mycophenolate mofetil 250 MG Oral Capsule
Generic Name: MYCOPHENOLATE MOFETIL
Brand Name: Mycophenolate Mofetil
- Substance Name(s):
- MYCOPHENOLATE MOFETIL
WARNINGS
(see boxed WARNING) Embryofetal Toxicity Mycophenolate mofetil can cause fetal harm when administered to a pregnant female.
Use of mycophenolate mofetil 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 (see PRECAUTIONS: Pregnancy).
Pregnancy Exposure Prevention and Planning Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning.
For recommended pregnancy testing and contraception methods (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning).
Lymphoma and Malignancy Patients receiving immunosuppressive regimens involving combinations of drugs, including mycophenolate mofetil, 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.
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.
Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of renal, cardiac and hepatic transplant patients (see ADVERSE REACTIONS).
In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed (see ADVERSE REACTIONS).
Combination with Other Immunosuppressive Agents Mycophenolate mofetil has been administered in combination with the following agents in clinical trials: antithymocyte globulin (ATGAM®†), OKT3 (Orthoclone OKT®† 3), cyclosporine (Sandimmune®† , Neoral®†) and corticosteroids.
The efficacy and safety of the use of mycophenolate mofetil in combination with other immunosuppressive agents have not been determined.
Serious Infections Patients receiving immunosuppressants, including mycophenolate mofetil, are at increased risk of developing bacterial, fungal, protozoal and new or reactivated viral infections, including opportunistic infections.
These infections may lead to serious, including fatal outcomes.
Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution (see ADVERSE REACTIONS).
New or Reactivated Viral Infections Polyomavirus associated nephropathy (PVAN), JC virus associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including mycophenolate mofetil.
Reduction in immunosuppression should be considered for patients who develop evidence of new or reactivated viral infections.
Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.
PVAN, especially due to BK virus infection, is associated with serious outcomes, including deteriorating renal function and renal graft loss (see ADVERSE REACTIONS: Post-Marketing Experience).
Patient monitoring may help detect patients at risk for PVAN.
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 (see ADVERSE REACTIONS: Post-Marketing Experience).
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.
The risk of CMV viremia and CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor.
Therapeutic approaches to limiting CMV disease exist and should be routinely provided.
Patient monitoring may help detect patients at risk for CMV disease.
Viral reactivation has been reported in patients infected with HBV or HCV.
Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended.
Neutropenia Severe neutropenia [absolute neutrophil count (ANC) < 0.5 x 103/µL] developed in up to 2% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant patients receiving mycophenolate mofetil 3 g daily (see ADVERSE REACTIONS).
Patients receiving mycophenolate mofetil should be monitored for neutropenia (see PRECAUTIONS: Laboratory Tests).
The development of neutropenia may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or some combination of these causes.
If neutropenia develops (ANC < 1.3 x 103/µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see DOSAGE AND ADMINISTRATION).
Neutropenia has been observed most frequently in the period from 31 to 180 days post-transplant in patients treated for prevention of renal, cardiac and hepatic rejection.
Patients receiving mycophenolate mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Pure Red Cell Aplasia (PRCA) Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents.
The mechanism for mycophenolate mofetil induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppression regimen are also unknown.
In some cases, PRCA was found to be reversible with dose reduction or cessation of mycophenolate mofetil therapy.
In transplant patients, however, reduced immunosuppression may place the graft at risk.
DRUG INTERACTIONS
Drug Interactions Drug interaction studies with mycophenolate mofetil have been conducted with acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives, sevelamer, trimethoprim/sulfamethoxazole, norfloxacin and metronidazole.
Drug interaction studies have not been conducted with other drugs that may be commonly administered to renal, cardiac or hepatic transplant patients.
Mycophenolate mofetil has not been administered concomitantly with azathioprine.
Acyclovir Coadministration of mycophenolate mofetil (1 g) and acyclovir (800 mg) to 12 healthy volunteers resulted in no significant change in MPA AUC and Cmax.
However, MPAG and acyclovir plasma AUCs were increased 10.6% and 21.9%, respectively.
Because MPAG plasma concentrations are increased in the presence of renal impairment, as are acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its prodrug (e.g., valacyclovir) to compete for tubular secretion, further increasing the concentrations of both drugs.
Antacids with Magnesium and Aluminum Hydroxides Absorption of a single-dose of mycophenolate mofetil (2 g) was decreased when administered to ten rheumatoid arthritis patients also taking Maalox® TC (10 mL qid).
The Cmax and AUC(0-24h) for MPA were 33% and 17% lower, respectively, than when mycophenolate mofetil was administered alone under fasting conditions.
Mycophenolate mofetil may be administered to patients who are also taking antacids containing magnesium and aluminum hydroxides; however, it is recommended that mycophenolate mofetil and the antacid not be administered simultaneously.
Proton Pump Inhibitors (PPIs) Coadministration of PPIs (e.g., lansoprazole, pantoprazole) in single doses to healthy volunteers and multiple doses to transplant patients receiving mycophenolate mofetil has been reported to reduce the exposure to mycophenolic acid (MPA).
An approximate reduction of 30% to 70% in the Cmax and 25% to 35% in the AUC of MPA has been observed, possibly due to a decrease in MPA solubility at an increased gastric pH.
The clinical impact of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and mycophenolate mofetil.
Because clinical relevance has not been established, PPIs should be used with caution when coadministered to transplant patients being treated with mycophenolate mofetil.
Cholestyramine Following single-dose administration of 1.5 g mycophenolate mofetil to 12 healthy volunteers pretreated with 4 g tid of cholestyramine for 4 days, MPA AUC decreased approximately 40%.
This decrease is consistent with interruption of enterohepatic recirculation which may be due to binding of recirculating MPAG with cholestyramine in the intestine.
Therefore, mycophenolate mofetil is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation.
Cyclosporine Cyclosporine (Sandimmune®†) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 g bid of mycophenolate mofetil in ten stable renal transplant patients.
The mean (± SD) AUC(0-12h) and Cmax of cyclosporine after 14 days of multiple doses of mycophenolate mofetil were 3290 (± 822) ng•h/mL and 753 (± 161) ng/mL, respectively, compared to 3245 (± 1088) ng•h/mL and 700 (± 246) ng/mL, respectively, one week before administration of mycophenolate mofetil.
In renal transplant patients, mean MPA exposure (AUC0-12h) was approximately 30% to 50% greater when mycophenolate mofetil is administered without cyclosporine compared with when mycophenolate mofetil is coadministered with cyclosporine.
This interaction is due to cyclosporine inhibition of multidrug-resistance-associated protein 2 (MRP-2) transporter in the biliary tract, thereby preventing the excretion of MPAG into the bile that would lead to enterohepatic recirculation of MPA.
This information should be taken into consideration when MMF is used without cyclosporine.
Ganciclovir Following single-dose administration to 12 stable renal transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 g) and intravenous ganciclovir (5 mg/kg).
Mean (± SD) ganciclovir AUC and Cmax (n = 10) were 54.3 (± 19) mcg•h/mL and 11.5 (± 1.8) mcg/mL, respectively, after coadministration of the two drugs, compared to 51 (± 17) mcg•h/mL and 10.6 (± 2) mcg/mL, respectively, after administration of intravenous ganciclovir alone.
The mean (± SD) AUC and Cmax of MPA (n = 12) after coadministration were 80.9 (± 21.6) mcg•h/mL and 27.8 (± 13.9) mcg/mL, respectively, compared to values of 80.3 (± 16.4) mcg•h/mL and 30.9 (± 11.2) mcg/mL, respectively, after administration of mycophenolate mofetil alone.
Because MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the two drugs will compete for tubular secretion and thus further increases in concentrations of both drugs may occur.
In patients with renal impairment in which mycophenolate mofetil and ganciclovir or its prodrug (e.g., valganciclovir) are coadministered, patients should be monitored carefully.
Oral Contraceptives A study of coadministration of mycophenolate mofetil (1 g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) was conducted in 18 women with psoriasis over three consecutive menstrual cycles.
Mean AUC(0-24h) was similar for ethinylestradiol and 3-keto desogestrel; however, mean levonorgestrel AUC(0-24h) significantly decreased by about 15%.
There was large inter-patient variability (%CV in the range of 60% to 70%) in the data, especially for ethinylestradiol.
Mean serum levels of LH, FSH and progesterone were not significantly affected.
Mycophenolate mofetil may not have any influence on the ovulation-suppressing action of the studied oral contraceptives.
It is recommended to coadminister mycophenolate mofetil with hormonal contraceptives (e.g., birth control pill, transdermal patch, vaginal ring, injection and implant) with caution and additional barrier contraceptive methods must be used (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning).
Sevelamer Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA Cmax and AUC0-12h by 36% and 26% respectively.
This data suggest that sevelamer and other calcium free phosphate binders should not be administered simultaneously with mycophenolate mofetil.
Alternatively, it is recommended that sevelamer and other calcium free phosphate binders preferentially could be given 2 hours after mycophenolate mofetil intake to minimize the impact on the absorption of MPA.
Trimethoprim/Sulfamethoxazole Following single-dose administration of mycophenolate mofetil (1.5 g) to 12 healthy male volunteers on day 8 of a 10 day course of trimethoprim 160 mg/sulfamethoxazole 800 mg administered bid, no effect on the bioavailability of MPA was observed.
The mean (± SD) AUC and Cmax of MPA after concomitant administration were 75.2 (± 19.8) mcg•h/mL and 34 (± 6.6) mcg/mL, respectively, compared to 79.2 (± 27.9) mcg•h/mL and 34.2 (± 10.7) mcg/mL, respectively, after administration of mycophenolate mofetil alone.
Norfloxacin and Metronidazole Following single-dose administration of mycophenolate mofetil (1 g) to 11 healthy volunteers on day 4 of a 5 day course of a combination of norfloxacin and metronidazole, the mean MPA AUC0-48h was significantly reduced by 33% compared to the administration of mycophenolate mofetil alone (p< 0.05).
Therefore, mycophenolate mofetil is not recommended to be given with the combination of norfloxacin and metronidazole.
There was no significant effect on mean MPA AUC0-48h when mycophenolate mofetil was concomitantly administered with norfloxacin or metronidazole separately.
The mean (± SD) MPA AUC0-48h after coadministration of mycophenolate mofetil with norfloxacin or metronidazole separately was 48.3 (± 24) mcg•h/mL and 42.7 (± 23) mcg•h/mL, respectively, compared with 56.2 (± 24) mcg•h/mL after administration of mycophenolate mofetil alone.
Ciprofloxacin and Amoxicillin plus Clavulanic Acid A total of 64 mycophenolate mofetil-treated renal transplant recipients received either oral ciprofloxacin 500 mg bid or amoxicillin plus clavulanic acid 375 mg tid for 7 days or at least 14 days.
Approximately 50% reductions in median trough MPA concentrations (pre-dose) from baseline (mycophenolate mofetil alone) were observed in 3 days following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid.
These reductions in trough MPA concentrations tended to diminish within 14 days of antibiotic therapy and ceased within 3 days after discontinuation of antibiotics.
The postulated mechanism for this interaction is an antibiotic-induced reduction in glucuronidase-possessing enteric organisms leading to a decrease in enterohepatic recirculation of MPA.
The change in trough level may not accurately represent changes in overall MPA exposure; therefore, clinical relevance of these observations is unclear.
Rifampin In a single heart-lung transplant patient, after correction for dose, a 67% decrease in MPA exposure (AUC0-12h) has been observed with concomitant administration of mycophenolate mofetil and rifampin.
Therefore, mycophenolate mofetil is not recommended to be given with rifampin concomitantly unless the benefit outweighs the risk.
Other Interactions The measured value for renal clearance of MPAG indicates removal occurs by renal tubular secretion as well as glomerular filtration.
Consistent with this, coadministration of probenecid, a known inhibitor of tubular secretion, with mycophenolate mofetil in monkeys results in a 3-fold increase in plasma MPAG AUC and a 2-fold increase in plasma MPA AUC.
Thus, other drugs known to undergo renal tubular secretion may compete with MPAG and thereby raise plasma concentrations of MPAG or the other drug undergoing tubular secretion.
Drugs that alter the gastrointestinal flora may interact with mycophenolate mofetil by disrupting enterohepatic recirculation.
Interference of MPAG hydrolysis may lead to less MPA available for absorption.
Live Vaccines During treatment with mycophenolate mofetil, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective (see PRECAUTIONS: Immunizations).
Influenza vaccination may be of value.
Prescribers should refer to national guidelines for influenza vaccination.
OVERDOSAGE
The experience with overdose of mycophenolate mofetil in humans is very limited.
The events received from reports of overdose fall within the known safety profile of the drug.
The highest dose administered to renal transplant patients in clinical trials has been 4 g/day.
In limited experience with cardiac and hepatic transplant patients in clinical trials, the highest doses used were 4 g/day or 5 g/day.
At doses of 4 g/day or 5 g/day, there appears to be a higher rate, compared to the use of 3 g/day or less, of gastrointestinal intolerance (nausea, vomiting and/or diarrhea), and occasional hematologic abnormalities, principally neutropenia, leading to a need to reduce or discontinue dosing.
In acute oral toxicity studies, no deaths occurred in adult mice at doses up to 4000 mg/kg or in adult monkeys at doses up to 1000 mg/kg; these were the highest doses of mycophenolate mofetil tested in these species.
These doses represent 11 times the recommended clinical dose in renal transplant patients and approximately 7 times the recommended clinical dose in cardiac transplant patients when corrected for BSA.
In adult rats, deaths occurred after single oral doses of 500 mg/kg of mycophenolate mofetil.
The dose represents approximately 3 times the recommended clinical dose in cardiac transplant patients when corrected for BSA.
Mycophenolic acid (MPA) and MPAG (metabolized to form the phenolic glucuronide of MPA) are usually not removed by hemodialysis.
However, at high MPAG plasma concentrations (> 100 mcg/mL), small amounts of MPAG are removed.
By increasing excretion of the drug, MPA can be removed by bile acid sequestrants, such as cholestyramine (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
DESCRIPTION
Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor.
The chemical name for mycophenolate mofetil is 2-Morpholinoethyl (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl)-4-methyl-4-hexenoate.
It has a molecular formula of C23H31NO7, a molecular weight of 433.5, and the following structural formula: Mycophenolate mofetil, USP is a white to almost white crystalline powder.
It is practically insoluble in water (43 mcg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6).
It is freely soluble in acetone, soluble in methanol, and sparingly soluble in anhydrous ethanol.
The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238.
The pKa values for mycophenolate mofetil are 5.6 for the morpholino group and 8.5 for the phenolic group.
Mycophenolate mofetil is available for oral administration as capsules containing 250 mg of mycophenolate mofetil and tablets containing 500 mg of mycophenolate mofetil.
Mycophenolate Mofetil Capsules USP, 250 mg contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), and sodium lauryl sulfate.
The empty gelatin capsule shells contain black iron oxide, FD&C Blue No.
2, gelatin, red iron oxide, titanium dioxide, and yellow iron oxide.
In addition, the imprinting ink contains the following: ammonium hydroxide, black iron oxide, propylene glycol, and shellac glaze.
Mycophenolate Mofetil Tablets USP, 500 mg contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, pregelatinized starch, red iron oxide, sodium lauryl sulfate, talc, titanium dioxide and yellow iron oxide.
Structural Formula
CLINICAL STUDIES
Adults The safety and efficacy of mycophenolate mofetil in combination with corticosteroids and cyclosporine for the prevention of organ rejection were assessed in randomized, double-blind, multicenter trials in renal (three trials), in cardiac (one trial) and in hepatic (one trial) adult transplant patients.
Renal Transplant Adults The three renal studies compared two dose levels of oral mycophenolate mofetil (1 g bid and 1.5 g bid) with azathioprine (two studies) or placebo (one study) when administered in combination with cyclosporine (Sandimmune®) and corticosteroids to prevent acute rejection episodes.
One study also included antithymocyte globulin (ATGAM®) induction therapy.
These studies are described by geographic location of the investigational sites.
One study was conducted in the USA at 14 sites, one study was conducted in Europe at 20 sites, and one study was conducted in Europe, Canada and Australia at a total of 21 sites.
The primary efficacy endpoint was the proportion of patients in each treatment group who experienced treatment failure within the first 6 months after transplantation (defined as biopsy-proven acute rejection on treatment or the occurrence of death, graft loss or early termination from the study for any reason without prior biopsy-proven rejection).
Mycophenolate mofetil, when administered with antithymocyte globulin (ATGAM®) induction (one study) and with cyclosporine and corticosteroids (all three studies), was compared to the following three therapeutic regimens: (1) antithymocyte globulin (ATGAM®) induction/azathioprine/cyclosporine/corticosteroids, (2) azathioprine/cyclosporine/corticosteroids, and (3) cyclosporine/corticosteroids.
Mycophenolate mofetil, in combination with corticosteroids and cyclosporine reduced (statistically significant at 0.05 level) the incidence of treatment failure within the first 6 months following transplantation.
Table 4 and Table 5 summarize the results of these studies.
These tables show (1) the proportion of patients experiencing treatment failure, (2) the proportion of patients who experienced biopsy-proven acute rejection on treatment, and (3) early termination, for any reason other than graft loss or death, without a prior biopsy-proven acute rejection episode.
Patients who prematurely discontinued treatment were followed for the occurrence of death or graft loss, and the cumulative incidence of graft loss and patient death are summarized separately.
Patients who prematurely discontinued treatment were not followed for the occurrence of acute rejection after termination.
More patients receiving mycophenolate mofetil discontinued without prior biopsy-proven rejection, death or graft loss than discontinued in the control groups, with the highest rate in the mycophenolate mofetil 3 g/day group.
Therefore, the acute rejection rates may be underestimates, particularly in the mycophenolate mofetil 3 g/day group.
Table 4 Renal Transplant Studies Incidence of Treatment Failure (Biopsy-proven Rejection or Early Termination for Any Reason) USA Study Antithymocyte globulin induction/mycophenolate mofetil or azathioprine/cyclosporine/corticosteriods (N = 499 patients) Mycophenolate Mofetil 2 g/day (n = 167 patients) Mycophenolate Mofetil 3 g/day (n = 166 patients) Azathioprine 1 to 2 mg/kg/day (n = 166 patients) All treatment failures 31.1% 31.3% 47.6% Early termination without prior acute rejectionDoes not include death and graft loss as reason for early termination 9.6% 12.7% 6% Biopsy-proven rejection episode on treatment 19.8% 17.5% 38% Europe/Canada/Australia Study Mycophenolate mofetil or azathioprine/cyclosporine/corticosteroids (N = 503 patients) Mycophenolate Mofetil 2 g/day (n = 173 patients) Mycophenolate Mofetil 3 g/day (n = 164 patients) Azathioprine 100 to 150 mg/day (n = 166 patients) All treatment failures 38.2% 34.8% 50% Early termination without prior acute rejection† 13.9% 15.2% 10.2% Biopsy-proven rejection episode on treatment 19.7% 15.9% 35.5% Europe Study Mycophenolate mofetil or placebo/cyclosporine/corticosteroids (N = 491 patients) Mycophenolate Mofetil 2 g/day (n = 165 patients) Mycophenolate Mofetil 3 g/day (n = 160 patients) Placebo (n = 166 patients) All treatment failures 30.3% 38.8% 56% Early termination without prior acute rejection† 11.5% 22.5% 7.2% Biopsy-proven rejection episode on treatment 17% 13.8% 46.4% The cumulative incidence of 12 month graft loss or patient death is presented below.
No advantage of mycophenolate mofetil with respect to graft loss or patient death was established.
Numerically, patients receiving mycophenolate mofetil 2 g/day and 3 g/day experienced a better outcome than controls in all three studies; patients receiving mycophenolate mofetil 2 g/day experienced a better outcome than mycophenolate mofetil 3 g/day in two of the three studies.
Patients in all treatment groups who terminated treatment early were found to have a poor outcome with respect to graft loss or patient death at one year.
Table 5 Renal Transplant Studies Cumulative Incidence of Combined Graft Loss or Patient Death at 12 Months Study Mycophenolate Mofetil 2 g/day Mycophenolate Mofetil 3 g/day Control (Azathioprine or Placebo) USA 8.5% 11.5% 12.2% Europe/Canada/Australia 11.7% 11% 13.6% Europe 8.5% 10% 11.5% Pediatrics One open-label, safety and pharmacokinetic study of mycophenolate mofetil oral suspension 600 mg/m2 bid (up to 1 g bid) in combination with cyclosporine and corticosteroids was performed at centers in the US (9), Europe (5) and Australia (1) in 100 pediatric patients (3 months to 18 years of age) for the prevention of renal allograft rejection.
Mycophenolate mofetil was well tolerated in pediatric patients (see ADVERSE REACTIONS), and the pharmacokinetics profile was similar to that seen in adult patients dosed with 1 g bid mycophenolate mofetil capsules (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
The rate of biopsy-proven rejection was similar across the age groups (3 months to < 6 years, 6 years to < 12 years, 12 years to 18 years).
The overall biopsy-proven rejection rate at 6 months was comparable to adults.
The combined incidence of graft loss (5%) and patient death (2%) at 12 months post-transplant was similar to that observed in adult renal transplant patients.
Cardiac Transplant A double-blind, randomized, comparative, parallel-group, multicenter study in primary cardiac transplant recipients was performed at 20 centers in the United States, one in Canada, five in Europe and two in Australia.
The total number of patients enrolled was 650; 72 never received study drug and 578 received study drug.
Patients received mycophenolate mofetil 1.5 g bid (n = 289) or azathioprine 1.5 to 3 mg/kg/day (n = 289), in combination with cyclosporine (Sandimmune®† or Neoral®†) and corticosteroids as maintenance immunosuppressive therapy.
The two primary efficacy endpoints were: (1) the proportion of patients who, after transplantation, had at least one endomyocardial biopsy-proven rejection with hemodynamic compromise, or were retransplanted or died, within the first 6 months, and (2) the proportion of patients who died or were retransplanted during the first 12 months following transplantation.
Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection for up to 6 months and for the occurrence of death for one year.
(1) Rejection: No difference was established between mycophenolate mofetil and azathioprine (AZA) with respect to biopsy-proven rejection with hemodynamic compromise.
(2) Survival: Mycophenolate mofetil was shown to be at least as effective as AZA in preventing death or retransplantation at one year (see Table 6).
Table 6 Rejection at 6 Months/Death or Retransplantation at One Year All Patients Treated Patients AZA N = 323 Mycophenolate Mofetil N = 327 AZA N = 289 Mycophenolate Mofetil N = 289 Biopsy-proven rejection with hemodynamic compromise at 6 monthsHemodynamic compromise occurred if any of the following criteria were met: pulmonary capillary wedge pressure ≥ 20 mm or a 25% increase; cardiac index < 2 L/min/m2 or a 25% decrease; ejection fraction ≤ 30%; pulmonary artery oxygen saturation ≤ 60% or a 25% decrease; presence of new S3 gallop; fractional shortening was ≤ 20% or a 25% decrease; inotropic support required to manage the clinical condition.
121 (38%) 120 (37%) 100 (35%) 92 (32%) Death or retransplantation at one year 49 (15.2%) 42 (12.8%) 33 (11.4%) 18 (6.2%) Hepatic Transplant A double-blind, randomized, comparative, parallel-group, multicenter study in primary hepatic transplant recipients was performed at 16 centers in the United States, two in Canada, four in Europe and one in Australia.
The total number of patients enrolled was 565.
Per protocol, patients received mycophenolate mofetil 1 g bid intravenously for up to 14 days followed by mycophenolate mofetil 1.5 g bid orally or azathioprine 1 to 2 mg/kg/day intravenously followed by azathioprine 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral®†) and corticosteroids as maintenance immunosuppressive therapy.
The actual median oral dose of azathioprine on study was 1.5 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) initially and 1.26 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) at 12 months.
The two primary endpoints were: (1) the proportion of patients who experienced, in the first 6 months post-transplantation, one or more episodes of biopsy-proven and treated rejection or death or retransplantation, and (2) the proportion of patients who experienced graft loss (death or retransplantation) during the first 12 months post-transplantation.
Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection and for the occurrence of graft loss (death or retransplantation) for one year.
Results In combination with corticosteroids and cyclosporine, mycophenolate mofetil obtained a lower rate of acute rejection at 6 months and a similar rate of death or retransplantation at one year compared to azathioprine.
Table 7 Rejection at 6 Months/Death or Retransplantation at One Year AZA N = 287 Mycophenolate Mofetil N = 278 Biopsy-proven, treated rejection at 6 months (includes death or retransplantation) 137 (47.7%) 107 (38.5%) Death or retransplantation at one year 42 (14.6%) 41 (14.7%)
HOW SUPPLIED
Mycophenolate Mofetil Capsules, USP are available containing 250 mg of mycophenolate mofetil, USP.
The 250 mg capsule is a caramel opaque cap/lavender opaque body, hard-shell gelatin capsule filled with white to off-white powder.
The capsule is axially printed with MYLAN over 2250 in black ink on both the cap and body.
They are available as follows: NDC 60429-059-01 bottles of 100 capsules NDC 60429-059-05 bottles of 500 capsules Mycophenolate Mofetil Tablets, USP are available containing 500 mg of mycophenolate mofetil, USP.
The 500 mg tablet is a light pink film-coated, oval, unscored tablet debossed with MYLAN on one side of the tablet and 472 on the other side.
They are available as follows: NDC 60429-070-01 bottles of 100 tablets NDC 60429-070-05 bottles of 500 tablets Storage and Handling Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
PHARMACIST: Dispense a Medication Guide with each prescription.
MECHANISM OF ACTION
Mechanism of Action Mycophenolate mofetil has been demonstrated in experimental animal models to prolong the survival of allogeneic transplants (kidney, heart, liver, intestine, limb, small bowel, pancreatic islets and bone marrow).
Mycophenolate mofetil has also been shown to reverse ongoing acute rejection in the canine renal and rat cardiac allograft models.
Mycophenolate mofetil also inhibited proliferative arteriopathy in experimental models of aortic and cardiac allografts in rats, as well as in primate cardiac xenografts.
Mycophenolate mofetil was used alone or in combination with other immunosuppressive agents in these studies.
Mycophenolate mofetil has been demonstrated to inhibit immunologically mediated inflammatory responses in animal models and to inhibit tumor development and prolong survival in murine tumor transplant models.
Mycophenolate mofetil is rapidly absorbed following oral administration and hydrolyzed to form MPA, which is the active metabolite.
MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA.
Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes.
MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation.
Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes.
MPA also suppresses antibody formation by B-lymphocytes.
MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection.
Mycophenolate mofetil did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of these events to DNA synthesis and proliferation.
INDICATIONS AND USAGE
Renal, Cardiac and Hepatic Transplant Mycophenolate mofetil is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.
Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids.
BOXED WARNING
WARNING: Embryofetal Toxicity, Malignancies and Serious Infections: Use during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations.
Females of reproductive potential (FRP) must be counseled regarding pregnancy prevention and planning (see WARNINGS and PRECAUTIONS).
Immunosuppression may lead to increased susceptibility to infection and possible development of lymphoma.
Only physicians experienced in immunosuppressive therapy and management of renal, cardiac or hepatic transplant patients should prescribe mycophenolate mofetil.
Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources.
The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient (see WARNINGS and PRECAUTIONS).
INFORMATION FOR PATIENTS
Information for Patients See Medication Guide •Inform females of reproductive potential that use of mycophenolate mofetil during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, and advise them as to the appropriate steps to manage these risks, including that they must use acceptable contraception (see WARNINGS: Embryofetal Toxicity and PRECAUTIONS: Pregnancy Exposure Prevention and Planning).
•Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential.
In the event of a positive pregnancy test, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations.
•Females of reproductive potential must use acceptable birth control during entire mycophenolate mofetil therapy and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses to avoid heterosexual intercourse completely (abstinence) (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning: Table 8).
•For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryofetal toxicity.
Risks and benefits of mycophenolate mofetil should be discussed with the patient.
•Give patients complete dosage instructions and inform them about the increased risk of lymphoproliferative disease and certain other malignancies.
•Inform patients that they need repeated appropriate laboratory tests while they are taking mycophenolate mofetil.
•Advise patients that they should not breast-feed during mycophenolate mofetil therapy.
DOSAGE AND ADMINISTRATION
Renal Transplantation Adults A dose of 1 g administered orally twice a day (daily dose of 2 g) is recommended for use in renal transplant patients.
Although a dose of 1.5 g administered twice daily (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients.
Patients receiving 2 g/day of mycophenolate mofetil demonstrated an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil.
Pediatrics (3 Months to 18 years of Age) The recommended dose of mycophenolate mofetil oral suspension is 600 mg/m2 administered twice daily (up to a maximum daily dose of 2 g/10 mL oral suspension).
Patients with a body surface area of 1.25 m2 to 1.5 m2 may be dosed with mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose).
Patients with a body surface area > 1.5 m2 may be dosed with mycophenolate mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose).
Cardiac Transplantation Adults A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients.
Hepatic Transplantation Adults A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients.
Mycophenolate Mofetil Capsules and Tablets The initial oral dose of mycophenolate mofetil should be given as soon as possible following renal, cardiac or hepatic transplantation.
Food had no effect on MPA AUC, but has been shown to decrease MPA Cmax by 40%.
Therefore, it is recommended that mycophenolate mofetil be administered on an empty stomach.
However, in stable renal transplant patients, mycophenolate mofetil may be administered with food if necessary.
Patients should be instructed to take a missed dose as soon as they remember, except if it is near the next scheduled dose, and then continue to take mycophenolate mofetil at the usual times.
Patients with Hepatic Impairment No dose adjustments are recommended for renal patients with severe hepatic parenchymal disease.
However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
No data are available for cardiac transplant patients with severe hepatic parenchymal disease.
Geriatrics The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac transplant patients and 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients (see PRECAUTIONS: Geriatric Use).
Dosage Adjustments In renal transplant patients with severe chronic renal impairment (GFR < 25 mL/min/1.73 m2) outside the immediate post-transplant period, doses of mycophenolate mofetil greater than 1 g administered twice a day should be avoided.
These patients should also be carefully observed.
No dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively (see CLINICAL PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: Patients with Renal Impairment).
No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
Mycophenolate mofetil may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.
If neutropenia develops (ANC < 1.3 x 103/µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed and the patient managed appropriately (see WARNINGS: Neutropenia, ADVERSE REACTIONS and PRECAUTIONS: Laboratory Tests).