biologic activity. In stable renal transplant patients on ciclosporin for microemulsion-based immunosuppression, approximately 28% of the Myfortic oral dose is converted to MPAG by presystemic metabolism. Its half-life is longer than that of MPA, approximately 15.7 hrs and clearance is 0.45 L/hrs.
Elimination: Although negligible amounts of MPA are present in the urine (<1%), the majority of MPA is eliminated in the urine as MPAG. Secretion in the bile is available for deconjugation by gut flora. The MPA resulting from this deconjugation may then be reabsorbed. Approximately 6-8 hrs after Myfortic dosing, a 2nd peak of MPA concentration can be measured, consistent with reabsorption of the deconjugated MPA.
Pharmacokinetics in Renal Transplant Patients on Ciclosporin for Microemulsion-Based Immunosuppression: The following table shows the mean pharmacokinetic parameters for MPA following the administration of Myfortic. Single-dose Myfortic pharmacokinetics predict multiple-dose and chronic-dosing Myfortic pharmacokinetics. In the early posttransplant period, mean MPA AUC and mean MPA Cmax was approximately ½ of that measured 6 months post-transplant (see Table 1).

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Renal Insufficiency: MPA pharmacokinetics appeared to be unchanged over the range of normal to absent renal function. In contrast, MPAG exposure increased with decreased renal function; MPAG exposure being approximately 8-fold higher in the setting of anuria. Clearance of either MPA or MPAG was unaffected by haemodialysis. Free MPA may also significantly increase in the setting of renal failure. This may be due to decreased plasma protein-binding of MPA in the presence of high blood urea concentration.
Hepatic Insufficiency: In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage eg, primary biliary cirrhosis, may show a different effect.
Pediatrics: Limited data are available on the use of Myfortic in children. In the previous table, the mean (SD) MPA pharmacokinetics are shown for stable pediatric renal transplant patients on ciclosporin microemulsion-based immunosuppression. Increased variability of MPA Cmax and AUC were noted in these pediatric patients compared to adult renal transplant patients. Mean MPA AUC at this dose was higher than typically measured in adults receiving Myfortic 720 mg. The mean apparent clearance of MPA was approximately 7.7 L/hr. A Myfortic dose of 200-300 mg/m2 would be expected to result in an MPA AUC of 30-50 mcg·hr/mL.
Gender: There are no clinically significant gender differences in Myfortic pharmacokinetics.
Elderly: Based on preliminary data, MPA exposure does not appear to vary to a clinically significant degree by age.
Ethnic Groups/Races: Following a single dose administration of 720 mg Myfortic to 18 Japanese and Caucasian healthy subjects, the exposure (AUCinf) for MPA and MPAG were 15 and 22% lower in Japanese subjects compared to Caucasians. The peak concentrations (Cmax) for MPAG were similar between the two populations, however, Japanese subjects had 9.6% higher Cmax for MPA. These results do not suggest any clinically relevant differences.
Clinical Studies: Two multi-center randomized, double-blind pivotal trials were used for Myfortic (MPA) approval in adults. Both studies were reference therapy-controlled clinical studies using commercially marketed Cellcept (MMF) as the comparator. Both studies demonstrated comparable efficacy and safety to MMF. The first study included 423 adult de novo renal transplants (ERLB301) and demonstrated that MPA was equivalent to MMF in efficacy and had a comparable safety profile. The second study was conducted in 322 maintenance kidney transplant recipients (ERLB302) and demonstrated that renal transplant patients receiving MMF maintenance immunosuppressive therapy could be safely converted to MPA without compromising efficacy.
De novo Adult Renal Transplant Patients (Study ERL B301): The double-blind, double-dummy randomized de novo study (ERLB301) was conducted in 423 renal transplant patients (MPA=213, MMF=210), aged 18-75 years, and was designed prospectively to test therapeutic equivalence of MPA to MMF as measured by the incidence of efficacy failure (i.e., biopsy proven acute rejection (BPAR), graft loss, death or loss to follow up) within the first 6 months of treatment (primary endpoint) and by the incidence of death, graft loss or loss to follow-up at 12 months (co-primary endpoint).
Patients were administered either MPA 1.44 g/day or MMF 2 g/day within 48 hours post-transplant for 12 months in combination with cyclosporine, and corticosteroids. In the MPA and MMF groups, 39.4% and 42.9%, respectively, received antibody therapy as an induction treatment.
Based on the incidence of efficacy failure at 6 months (MPA 25.8% vs. MMF 26.2%; 95% CI: [-8.7, +8.0]) therapeutic equivalence was demonstrated. At 12 months, the incidence of BPAR, graft loss or death was 26.3% and 28.1%, and of BPAR alone was 22.5% and 24.3% for MPA and MMF, respectively. Among those with BPAR, the incidence of severe acute rejection was 2.1% with MPA and 9.8% with MMF (p=ns). (See Table 2).

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The overall safety and hematologic profiles were similar between the two treatment groups. Drug-suspected AEs were 51.1% and 60.5% in the MPA vs. MMF groups, respectively. No difference in overall incidence of infection was observed. The overall incidence of serious infections was 22.1% in the MPA group and 27.1% in the MMF group. The incidence of serious pneumonia was lower in the MPA group (0.5% vs 4.3%, p=0.01). No difference in the overall incidence of GI AEs was observed (80.8% vs. 80%, p=ns, MPA vs. MMF, respectively).
Maintenance Adult Renal Transplant Patients (Study ERL B302): The maintenance study was conducted in 322 renal transplant patients (MPA=159, MMF=163), aged 18 to 75 years, who were at least 6 months post-transplant receiving 2 g/day MMF in combination with cyclosporine, with or without corticosteroids for at least four weeks prior to entry in the study. Patients were randomized 1:1 to MPA 1.44 g/day or MMF 2 g/day for 12 months. The efficacy endpoint was the incidence of efficacy failure (i.e., BPAR, graft loss, or death) at 6 and 12 months.
At 12 months, similar rates of efficacy failure (MPA 2.5%; MMF 6.1%; p=ns), biopsy-proven acute rejection (MPA 1.3%; MMF 3.1%; p=ns) and biopsy-proven chronic rejection (MPA 3.8%; MMF 4.9%; p=ns) were observed in both groups. (See Table 3).

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The maintenance study also demonstrated an overall similar safety profile, with the exception of the incidence of serious infections (8.8 vs 16%, p<0.05, MPA vs. MMF). The incidence of overall infections was 59% in each group. Less pneumonia was observed in the MPA group (1.9%) than the MMF group (4.9%), but it was not statistically significant. A similar incidence of overall GI AEs was observed (69.2 vs 61.8%, MPA vs. MMF), although "any GI AE" was numerically higher in the MPA-treated patients up to 12 months (29.6% vs. 24.5% at month 12), and the increase in GI severity tended to be lower in MPA patients.
Toxicology: Nonclinical Safety Data: Carcinogeneis, Mutagenesis, Impairment of Fertility: In a 104-week oral carcinogenicity study in rats, mycophenolate sodium at daily doses up to 9 mg/kg was not tumorigenic. The highest dose tested resulted in approximately 0.6 to 1.2 times the systemic exposure observed in renal transplant patients at the recommended dose of 1.44 g/day. Similar results were observed in a parallel study in rats performed with mycophenolate mofetil. In a 26-week oral carcinogenicity assay in a P53± (heterozygous) transgenic mouse model, mycophenolate sodium at daily doses up to 200 mg/kg was not tumorigenic. The highest dose tested was 200 mg/kg, resulting in approximately 5 times the systemic exposure observed in renal transplant patients (1.44 g/day).
The genotoxic potential of mycophenolate sodium was determined in five assays. MPA was genotoxic in the mouse lymphoma/thymidine kinase assay, the micronucleus test in V79 Chinese hamster cells and the in vivo mouse micronucleus assay. Mycophenolate sodium was not genotoxic in the bacterial mutation assay or the chromosomal aberration assay in human lymphocytes. The lowest dose showing genotoxic effects in a mouse bone marrow micronucleus resulted in approximately 3 times the systemic exposure (AUC or Cmax) observed in renal transplant patients at the tested clinical dose of 1.44 g of Myfortic per day. It is probable that the mutagenic activity observed was due to a shift in the relative abundance of the nucleotides in the cellular pool used for DNA synthesis.
Mycophenolate sodium had no effect on fertility of male rats at oral doses up to 40 mg/kg/day. The systemic exposure at this dose represents approximately 9 times the clinical exposure at the tested clinical dose of 1.44 g of Myfortic per day. No effects on female fertility were seen up to a dose of 20 mg/kg, a dose at which maternal toxicity and embryotoxicity were already observed.
Animal Toxicity and Pharmacology: The hematopoetic and lymphoid system were the primary organs affected in toxicology studies conducted with mycophenolate sodium in rats and mice. Aplastic, regenerative anemia was identified as being the dose-limiting toxicity in rodents exposed to MPA. Evaluation of myelograms showed a marked decrease in erythroid cells (polychromatic erythroblasts and normoblasts) and a dose-dependent enlargement of the spleen and increase in extramedullary hematopoiesis. These effects occurred at systemic exposure levels which are equivalent to or less than the clinical exposure at the recommended dose of 1.44 g/day of Myfortic in renal transplant patients.
The non-clinical toxicity profile of mycophenolate sodium appears to be consistent with adverse events observed in humans exposed to MPA, which now provide safety data of more relevance to the patient population (see Adverse Reactions).
Single oral doses of MPA are moderately well tolerated in rats (LD50 of 350 to 700 mg/kg), well tolerated in mice or monkeys (LD50 of more than 1,000 mg/kg), and extremely well tolerated in rabbits (LD50 of more than 6,000 mg/kg).
In a teratology study performed with mycophenolate sodium in rats, at a dose as low as 1 mg/kg, malformations in the offspring were observed, including anophthalmia, exencephaly and umbilical hernia. The systemic exposure at this dose represents 0.05 times the clinical exposure at the dose of 1.44 g/day of Myfortic (see Use in Pregnancy & Lactation). In a pre- and postnatal development study in rat, mycophenolic acid (as sodium salt) caused developmental delays (abnormal pupillary reflex in females and preputial separation in males) at the highest dose of 3 mg/kg.
Indications/Uses
In combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adult patients receiving allogeneic renal transplants.
Dosage/Direction for Use
Recommended Dose: 720 mg (four 180-mg or two 360-mg tabs) administered twice daily (1,440 mg daily dose). In patients receiving mycophenolate mofetil 2 g, treatment can be replaced by Myfortic 720 mg administered twice daily (1,440 mg daily dose).
Treatment with Myfortic must be initiated and maintained by appropriately qualified transplant specialists.
Myfortic should be initiated in de novo patients within 48 hrs following transplantation.
Myfortic tablets should not be crushed and should be swallowed whole. Patients should be advised to take Myfortic consistently either with or without food, but not switch between fed and fasted states because of the risk of increased MPA AUC variability.
Children: Safety and efficacy in pediatric patients have not been established. Limited pharmacokinetic data are available for pediatric renal transplant patients (see Pharmacology under Actions).
Elderly: No dose adjustment is required in this patient population.
Renal Impairment: No dose adjustments are needed in patients experiencing delayed renal graft function postoperatively (see Pharmacology: Pharmacokinetics under Actions). Patients with severe chronic renal impairment (glomerular filtration rate <25 mL·min-1·1.73 m-2) should be carefully followed up.
Hepatic Impairment: No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease.
Treatment During Rejection Episodes: Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of Myfortic is not required.
Administration: Myfortic can be taken with or without food.
Myfortic tablets should not be crushed in order to remain the integrity of the enteric coating (see Pharmacology under Actions and Cautions for Usage).
Overdosage
There have been anecdotal reports of deliberate or accidental overdoses with Myfortic, whereas not all patients experienced related adverse events.
In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the class. Accordingly an overdose of Myfortic could possibly result in oversuppression of the immune system and may increase the susceptibility to infection including opportunistic infections, fatal infections and sepsis. If blood dyscrasias occur (e.g. neutropenia with absolute neutrophil count <1.5 x 103 / micro L or anemia), it may be appropriate to interrupt or discontinue Myfortic (see Precautions and Adverse Drug Reactions).
Although dialysis may be used to remove the inactive metabolite MPAG, it would not be expected to remove clinically significant amounts of the active moiety MPA. This is in large part due to the very high plasma protein binding of MPA, 97%. By interfering with enterohepatic circulation of MPA, bile acid sequestrants, such as cholestyramine, may reduce the systemic MPA exposure.
Contraindications
Myfortic is contraindicated in patients with a hypersensitivity to mycophenolate sodium, mycophenolic acid or mycophenolate mofetil or to any of the excipients (see Descriptions).
Special Precautions
Patients with Rare Hereditary Deficiency of Hypoxanthine-Guanine Phosphoribosyl-Transferase (HGPRT): Myfortic is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. On theoretical grounds, 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.
Women of Child Bearing Potential (WOCBP), Pregnancy and Breast-Feeding: Use of Myfortic during pregnancy is associated with an increased risk of pregnancy loss including spontaneous abortion and congenital malformations. Myfortic therapy should not be initiated in WOCBP until a negative pregnancy test has been obtained. For information on use in pregnancy and contraceptive requirements see Use in Pregnancy & Lactation.
Myfortic should not be used during breast-feeding (see Use in Pregnancy & Lactation).
Malignancies: Patients receiving immunosuppressive regimens involving combinations of drugs, including Myfortic, 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 general advice to minimize the 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:Patients receiving Myfortic should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Oversuppression of the immune system increases the susceptibility to infection including opportunistic infections, fatal infections and sepsis (see Adverse Reactions).
Reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including the mycophenolic acid (MPA) derivatives Myfortic and MMF. Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended.
Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with MPA derivatives which include mycophenolate mofetil and mycophenolate sodium (see Adverse Reactions). The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune functions. 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. Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection, should be included in the differential diagnosis in immunosuppressed patients with deteriorating renal function (see Adverse Reactions). Consideration should be given to reducing the total immunosuppression in patients who develop PML or PVAN. In transplant patients, however, reduced immunosuppression may place the graft at risk.
Blood Dyschrasias: Patients receiving Myfortic should be monitored for blood dyscrasias (e.g. neutropenia or anamia, see Adverse Reactions), which may be related to MPA itself, concomitant medications, viral infections, or some combination of these causes. Patients taking Myfortic should have complete blood cell counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If blood dyscrasias occur (e.g. neutropenia with absolute neutrophil count <1.5 x 103 / micro L or anamia) it may be appropriate to interrupt or discontinue Myfortic.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressive agents (see Adverse Reactions). The mechanism for MPA derivatives induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppressive regimen are also unknown. However, MPA derivatives may cause blood dyscrasias (see previous text). In some cases PRCA was found to be reversible with dose reduction or cessation of therapy with MPA derivatives. In transplant patients, however, reduced immunosuppression may place the graft at risk. Changes to Myfortic therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimize the risk of graft rejection.
Vaccinations: Patients should be advised that during treatment with MPA vaccinations may be less effective and the use of the live attenuated vaccines should be avoided (see Interactions). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
Gastrointestinal Disorders: Because MPA derivatives have been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration and hemorrhage and perforation, Myfortic should be administered with caution in patients with active serious digestive system disease.
Combination with Other Agents: Myfortic has been administered in combination with the following agents in clinical trials: antithymocyte globulin, basiliximab, ciclosporin for microemulsion and corticosteroids. The efficacy and safety of the use of Myfortic with other immunosuppressive agents have not been studied.
Male Patients: Sexually active men are recommended to use condoms during treatment, and for a total of 13 weeks after their last dose of Myfortic. In addition, female partners of the male patients are recommended to use highly effective contraception during treatment and for a total of 13 weeks after the last dose of Myfortic.
Use In Pregnancy & Lactation
Use in Pregnancy: Use of Myfortic during pregnancy is associated with an increased risk of congenital malformations. Although there are no adequate and well controlled studies in pregnant women conducted with Myfortic, based on data from the US National Transplant Pregnancy Registry (NTPR), use of mycophenolate mofetil in combination with other immunosuppressants during pregnancy was associated with an increased rate of 22% (four cases in 18 liveborn with exposure) of congenital malformations, compared to the rate of 4 to 5% for malformations seen among transplant patients in the NTPR. Congenital malformations that have been reported with mycophenolate mofetil include outer ear and other facial abnormalities including cleft lip and palate, congenital diaphragmatic hernia, anomalies of the distal limbs and heart, esophagus and kidney. Use of mycophenolate mofetil during pregnancy was also reported to be associated with increased risk of spontaneous abortion. Since MMF is converted to MPA following oral or IV administration, the above risks must be taken into account for Myfortic as well. The teratogenic potential of MPA was observed in animal studies (see Pharmacology: Toxicology: Nonclinical Safety Data under Actions).
Myfortic should be used in pregnant women only if the potential benefit outweighs the potential risk to the foetus. Patients should be instructed to consult their physician immediately should pregnancy occur.
Women of Child-Bearing Potential: Myfortic therapy should not be initiated until a negative pregnancy test has been obtained.
Women of childbearing potential must use highly effective contraception before beginning Myfortic therapy, during therapy, and for six weeks after their last dose of Myfortic (see Interactions).
Use in Lactation: It is not known whether MPA is excreted in human milk.
Myfortic should not be used during breast-feeding (see Precautions).
Because many drugs are excreted in human milk, and of the potential for serious adverse reactions in breast-fed newborns/infants, a decision should be made whether to abstain from breast-feeding while on treatment and during 6 weeks after stopping the therapy or to abstain from using the medicinal product, taking into account the importance of the drug to the mother.
Adverse Reactions
Summary of the Safety Profile: The following undesirable effects cover adverse drug reactions from 2 controlled clinical trials. The trials evaluated the safety of Myfortic and mycophenolate mofetil in 423 de novo and in 322 maintenance renal transplant patients (randomized 1:1); the incidence of adverse events was similar between treatments in each population.
The very common (≥10%) adverse drug reactions associated with the administration of Myfortic in combination with ciclosporin for microemulsion and corticosteroids include leucopenia and diarrhea.
Malignancies: Patient receiving immunosuppressive regimens involving combinations of drugs, including MPA, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see Precautions). Overall rates of malignancies observed in Myfortic clinical trials are the following: Lymphoproliferative disease or lymphoma developed in 2 de novo patients (0.9%) and in 2 maintenance patients (1.3%) receiving Myfortic for up to 1 year; non-melanoma skin carcinomas occurred in 0.9% de novo and 1.8% maintenance patients receiving Myfortic for up to 1 year; other types of malignancy occurred in 0.5% de novo and 0.6% maintenance patients.
Opportunistic Infections: All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load (see Precautions). The most common opportunistic infections in de novo renal transplant patients receiving Myfortic with other immunosuppressants in controlled clinical trials of renal transplant patients followed for 1 year were CMV, candidiasis and herpes simplex. The overall rate of CMV infections (serology, viraemia or disease) observed in Myfortic clinical trials was reported in 21.6% of de novo and in 1.9% of maintenance renal transplant patients.
Tabulated Summary of Adverse Drug Reactions from Clinical Trials: Adverse reactions (Table 4) are ranked under heading of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, < 1/100); rare (≥1/10,000, < 1/1,000) very rare (<1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Table 4 as follows contains adverse drug reactions possibly or probably related to Myfortic reported in the two phase III randomized, double blind, controlled, multi-center trials: 1 in de novo kidney transplant patients and 1 in maintenance kidney transplant patients, in which Myfortic was administered at a dose of 1,440 mg /day for 12 months together with ciclosporin microemulsion and corticosteroids. It is compiled according to MedDRA system organ class. (See Table 4).

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Note: Renal transplant patients were treated with 1,440 mg Myfortic daily up to one year. A similar profile was seen in the de novo and maintenance transplant population although the incidence tended to be lower in the maintenance patients.
Listing of Adverse Drug Reactions from Post-Marketing Experience: The following adverse drug reactions have been derived from post-marketing experience with Myfortic via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.
Skin and Subcutaneous Tissue Disorders: Rash has been identified as an adverse drug reaction from post-approval clinical trials, post marketing surveillance and spontaneous reports.
The following adverse reactions are attributed to MPA derivatives as a class effect: Infections and Infestations: Serious, sometimes life-threatening infections, including meningitis, infectious endocarditis, tuberculosis, and atypical mycobacterial infection. Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported (see Precautions).
Blood and Lymphatic System Disorders: Agranulocytosis, neutropenia, pancytopenia. Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressive agents (see Precautions).
Gastrointestinal Disorders: Colitis, esophagitis (including CMV-colitis and -esophagitis), CMV gastritis, pancreatitis, intestinal perforation, gastrointestinal hemorrhage, gastric ulcers, duodenal ulcers, ileus.
Geriatric Population: Elderly patients may generally be at increased risk of adverse drug reactions due to immunosuppression. Elderly patients receiving Myfortic as part of a combination immunosuppressive regimen did not show an increased risk of adverse reactions, compared to younger individuals in the Myfortic clinical trials.
Drug Interactions
Observed Interactions Resulting in a Concomitant Use Not Recommended: Azathioprine: It is recommended that Myfortic should not be administered concomitantly with azathioprine because such concomitant administration has not been studied (see Precautions).
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).
Observed Interactions to be Considered: Aciclovir: Higher plasma concentrations of both mycophenolic acid glucuronide (MPAG) and aciclovir may occur in the presence of renal impairment. Therefore, the potential exists for these 2 drugs to compete for tubular secretion, resulting in a further increase in the concentration of both MPAG and aciclovir. In this situation, patients should be carefully followed up.
Gastroprotective Agents: Antacids with Magnesium and Aluminum Hydroxides: The absorption of mycophenolate sodium was decreased when administered with antacids. Concomitant administration of Myfortic and antacids containing magnesium and aluminium hydroxide results in a 37% decrease in MPA systemic exposure and a 25% decrease in MPA maximal concentration. Caution should be used when co-administering antacids (containing magnesium and aluminium hydroxide) with Myfortic.
Proton Pump Inhibitors: In healthy volunteers, concomitant administration of MMF 1,000 mg and pantoprazole 40 mg twice daily led to a 27% decrease in the MPA AUC and to a 57% decrease in the MPA Cmax. However, in the same study, no changes in the pharmacokinetics of MPA were observed following concomitant administration of Myfortic and pantoprazole.
Ganciclovir: MPA and MPAG pharmacokinetics are unaffected by the addition of ganciclovir. The clearance of ganciclovir is unchanged in the setting of therapeutic MPA exposure. However, in patients with renal impairment in which Myfortic and ganciclovir are coadministered the dose recommendations for ganciclovir should be observed and patients monitored carefully.
Tacrolimus: In a calcineurin cross-over study in stable renal transplant patients, steady state Myfortic pharmacokinetics were measured during both Neoral and tacrolimus treatments.
Mean MPA AUC was 19% higher and Cmax about 20% lower. Conversely mean MPAG AUC and Cmax were about 30% lower on tacrolimus treatment compared to Neoral treatment.
Ciclosporin A: When studied in stable renal transplant patients, ciclosporin A pharmacokinetics were unaffected by steady state dosing of Myfortic.
Anticipated Interactions to be Considered: Cholestyramine and Drugs that Interfere with Enterohepatic Circulation: Due to its capacity to block the enteric circulation of drugs, cholestyramine may decrease the systemic exposure of MPA. Caution should be used when co-administering cholestyramine or drugs that interfere with enterohepatic circulation because of the potential to reduce the efficacy of Myfortic.
Oral contraceptives: Oral contraceptives undergo oxidative metabolism while Myfortic is metabolized by glucuronidation. A clinically significant effect of oral contraceptives on Myfortic pharmacokinetics is not anticipated. However, given that the long term effect of Myfortic dosing on the pharmacokinetics of oral contraceptives is not known, it is possible that the efficacy of oral contraceptives may be adversely affected (see Use in Pregnancy & Lactation).
Caution For Usage
Instructions for Use and Handling: Myfortic tablets should not be crushed in order to remain the integrity of the enteric coating (see Pharmacology under Actions and Dosage & Administration).
Mycophenolate sodium has demonstrated teratogenic effects (see Use in Pregnancy & Lactation). If for any reasons the Myfortic tablet is crushed, avoid inhalation or direct contact with skin or mucous membrane of the powder.
Special Precautions for Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.
MIMS Class
ATC Classification
L04AA06 - mycophenolic acid ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.
Presentation/Packing
Gastro-resistant tab 180 mg (film-coated, lime green, round with beveled edges and debossing imprint "C" on one side) x 120's. 360 mg (film-coated, pale orange-red, ovaloid with debossing imprint "CT" on one side) x 120's.
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