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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 (Cmax) 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.)
Click on icon to see table/diagram/imageSpecial 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 (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-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).
Click on icon to see table/diagram/imageThe 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).
Click on icon to see table/diagram/imageThe 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 Cmax) 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.
