DESCRIPTION

Myfortic® (mycophenolicacid) delayed-release tablets are an enteric formulation of mycophenolatesodium that delivers the active moiety mycophenolic acid (MPA). Myfortic is an immunosuppressive agent. As the sodium salt, MPA is chemically designated as (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid sodium salt.

Its empirical formula is C17H19O6Na. The molecular weight is 342.32 and the structural formula is

Myfortic, as the sodium salt, is a white to off-white, crystalline powder and is highly soluble in aqueous media at physiological pH and practically insoluble in 0.1N hydrochloric acid.

Myfortic is available for oral use as delayed-release tablets containing either 180mg or 360mg of mycophenolicacid. Inactive ingredients include colloidal silicon dioxide, crospovidone, lactose anhydrous, magnesium stearate, povidone (K-30), and starch. The enteric coating of the tablet consists of hypromellose phthalate, titanium dioxide, iron oxide yellow, and indigotine (180mg) or iron oxide red (360mg).

CLINICAL PHARMACOLOGY

Mechanism of Action

MPA is an uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the denovo pathway of guanosine nucleotide synthesis without incorporation to DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on denovo synthesis of purines, whereas other cell types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes.

Mycophenolatesodium has been shown to prevent the occurrence of acute rejection in rat models of kidney and heart allotransplantation. Mycophenolatesodium also decreases antibody production in mice.

Pharmacokinetics

Absorption

In-vitro studies demonstrated that the enteric-coated Myfortic® (mycophenolicacid) tablet does not release MPA under acidic conditions (pH<5) as in the stomach but is highly soluble in neutral pH conditions as in the intestine. Following Myfortic oral administration without food in several pharmacokinetic studies conducted in renal transplant patients, consistent with its enteric-coated formulation, the median delay (Tlag) in the rise of MPA concentration ranged between 0.25 and 1.25hours and the median time to maximum concentration (Tmax) of MPA ranged between 1.5 and 2.75hours. In comparison, following the administration of mycophenolate mofetil, the median Tmax ranged between 0.5 and 1.0hours. In stable renal transplant patients on cyclosporine, USP (MODIFIED) based immunosuppression, gastrointestinal absorption and absolute bioavailability of MPA following the administration of Myfortic delayed-release tablet was 93% and 72%, respectively. Myfortic pharmacokinetics is dose proportional over the dose range of 360 to 2160mg.

Distribution

The mean (±SD) volume of distribution at steady state and elimination phase for MPA is 54(±25)L and 112(±48)L, respectively. MPA is highly protein bound to albumin, >98%. The protein binding of mycophenolicacid glucuronide (MPAG) is 82%. The free MPA concentration may increase under conditions of decreased protein binding (uremia, hepatic failure, and hypoalbuminemia).

Metabolism

MPA is metabolized principally by glucuronyl transferase to glucuronidated metabolites. The phenolic glucuronide of MPA, mycophenolicacid glucuronide (MPAG), is the predominant metabolite of MPA and does not manifest pharmacological activity. The acyl glucuronide is a minor metabolite and has comparable pharmacological activity to MPA. In stable renal transplant patients on cyclosporine, USP (MODIFIED) based immunosuppression, approximately 28% of the oral Myfortic dose was converted to MPAG by presystemic metabolism. The AUC ratio of MPA:MPAG:acyl glucuronide is approximately 1:24:0.28 at steady state. The mean clearance of MPA was 140(±30)mL/min.

Elimination

The majority of MPA dose administered is eliminated in the urine primarily as MPAG (>60%) and approximately 3% as unchanged MPA following Myfortic administration to stable renal transplant patients. The mean renal clearance of MPAG was 15.5(±5.9)mL/min. MPAG is also secreted in the bile and available for deconjugation by gut flora. MPA resulting from the deconjugation may then be reabsorbed and produce a second peak of MPA approximately 6–8hours after Myfortic dosing. The mean elimination half-life of MPA and MPAG ranged between 8 and 16hours, and 13 and 17hours, respectively.

Food Effect

Compared to the fasting state, administration of Myfortic 720mg with a high-fat meal (55gfat, 1000calories) had no effect on the systemic exposure (AUC) of MPA. However, there was a 33% decrease in the maximal concentration (Cmax), a 3.5-hour delay in the Tlag (range, -6 to 18hours), and 5.0-hour delay in the Tmax (range, -9 to 20hours) of MPA. To avoid the variability in MPA absorption between doses, Myfortic should be taken on an empty stomach (see DOSAGE AND ADMINISTRATION and PRECAUTIONS, Information for Patients).

Pharmacokinetics in Renal Transplant Patients

The mean pharmacokinetic parameters for MPA following the administration of Myfortic in renal transplant patients on cyclosporine, USP (MODIFIED) based immunosuppression are shown in Table1. Single-dose Myfortic pharmacokinetics predicts multiple-dose pharmacokinetics. However, in the early posttransplant period, mean MPA AUC and Cmax were approximately one-half of those measured 6months posttransplant.

After near equimolar dosing of Myfortic 720mg BID and mycophenolate mofetil 1000mg BID (739mg as MPA) in both the single- and multiple-dose cross-over trials, mean systemic MPA exposure (AUC) was similar.

Special Populations

Renal Insufficiency: No specific pharmacokinetic studies in individuals with renal impairment were conducted with Myfortic. However, based on studies of renal impairment with mycophenolate mofetil, MPA exposure is not expected to be appreciably increased over the range of normal to severelyimpaired renal function following Myfortic administration. In contrast, MPAG exposure would be increased markedly with decreased renal function; MPAG exposure being approximately 8-fold higher in the setting of anuria. 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 high plasma protein binding of MPA.

Hepatic Insufficiency: No specific pharmacokinetic studies in individuals with hepatic impairment were conducted with Myfortic. In a single dose (mycophenolate mofetil 1000mg) study of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when the pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this study were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this study had about a 50% lower AUC compared to healthy volunteers in other studies, thus making comparison between volunteers with alcoholic cirrhosis and health volunteers difficult. Effects of hepatic disease on this process probably depend on the particular disease. Hepatic disease, such as primary biliary cirrhosis, with other etiologies may show a different effect.

Pediatrics: Limited data are available on the use of Myfortic at a dose of 450mg/m2 body surface area in children. The mean MPA pharmacokinetic parameters for stable pediatric renal transplant patients, 5–16 years, on cyclosporine, USP (MODIFIED) are shown in Table 1. At the same dose administered based on body surface area, the respective mean Cmax and AUC of MPA determined in children were higher by 33% and 18% than those determined for adults. The clinical impact of the increase in MPA exposure is not known.

Gender: There are no significant gender differences in Myfortic pharmacokinetics.

Elderly: Pharmacokinetics in the elderly have not been formally studied.

CLINICAL STUDIES

The safety and efficacy of Myfortic® (mycophenolicacid) in combination with cyclosporine, USP (MODIFIED) and corticosteroids for the prevention of organ rejection was assessed in two multicenter, randomized, double-blind trials in denovo and maintenance renal transplant patients compared to mycophenolate mofetil.

The denovo study was conducted in 423 renal transplant patients (ages 18-75 years) in Austria, Canada, Germany, Hungary, Italy, Norway, Spain, UK and USA. Cadaveric donor specimens accounted for 84% of randomized patients. Patients were administered either Myfortic 1.44g/day or mycophenolate mofetil 2g/day within 48hours posttransplant for 12months in combination with cyclosporine, USP (MODIFIED) and corticosteroids. Forty-one percent of patients received antibody therapy as induction treatment. Treatment failure was defined as the first occurrence of biopsy-proven acute rejection, graft loss, death or lost to follow-up at 6months. The incidence of treatment failure was similar in Myfortic- and mycophenolate mofetil-treated patients at 6 and 12months (Table2). The cumulative incidence of graft loss, death and lost to follow-up at 12months is also given in Table2.

The maintenance study was conducted in 322 renal transplant patients (ages 18–75 years), who were at least 6months posttransplant receiving 2g/day mycophenolate mofetil in combination with cyclosporine USP (MODIFIED), with or without corticosteroids for at least two weeks prior to entry in the study. Patients were randomized to Myfortic 1.44g/day or mycophenolate mofetil 2g/day for 12months. The study was conducted in Austria, Belgium, Canada, Germany, Italy, Spain, and USA. Treatment failure was defined as the first occurrence of biopsy-proven acute rejection, graft loss, death, or lost to follow-up at 6 and 12months. The incidences of treatment failure at 6 and 12months were similar between Myfortic- and mycophenolate mofetil-treated patients (Table3). The cumulative incidence of graft loss, death and lost to follow-up at 12months is also given in Table3.

The safety and efficacy of Myfortic has not been studied in hepatic or cardiac transplant trials.

INDICATIONS AND USAGE

Myfortic® (mycophenolicacid) delayed-release tablets are indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal transplants, administered in combination with cyclosporine and corticosteroids.

CONTRAINDICATIONS

Myfortic® (mycophenolicacid) is contraindicated in patients with a hypersensitivity to mycophenolate sodium, mycophenolicacid, mycophenolate mofetil, or to any of its excipients.

WARNINGS (SEE BOXED WARNING)

Lymphoma and Other Malignancies

Patients receiving immunosuppressive regimens involving combinations of drugs, including Myfortic® (mycophenolicacid), as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see ADVERSE REACTIONS). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

The rates for lymphoproliferative disease or lymphoma in Myfortic-treated patients were comparable to the mycophenolate mofetil group in the denovo and maintenance studies (see ADVERSE REACTIONS). As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Infections

Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections, fatal infections, and sepsis. Fatal infections can occur in patients receiving immunosuppressive therapy (see ADVERSE REACTIONS).

Polyomavirus Infections

Patients receiving immunosuppressants, including Myfortic are at increased risk for opportunistic infections, including Polyomavirus infections. Polyomavirus infections in transplant patients may have serious, and sometimes, fatal outcomes. These include cases of JC virus associated progressive multifocal leukoencephalopathy (PML) and Polyomavirus associated nephropathy (PVAN) especially due to BK virus infection which have been observed in patients receiving Myfortic.

PVAN, especially due to BK virus infection, is associated with serious outcomes, including deteriorating renal function and renal graft loss (see ADVERSE REACTIONS). Patient monitoring may help detect patients at risk for PVAN.

Cases of PML, have been reported in patients treated with MPA derivatives which include mycophenolate mofetil (MMF) and mycophenolate sodium (see ADVERSE REACTIONS). PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

Reduction in immunosuppression should be considered for patients who develop evidence of PML or PVAN. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.

Blood Dyscrasias Including Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolic acid (MPA) derivatives in combination with other immunosuppressive agents. The mechanism for MPA derivatives induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppressive regimen is also unknown. 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 (see ADVERSE REACTIONS, Postmarketing Experience).

Patients receiving Myfortic should be monitored for blood dyscrasias (e.g. neutropenia or anemia (see PRECAUTIONS, Laboratory Tests). The development of neutropenia may be related to Myfortic itself, concomitant medications, viral infections, or some combination of these events. If blood dyscrasias occur (e.g. neutropenia (ANC <1.3x103/ µL or anemia)), dosing with Myfortic should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see DOSAGE AND ADMINISTRATION).

Patients receiving Myfortic should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding, or any other manifestation of bone marrow suppression.

Concomitant Use

Myfortic has been administered in combination with the following agents in clinical trials: antithymocyte/lymphocyte immunoglobulin, muromonab-CD3, basiliximab, daclizumab, cyclosporine, and corticosteroids. The efficacy and safety of Myfortic in combination with other immunosuppression agents have not been determined.

Pregnancy: Teratogenic Effects: Pregnancy Category D

Mycophenolate mofetil (MMF) can cause fetal harm when administered to a pregnant woman. Following oral or IV administration, MMF is metabolized to mycophenolicacid (MPA), the active ingredient in Myfortic and the active form of the drug. Use of Myfortic during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney. In the National Transplantation Pregnancy Registry (NTPR), there were data on 33 MMF-exposed pregnancies in 24 transplant patients; there were 15 spontaneous abortions (45%) and 18 live-born infants. Four of these 18 infants had structural malformations (22%). In postmarketing data (collected from 1995 to 2007) on 77 women exposed to systemic MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or fetus. Six of 14 malformed offspring had ear abnormalities. Because these postmarketing data are reported voluntarily, it is not always possible to reliably estimate the frequency of particular adverse outcomes. These malformations are similar to findings in animal reproductive toxicology studies. For comparison, the background rate for congenital anomalies in the United States is about 3%, and NTPR data show a rate of 4-5% among babies born to organ transplant patients using other immunosuppressive drugs.

In a teratology study performed with mycophenolate sodium in rats, at a dose as low as 1mg/kg, malformations in the offspring were observed, including anophthalmia, exencephaly and umbilical hernia. The systemic exposure at this dose represents 0.05times the clinical exposure at the dose of 1.44g/day Myfortic. In teratology studies in rabbits, fetal resorptions and malformations occurred from 80mg/kg/day, in the absence of maternal toxicity (dose levels are equivalent to about 0.8times the recommended clinical dose, corrected for BSA). There are no relevant qualitative or quantitative differences in the teratogenic potential of mycophenolate sodium and mycophenolate mofetil.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In certain situations, the patient and her healthcare practitioner may decide that the maternal benefits outweigh the risks to the fetus. Women using Myfortic at any time during pregnancy should be encouraged to enroll in the National Transplantation Pregnancy Registry.

Pregnancy Exposure Prevention

Women of childbearing potential should have a negative serum or urine pregnancy test with a sensitivity of at least 25mIU/mL within 1week prior to beginning therapy. Myfortic therapy should not be initiated until a negative pregnancy test report is obtained.

Women of childbearing potential (including pubertal girls and perimenopausal women) taking Myfortic must receive contraceptive counseling and use effective contraception. The patient should begin using her two chosen methods of contraception 4weeks prior to starting Myfortic therapy, unless abstinence is the chosen method. She should continue contraceptive use during therapy and for 6weeks after stopping Myfortic. Patients should be aware that Myfortic reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness(see PRECAUTIONS, Information for Patients and PRECAUTIONS, Drug Interactions, Oral Contraceptives).

PRECAUTIONS

General

Gastrointestinal bleeding (requiring hospitalization) has been reported in denovo renal transplant patients (1.0%) and maintenance patients (1.3%) treated with Myfortic®(mycophenolicacid) (up to 12months). Intestinal perforations, gastrointestinal hemorrhage, gastric ulcers and duodenal ulcers haverarely been observed. Most patients receiving Myfortic were also receiving other drugs known to be associated with these complications. Patients with active peptic ulcer disease were excluded from enrollment in studies with Myfortic. Because MPA derivatives have been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hemorrhage, and perforation, Myfortic should be administered with caution in patients with active serious digestive system disease (see ADVERSE REACTIONS).

Subjects with severe chronic renal impairment (GFR <25mL/min/1.73m2) may present higher plasma MPA and MPAG AUCs relative to subjects with lesser degrees of renal impairment or normal healthy volunteers. No data are available on the safety of long-term exposure to these levels of MPAG.

In the denovo study, 18.3% of Myfortic patients versus 16.7% in the mycophenolate mofetil group experienced delayed graft function (DGF). Although patients with DGF experienced a higher incidence of certain adverse events (anemia, leukopenia, and hyperkalemia) than patients without DGF, these events in DGF patients were not more frequent in patients receiving Myfortic compared to mycophenolate mofetil. No dose adjustment is recommended for these patients; however, such patients should be carefully observed (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

In view of the significant reduction in the AUC of MPA by cholestyramine when administered with mycophenolate mofetil, caution should be used in the concomitant administration of Myfortic with drugs that interfere with enterohepatic recirculation because of the potential to reduce the efficacy (see PRECAUTIONS, Drug Interactions).

On theoretical grounds, because Myfortic is an IMPDH Inhibitor, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective (see PRECAUTIONS, Drug Interactions, Live Vaccines).

Information for Patients