Myfortic

Mycophenolate sodium.

Each enteric coated tablet contains 180 mg or 360 mg mycophenolic acid/MPA equivalent to 192.4 and 384.4 mycophenolate sodium.
Mycophenolate sodium is the sodium salt of the active moiety, mycophenolic acid.
Excipients/Inactive Ingredients: Maize starch, povidone (K-30), crospovidone, lactose, colloidal silicon dioxide, magnesium stearate, hypromellose phthalate/hydroxypropyl-methylcellulose phthalate, titanium dioxide, iron oxide yellow; indigotin (180-mg tablet only) and iron oxide red (360-mg tablet only).

Pharmacotherapeutic group: Immunosuppressant. ATC code: L04AA06.
Pharmacology: Pharmacodynamics: Mycophenolate sodium is the sodium salt of mycophenolic acid (MPA). MPA is selective, non-competitive and reversible inhibitor of inosine monophosphate dehydrogenase (MPDH), which inhibits the de novo pathway of guanosine nucleotide synthesis without being built into the DNA.
MPA exerts a more potent cytostatic effect on lymphocytes than on other cells because in purines, in contrast to other cell types which can utilise salvage pathways, T and B lymphocyte proliferation is critically dependent on de novo synthesis. The mode of action of MPA is thus complementary to that of the calcineurin inhibitors, which interfere with cytokine transcription and resting T-lymphocytes.
Two double-blind studies were performed comparing 720 mg Myfortic to 1000 mg Cellcept in combination with ciclosporin for microemulsion and prednisone. One study included 423 de novo patients, while the second investigated the switch from Cellcept to Myfortic in 322 stable patients on maintenance therapy.
In the pivotal study in de novo renal transplant patients treated for 12 months, the compounds were therapeutically equivalent as regards to the combined primary endpoint (incidence of biopsy-proven rejection, graft loss and lost to follow-up) after 6 months (PP analysis 27.4% vs 27.7%, difference -0.4%(CI₉₅ - 9.1 %; 8.4%). The same also applied at 12 months. Other efficacy endpoints, such as treated acute rejection reaction (23.4% vs 25.7%), rejection reaction with antibody therapy (both 4.5%) or graft loss (3.5% vs 4.0 %), were comparable with Myfortic.
Pharmacokinetics: The pharmacokinetics of Myfortic are dose-proportional and linear over the dose range of 180 to 2160 mg.
Absorption: Following oral administration, mycophenolate sodium is extensively absorbed. The absolute bioavailability of mycophenolic acid (MPA) is 71 %. There is a limited first-pass effect. The peak plasma concentration of MPA is attained after 1.5-2 hours.
Compared to the fasting state, administration of Myfortic 720 mg with a high fat meal (55 g fat, 1000 calories) had no effect on the AUC of MPA. However, a 33 % decrease in the peak concentration of MPA (C_max) was observed. A second MPA peak is detectable approx. 6-8 hours after administration of Myfortic; this is due to enterohepatic circulation.
Distribution: The steady state volume of distribution at for MPA is 50 liters. Both mycophenolic acid and mycophenolic acid glucuronide are highly protein bound (97 % and 82 %, respectively). The concentration of free MPA may increase under conditions of decreased plasma protein (uremia, liver failure, hypoalbuminemia) as well as with concomitant use of other drugs with high protein binding. This is associated with an increased risk of MPA-related adverse effects (see Precautions).
Metabolism: MPA is metabolized principally by glucuronyl transferase to form the inactive mycophenolic acid glucuronide (MPAG).
Elimination: The majority of MPA is eliminated in the urine as MPAG. MPAG secreted in the bile is subject to enterohepatic circulation. The half life of MPA is 11.7 hours and clearance is 8.6 litres/h. The half life of MPAG is longer than that of MPA, amounting to approx. 15.7 hours. Its clearance is 0.45 litres/hour.
Pharmacokinetics in Renal Transplant Patients on ciclosporin for microemulsion based immunosuppression: Shown in the following Table 1 are mean pharmacokinetic parameters for MPA following the administration of Myfortic. In the early post transplant period, mean MPA AUC and mean MPA Cmax was approximately one-half of that measured six months post transplant. (See Table 1.)


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Special population: Renal impairment: The plasma level of MPA was comparable over the range of normal to absent renal function (glomerular filtration rate < 5 ml/min). MPAG exposure increased with decreased renal function; in conditions of anuria, it was approx. eight times higher than normal. Clearance of both MPA and MPAG was unaffected by hemodialysis.
Free MPA may increase significantly in the presence of renal failure. This is probably due to decreased plasma protein binding of MPA in the presence of high blood urea concentration.
Hepatic impairment: In volunteers with alcoholic cirrhosis, hepatic MPAG glucuronidation processes were relatively unaffected by hepatic and by hepatic parenchymal disease. However, in patients with hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, an effect on the enterohepatic circulation cannot be ruled out.
Children and adolescents: Data on the use of Myfortic in children and adolescents is extremely limited.
Gender: There are no clinically significant gender differences in the pharmacokinetics of Myfortic.
Elderly: Pharmacokinetics in the elderly have not been specifically studied. Increasing age does not appear to be associated with a clinically significant change in the bioavailability of MPA.
Ethnic groups/races: Following a single dose administration of 720 mg Myfortic to 18 Japanese and Caucasian healthy subjects, the exposure (AUC_inf) 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-centre randomised, 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 18-75 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.
Lupus nephritis: One exploratory randomised open-label 6-month study (A2420; Zeher et al., 2011) has been conducted comparing the efficacy and safety of Myfortic and a standard corticosteroid regimen (prednisolone 1 mg/kg bodyweight/day, tapered) with Myfortic and a reduced corticosteroid regimen (prednisolone 0.5 mg/kg bodyweight/day, tapered) for induction treatment of lupus nephritis. Male and female patients aged ≥ 18 years were eligible to enter the study if they met the following criteria: diagnosed with SLE, defined as meeting at least four classification criteria of the American College of Rheumatology; presence of proliferative lupus nephritis flare class III or IV (ISN/RPS classification of lupus nephritis) documented by a renal biopsy performed within 24 months preceding the study entry; proteinuria defined as >0.5 gram urine protein per gram urine creatinine at screening and baseline and clinical activity defined by serum creatinine >1.0 mg/dL (88.4 μmol/L), microscopic hematuria (>5 red cells per high power field) or presence of cellular casts were the other key inclusion criteria. The key inclusion criteria were patients with calculated creatinine clearance <30 mL/min (using the Cockcroft-Gault formula); patients having received i.v. CS bolus, oral or i.v. cyclophosphamide or MMF during the last 3 months; use of any antibodies during the last 6 months. Myfortic was administered at a dose of 720 mg twice daily for 2 weeks and then 1080 mg twice daily (or 720 mg three times daily) for 22 weeks. A total of 81 patients with biopsy proven lupus nephritis WHO class III, IV, or V and clinical activity were treated in this study.
The primary efficacy variable was the complete remission rate at 24 weeks defined as the proportion of patients with urine protein/urine creatinine ratio < 0.5 gram urine protein per gram urine creatinine, urine sediment normalized (no cellular casts, < 5 red cells per high power field), and serum creatinine is within 10% of normal value. Secondary efficacy variables included the proportion patients in partial remission after 24 weeks of treatment, with partial response defined as a reduction in urine protein: creatinine ratio of ≥50% compared with base line, and serum creatinine within 10% of baseline value; proportion of patients with mild SLE flare after 12 and 24 weeks of treatment; disease activity index measured with BILAG score and SLEDAI index; renal function assessed by serum creatinine, creatinine clearance, glomerular filtration rate (GFR) and urine protein: creatinine ratio.
The demographic and other baseline characteristics were balanced between the two dose groups. Most patients had a histological diagnosis of Class IV lupus nephritis. At 6 months, 8/42 (19.0%) of Myfortic and standard corticosteroid-treated patients and 8/39 (20.5%) of Myfortic and reduced corticosteroid-treated patients achieved complete remission. Partial response occurred in 20/42 (47.6%) of patients in the standard dose group and 14/39 (35.9%) of patients in the low dose group. Patients in whom treatment failed included those without complete or partial remission at 6 months or who prematurely discontinued treatment during the first 24 weeks for any reason, yielding failure rates of 21/42 (50%) in the standard dose group and 23/39 (59.0%) in the low dose group. At 6 months, the mean change from baseline for urine protein to creatinine ratio decreased by 1.1 in the standard dose group and by 0.8 in the low dose group. Only one patient in the standard-dose group reported a moderate to mild SLE flare at 24 weeks. The mean BILAG and SLEDI scores decreased from Week 4 to Week 24 in both treatment groups.
Published studies: Studies comparing the use of mycophenolate (sodium or mofetil) with intravenous cyclophosphamide (IVC) and azathioprine (AZA) in patients with proliferative lupus nephritis have been reported in the literature. Results from the two pivotal published studies with MMF in induction and maintenance therapy are given as follows: The ALMs study (Appel et al., 2009) compared MMF and IVC as induction treatment for active lupus nephritis in a 24 week open-label parallel group multicentre study. 370 patients with Class III to V lupus nephritis were randomly assigned to a target dose of 3g/day MMF or 0.5 to 1.0 g/m² IVC. Both groups received prednisone, tapered from a maximum starting dose of 60mg/day. The primary endpoint was a pre-specified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary endpoints included complete renal remission, systemic disease activity and damage, and safety. No significant difference in response rate between the two groups was detected. The primary efficacy endpoint was achieved in 104 (56.2%) patients receiving MMF, compared with 98 (53.0%) patients receiving IVC. No significant differences were detected between the MMF and IVC groups with regard to the rates of adverse events, serious adverse events or infections.
Dooley et al., 2011 conducted a 36 month randomized, double-blind, double dummy study comparing MMF (2g per day) plus placebo and AZA (2mg per kg per day) plus placebo for the maintenance of remission in 227 patients who met the response criteria during the ALMS 6-month induction trial with either MMF or IVC. 116 patients were randomly assigned to MMF and 111 to AZA. The primary endpoint was the time to treatment failure measured as the time until the first event defined as death, end-stage renal disease, sustained doubling of the serum creatinine level, renal flare, or the need for rescue therapy. Secondary assessments included the time to the individual component of treatment failure and adverse events. MMF was superior to AZA with respect to the primary end point, time to treatment failure (hazard ratio, 0.44; 95% confidence interval, 0.25 to 0.77; P = 0.003), and with respect to time to renal flare and time to rescue therapy (hazard ratio, <1.00; P<0.05). Observed rates of treatment failure were 16.4% (19 of 116 patients) in the MMF group and 32.4% (36 of 111) in the AZA. Adverse events, most commonly minor infections and gastrointestinal disorders, occurred in more than 95% of the patients in both groups (P = 0.68). Serious adverse events occurred in 33.3% of patients in the AZA group and in 23.5% of those in the MMF group (P = 0.11), and the rate of withdrawal due to adverse events was higher with AZA than with MMF (39.6% vs. 25.2%, P = 0.02).
Doses used in clinical studies: The doses of mycophenolate sodium (or the equivalent doses when administered as mycophenolate mofetil) used in the published clinical studies were varied. Doses used for induction: In the pivotal 24-week ALMS study (Appel et al., 2009) the target dose of MMF was 3g per day (equivalent of 2.16g mycophenolate sodium or 720mg three times daily). The median dosage of MMF was calculated as 2.6g/day. In another 24-week published study (Ginzler et al., 2005), patients were treated with escalating doses of MMF up to 3g per day (equivalent of 2.16g mycophenolate sodium or 720mg three times daily). In this study the mean maximum tolerated dose of MMF was 2.68g per day (equivalent to 1.93g mycophenolate sodium or nearly 720mg three times daily). Doses used for maintenance: In the pivotal long term maintenance study (Dooley et al., 2011), the target dose of MMF was 2g/day (equivalent to mycophenolate sodium 720mg twice daily); 80% of patients received a daily dose of 1.6mg or more.
Toxicology: Non-clinical safety data: Carcinogenesis, 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 0.6-1.2 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. Since experience with this model is limited, the results cannot be definitely evaluated at present.
The genotoxic potential of mycophenolate sodium was determined in five assays. MPA was mutagenic 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 assay resulted in approximately 3 times the systemic exposure (AUC or C_max) observed in renal transplant patients at the tested clinical dose of 1.44 g/day Myfortic.
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 and no effect on female fertility at doses up to 20 mg/kg. These doses are five to nine times higher than the recommended clinical dose.
Animal toxicity and pharmacology: The haematopoetic and lymphoid systems were the primary organ systems 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 levels observed following administration of the recommended daily dose of 1.44 g/day 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).
In a teratology study performed with mycophenolate sodium in rats at a dose of 1 mg/kg, malformations in the offspring such as anophthalmia, exencephaly and umbilical hernia were observed. The systemic exposure at this dose represents 0.05 times the clinical exposure at a daily dose of 1.44 g 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.

Myfortic is indicated in combination with ciclosporin for microemulsion and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogenic renal transplants.
Myfortic is indicated for induction and maintenance treatment of adult patients with WHO Class III, IV or V lupus nephritis.
This indication is based on the evidence in the literature reports of studies of treatment in patients with lupus nephritis, the majority of whom were ISN/RPS (2003) Class IV. The evidence for efficacy was based on surrogate endpoints.

Dosage: The recommended dose is 720 mg (four 180 mg or two 360 mg Myfortic gastro-resistant tablets) administered twice daily (1,440 mg daily dose). In patients receiving mycophenolate mofetil (MMF) 2 g, treatment can be replaced by 720 mg administered twice daily (1,440 mg daily dose) of Myfortic.
General target population: Treatment with Myfortic should be initiated and maintained by appropriately qualified transplant specialists.
Myfortic should be initiated in de-novo patients within 48 hours following transplantation.
Myfortic can be taken with or without food.
Special populations: Paediatric patients: Safety and efficacy in paediatric patients have not been established. Limited pharmacokinetic data are available for paediatric renal transplant patients (see Pharmacology under Actions). Its use in these patients group therefore cannot be recommended.
Geriatric patients: No dose adjustment is required in this patient population.
Renal impairment: No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively (see Pharmacology: Pharmacokinetics under Actions). Patients with severe chronic renal impairment (creatinine clearance < 10 ml/min) should be carefully followed up.
Hepatic impairment: No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease.
Lupus nephritis patients: Adequate dose finding studies have not been performed. The prescriber should adjust the dose based on clinical response.
Induction treatment with Myfortic is administered in combination with a corticosteroid. The recommended dose is 720 mg administered twice daily (1440 mg daily dose). A daily dose of greater than 1440 mg/day has been used for induction therapy in some studies, with the maximum dose of 2160 mg/day (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions). This dose may be tapered for maintenance purposes following a complete or partial response.
Method of administration: Myfortic tablets should not be crushed in order to remain the integrity of the enteric coating (see Pharmacology under Actions and Cautions for Usage).

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 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.

Myfortic is contraindicated in patients with a hypersensitivity to mycophenolate sodium, mycophenolic acid or mycophenolate mofetil or to any of the excipients (see Description).

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-Segmiller 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 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). For Myfortic there is additional evidence of genotoxic effect. As general advice to minimise 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 dyscrasias: Patients receiving Myfortic should be monitored for blood dyscrasias (e.g. neutropenia or anaemia - 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 anaemia) 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 live attenuated vaccines should be avoided (see Interactions). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccinations.
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 (e.g. azathioprine) have not been studied. These combinations are therefore not recommended.
Effects on ability to drive and use machine: No studies on the effects on the ability to drive and use machines have been performed. The mechanism of action and pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.

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).
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 4-5% 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 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 Toxicology: Non-clinical 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.
Breast feeding: 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 the potential for serious adverse reactions in breastfed 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.
Fertility: Not applicable.
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.

Summary of the safety profile: The following undesirable effects cover adverse drug reactions from two controlled clinical trials. The trials evaluated the safety of Myfortic and mycophenolate mofetil in 423 de novo and in 322 maintenance (> 6 months) renal transplant patients (randomized 1:1); the incidence of adverse events was similar between treatments in each populations.
The very common (≥ 10 %) adverse drug reactions associated with the administration of Myfortic in combination with ciclosporin for microemulsion and corticosteroids include leucopenia (19.2 %) and diarrhoea (23.5%).
Malignancies: Patients 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 as follows: lymphoproliferative disease or lymphoma developed in 2 de novo (0.9%) patients 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 a Myfortic clinical trial 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-centre trials: 1 in de novo kidney transplant patients and 1 in maintenance kidney transplant patients, in which Myfortic was administered at a dose of 1440 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 1440 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 -oesophagitis), 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.
Adverse effects from a clinical trial in lupus nephritis patients (A2420): Myfortic was administered at a dose of 720 mg twice daily for 2 weeks and then 1080 mg twice daily (or 720 mg three times daily) for 22 weeks in an open-label trial comparing the efficacy and safety of Myfortic and a standard corticosteroid regimen (prednisolone 1 mg/kg bodyweight/day, tapered) with Myfortic and a reduced corticosteroid regimen (prednisolone 0.5 mg/kg bodyweight/day, tapered) for induction treatment of lupus nephritis. Adverse events were reported by 35/42 (83.3%) patients in the Myfortic and standard corticosteroid group and by 30/39 (76.9%) patients in the Myfortic and reduced corticosteroid group. The incidence of gastrointestinal events (standard: 18/42, 42.9%; reduced: 13/39, 33.3%), infections (standard: 25/42, 59.5%; reduced: 14/39, 35.9%), and general disorders (standard: 14/42, 33.3%; reduced: 8/39, 20.5%) were higher in the Myfortic and standard corticosteroid group compared with the Myfortic and reduced corticosteroid group.

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 MPAG (mycophenolic acid glucuronide) and aciclovir may occur in the presence of renal impairment. Therefore, the potential exists for these two 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 aluminum 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 aluminum hydroxide) with Myfortic.
Pantoprazole: In healthy volunteers, concomitant administration of Mycophenolate sodium enteric coated 720 mg and pantoprazole 40 mg twice daily show no changes in the pharmacokinetics of MPA (AUC and C_max).
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. No studies with antibiotic has been performed.
In addition, MPA AUC intra-subject variability was doubled when switching from Neoral (ciclosporin) to tacrolimus. Clinicians should note this increase both in MPA AUC and variability, and adjustment to Myfortic dosing should be dictated by the clinical situation. Close clinical monitoring should be performed when a switch from one calcineurin inhibitor to another is planned.
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).
When co-administered with mycophenolate mofetil, ciclosporin is known to decrease the exposure of MPA. When co-administered with Myfortic, ciclosporin may decrease the concentration of MPA as well (by approximately 20%, extrapolated from mycophenolate mofetil data), but the exact extent of this decrease is unknown because such an interaction has not been studied. However, as efficacy studies were conducted in combination with ciclosporin, this interaction does not modify the recommended posology of Myfortic. In case of interruption or discontinuation of ciclosporin, Myfortic dosage should be re-evaluated depending on the immunosuppressive regimen.

Instructions for use and handling and precaution: 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 in rats and rabbits (see Use in Pregnancy & Lactation). Avoid inhalation or direct contact with skin or mucous membrane of the powder, in case or crushing Myfortic tablets is necessary.
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.

Do not store above 30°C. Myfortic 180 mg and Myfortic 360 mg enteric coated tablet should be protected from moisture. Store in the original package and container.
Shelf-life: 36 months.

Immunosuppressants

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

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