^ Administration Instructions
^ Liver Transplantation
A double-blind, randomized, comparative, parallel-group, multicenter study in primary hepatic transplant recipients was performed at centers in the United States (16), in Canada (2), in Europe (4) and in Australia (1). The total number of patients enrolled was 565. Per protocol, patients received Mycophenolate Mofetil 1 g twice daily intravenously for up to 14 days followed by Mycophenolate Mofetil 1.5 g twice daily orally or AZA 1 to 2 mg/kg/day intravenously followed by AZA 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral ®) and corticosteroids as maintenance immunosuppressive therapy. The actual median oral dose of AZA 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 re-transplantation, and (2) the proportion of patients who experienced graft loss (death or re-transplantation) 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 re-transplantation) for 1 year.
In combination with corticosteroids and cyclosporine, Mycophenolate Mofetil demonstrated a lower rate of acute rejection at 6 months and a similar rate of death or re-transplantation at 1 year compared to AZA ( Table 16 ).
^ Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
^ Description
Mycophenolate Mofetil (mycophenolate mofetil) is an antimetabolite immunosuppressant. It is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor.
The chemical name for mycophenolate mofetil (MMF) is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has an empirical formula of C 23H 31NO 7, a molecular weight of 433.50, and the following structural formula:
MMF is a white to off-white crystalline powder. It is slightly soluble in water (43 μg/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 ethanol. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for MMF are 5.6 for the morpholino group and 8.5 for the phenolic group.
MMF hydrochloride has a solubility of 65.8 mg/mL in 5% Dextrose Injection USP (D5W). The pH of the reconstituted solution is 2.4 to 4.1.
Mycophenolate Mofetil for Injection USP is the hydrochloride salt of MMF. The chemical name for the hydrochloride salt of MMF is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate hydrochloride. It has an empirical formula of C 23H 31NO 7HCl and a molecular weight of 469.96.
Mycophenolate Mofetil for Injection USP is available as a sterile white to off-white lyophilized powder in single-dose vials containing MMF hydrochloride for administration by intravenous infusion only. Each vial contains 500 mg of mycophenolate mofetil equivalent to 542 mg of mycophenolate mofetil hydrochloride. The inactive ingredients are polysorbate 80, 25 mg, and citric acid, 5 mg. Sodium hydroxide and/or hydrochloric acid may have been used in the manufacture of Mycophenolate Mofetil for Injection USP to adjust the pH. Reconstitution and dilution with 5% Dextrose Injection USP yields a slightly yellow solution of MMF, 6 mg/mL [see Dosage and Administration (2.6)].
^ Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
An estimated total of 1557 adult patients received Mycophenolate Mofetil during pivotal clinical trials in the prevention of acute organ rejection. Of these, 991 were included in the three renal studies, 277 were included in one hepatic study, and 289 were included in one cardiac study. Patients in all study arms also received cyclosporine and corticosteroids.
The data described below primarily derive from five randomized, active-controlled double-blind 12-month trials of Mycophenolate Mofetil in de novokidney (3) heart (1) and liver (1) transplant patients [see Clinical Studies (14.1, 14.2, and 14.3)] .
^Principal Display Panel - Mg Vial Carton
NDC 54288-141-01Mycophenolate Mofetil for injection USP500 mg per vialFOR INTRAVENOUS INFUSION ONLY.Rx onlySingle-Dose Vial
NDC 54288-141-04Mycophenolate Mofetil for injection USP500 mg per VialFOR INTRAVENOUS INFUSION ONLY.Rx only4 Single-Dose Vials
Manufactured For:BPI Labs, LLC12393 Belcher Rd S, Suite 450,Largo 33773
^ Embryofetal Toxicity
Use of MMF 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, kidney and nervous system. Females of reproductive potential must be made aware of these risks and must be counseled regarding pregnancy prevention and planning. Avoid use of MMF during pregnancy if safer treatment options are available [see Use in Specific Populations (8.1, 8.3)].
^Warning: Embryofetal Toxicity, Malignancies And Serious Infections
^ Gastrointestinal Tract Complications
Inform patients that Mycophenolate Mofetil can cause gastrointestinal tract complications including bleeding, intestinal perforations, and gastric or duodenal ulcers. Advise the patient to contact their healthcare provider if they have symptoms of gastrointestinal bleeding, or sudden onset or persistent abdominal pain [see Warnings and Precautions (5.5)] .
^ Acute Inflammatory Syndrome Associated With Mycophenolate Products
Acute inflammatory syndrome (AIS) has been reported with the use of MMF and mycophenolate products, and some cases have resulted in hospitalization. AIS is a paradoxical pro-inflammatory reaction characterized by fever, arthralgias, arthritis, muscle pain and elevated inflammatory markers including, C-reactive protein and erythrocyte sedimentation rate, without evidence of infection or underlying disease recurrence. Symptoms occur within weeks to months of initiation of treatment or a dose increase. After discontinuation, improvement of symptoms and inflammatory markers are usually observed within 24 to 48 hours.
Monitor patients for symptoms and laboratory parameters of AIS when starting treatment with mycophenolate products or when increasing the dosage. Discontinue treatment and consider other treatment alternatives based on the risk and benefit for the patient.
^ Local Reactions With Rapid Intravenous Administration
Mycophenolate Mofetil for Injection solution must not be administered by rapid or bolus intravenous injection as rapid infusion increases the risk of local adverse reactions such as phlebitis and thrombosis [see Adverse Reactions (6.1)] .
^ Effect Of Concomitant Medications On Mycophenolic Acid Concentrations
A variety of drugs have potential to alter systemic MPA exposure when co-administered with Mycophenolate Mofetil. Therefore, determination of MPA concentrations in plasma before and after making any changes to immunosuppressive therapy, or when adding or discontinuing concomitant medications, may be appropriate to ensure MPA concentrations remain stable.
^ Semen Donation
Advise males of childbearing potential not to donate semen during therapy and for 90 days following discontinuation of Mycophenolate Mofetil [see Warnings and Precautions (5.12)] .
^4 Contraindications
Allergic reactions to Mycophenolate Mofetil have been observed; therefore, Mycophenolate Mofetil is contraindicated in patients with a hypersensitivity to mycophenolate mofetil (MMF), mycophenolic acid (MPA) or any component of the drug product. Mycophenolate Mofetil for Injection is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN).
^ Blood Donation
Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of Mycophenolate Mofetil because their blood or blood products might be administered to a female of reproductive potential or a pregnant woman.
^ Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Mycophenolate Mofetil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
^ Immunizations
Inform patients that Mycophenolate Mofetil can interfere with the usual response to immunizations. Before seeking vaccines on their own, advise patients to discuss first with their physician [see Warnings and Precautions (5.8)] .
^ Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a 104-week oral carcinogenicity study in mice, MMF in daily doses up to 180 mg/kg was not tumorigenic. The highest dose tested was 0.2 times the recommended clinical dose (2 g/day) in renal transplant patients and 0.15 times the recommended clinical dose (3 g/day) in cardiac transplant patients when corrected for differences in body surface area (BSA). In a 104-week oral carcinogenicity study in rats, MMF in daily doses up to 15 mg/kg was not tumorigenic. The highest dose was 0.035 times the recommended clinical dose in kidney transplant patients and 0.025 times the recommended clinical dose in heart transplant patients when corrected for BSA. While these animal doses were lower than those given to patients, they were maximal in those species and were considered adequate to evaluate the potential for human risk [see Warnings and Precautions (5.2)].
The genotoxic potential of MMF was determined in five assays. MMF was genotoxic in the mouse lymphoma/thymidine kinase assay and the in vivomouse micronucleus assay. MMF was not genotoxic in the bacterial mutation assay, the yeast mitotic gene conversion assay or the Chinese hamster ovary cell chromosomal aberration assay.
MMF had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. This dose represents 0.05 times the recommended clinical dose in renal transplant patients and 0.03 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (principally of the head and eyes) in the first generation offspring in the absence of maternal toxicity. This dose was 0.01 times the recommended clinical dose in renal transplant patients and 0.005 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.
^ Gastrointestinal Complications
Gastrointestinal bleeding requiring hospitalization, ulceration and perforations were observed in clinical trials. Physicians should be aware of these serious adverse effects particularly when administering Mycophenolate Mofetil to patients with a gastrointestinal disease.
^ Effect Of Other Drugs On Mycophenolate Mofetil
^ 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. The risk increases with the total immunosuppressive load. These infections may lead to serious outcomes, including hospitalizations and death [see Adverse Reactions (6.1, 6.2)].
Serious viral infections reported include:
Consider dose reduction or discontinuation of Mycophenolate Mofetil in patients who develop new infections or reactivate viral infections, weighing 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 (6.2)]. 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 [see Adverse Reactions (6.2)] . In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms.
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.
^ Females And Males Of Reproductive Potential
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.
^ Increased Risk Of Serious Infections
Inform patients that they are at increased risk of developing a variety of infections due to immunosuppression. Instruct them to contact their physician if they develop any of the signs and symptoms of infection explained in the Medication Guide [see Warnings and Precautions (5.3)] .
^ Risks In Patients With Phenylketonuria
Phenylalanine can be harmful to patients with phenylketonuria (PKU). CELLCEPT oral suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine/mL suspension). Before prescribing CELLCEPT oral suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including Mycophenolate Mofetil.
^ Blood Dyscrasias
Inform patients that they are at increased risk for developing blood adverse effects such as anemia or low white blood cells. Advise patients to immediately contact their healthcare provider if they experience any evidence of infection, unexpected bruising, or bleeding, or any other manifestation of bone marrow suppression [see Warnings and Precautions (5.4)] .
^ Pharmacodynamics
There is a lack of information regarding the pharmacodynamic effects of MMF.
^ Patients With Hypoxanthine-guanine Phosphoribosyl-transferase Deficiency (hgprt)
Mycophenolate Mofetil is an inosine monophosphate dehydrogenase (IMPDH) inhibitor; therefore it should be avoided in patients with hereditary deficiencies of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndromes because it may cause an exacerbation of disease symptoms characterized by the overproduction and accumulation of uric acid leading to symptoms associated with gout such as acute arthritis, tophi, nephrolithiasis or urolithiasis and renal disease including renal failure.
^ Lymphoma And Other Malignancies
Patients receiving immunosuppressants, including Mycophenolate Mofetil, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Adverse Reactions (6.1)]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. For patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor.
Post-transplant lymphoproliferative disorder (PTLD) 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 kidney, heart and liver transplant patients [see Adverse Reactions (6.1)]. The majority of PTLD cases appear to be related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. In pediatric patients, no other malignancies besides PTLD were observed in clinical trials [see Adverse Reactions (6.1)].
^ Potential Impairment Of Ability To Drive Or Operate Machinery
Mycophenolate Mofetil may impact the ability to drive and use machines. Patients should avoid driving or using machines if they experience somnolence, confusion, dizziness, tremor, or hypotension during treatment with Mycophenolate Mofetil [see Adverse Reactions (6.1)] .
^ Potential To Impair Driving And Use Of Machinery
Advise patients that Mycophenolate Mofetil can affect the ability to drive or operate machines. Patients should avoid driving or operating machines if they experience somnolence, confusion, dizziness, tremor or hypotension during treatment with Mycophenolate Mofetil [see Warnings and Precautions (5.14)] .
^ Overdosage
Possible signs and symptoms of acute overdose include hematological abnormalities such as leukopenia and neutropenia, and gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, vomiting, and dyspepsia.
The experience with overdose of Mycophenolate Mofetil in humans is limited. The reported effects associated with overdose fall within the known safety profile of the drug. The highest dose administered to kidney transplant patients in clinical trials has been 4 g/day. In limited experience with heart and liver 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, particularly neutropenia [see Warnings and Precautions (5.4)] .
^ Development Of Lymphoma And Other Malignancies
^3 Dosage Forms And Strengths
Mycophenolate Mofetil for Injection, USP is available in the following dosage forms and strengths:
^ Important Administration Instructions
Mycophenolate Mofetil should not be used without the supervision of a physician with experience in immunosuppressive therapy
^ Pediatric Use
Safety and effectiveness have been established in pediatric patients 3 months and older for the prophylaxis of organ rejection of allogenic kidney, heart or liver transplants.
^ Heart Transplantation
A double-blind, randomized, comparative, parallel-group, multicenter study in primary de novoheart transplant recipients was performed at centers in the United States (20), in Canada (1), in Europe (5) and in Australia (2). The total number of patients enrolled (ITT population) was 650; 72 never received study drug and 578 received study drug (Safety Population). Patients received Mycophenolate Mofetil 1.5 g twice daily (n=289) or AZA 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 re-transplanted or died, within the first 6 months, and (2) the proportion of patients who died or were re-transplanted 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 1 year.
The analyses of the endpoints showed:
^ Geriatric Use
Clinical studies of Mycophenolate Mofetil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between geriatric and younger patients. In general, dose selection for a geriatric patient should take into consideration the presence of decreased hepatic, renal or cardiac function and of concomitant drug therapies [see Adverse Reactions (6.1), Drug Interactions (7)].
^ Acute Inflammatory Syndrome
Inform patients that acute inflammatory reactions have been reported in some patients who received Mycophenolate Mofetil. Some reactions were severe, requiring hospitalization. Advise patients to contact their physician if they develop fever, joint stiffness, joint pain, or muscle pains [see Warnings and Precautions (5.7)] .
^ Mycophenolate Mofetil For Injection, Usp
^ Effect Of Mycophenolate Mofetil On Other Drugs
^ Blood Dyscrasias: Neutropenia And Pure Red Cell Aplasia (prca)
Severe neutropenia [absolute neutrophil count (ANC) <0.5 × 10 3/µL] developed in transplant patients receiving Mycophenolate Mofetil 3 g daily [see Adverse Reactions (6.1)]. Patients receiving Mycophenolate Mofetil should be monitored for neutropenia .Neutropenia has been observed most frequently in the period from 31 to 180 days post-transplant in patients treated for prevention of kidney, heart and liver rejection. The development of neutropenia may be related to Mycophenolate Mofetil itself, concomitant medications, viral infections, or a combination of these causes. If neutropenia develops (ANC <1.3 × 10 3/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 (2.5)].
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.
Consider monitoring with complete blood counts weekly for the first month, twice monthly for the second and third months, and monthly for the remainder of the first year.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Mycophenolate Mofetil in combination with other immunosuppressive agents. 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.
^ Blood Donation
Advise patients not to donate blood during therapy and for at least 6 weeks following discontinuation of Mycophenolate Mofetil [see Warnings and Precautions (5.11)] .
^ Immunizations
During treatment with Mycophenolate Mofetil, the use of live attenuated vaccines should be avoided (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines) and patients should be advised that vaccinations may be less effective. Advise patients to discuss with the physician before seeking any immunizations.
^6 Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the label:
^ Semen Donation
Based on animal data, men should not donate semen during therapy and for 90 days following discontinuation of Mycophenolate Mofetil [see Use In Specific Populations (8.3)] .
^ References
1. "OSHA Hazardous Drugs." OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
^ Handling And Disposal
Mycophenolate mofetil (MMF) has demonstrated teratogenic effects in humans [see Warnings and Precautions (5.1)and Use in Specific Populations (8.1)] . Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in Mycophenolate Mofetil for Injection USP (during or after preparation) [see Dosage and Administration (2.6)]. Follow applicable special handling and disposal procedure 1.
^1 Indications And Usage
Mycophenolate Mofetil [mycophenolate mofetil (MMF)] is indicated for the prophylaxis of organ rejection, in adult and pediatric recipients 3 months of age and older of allogeneic kidney [see Clinical Studies (14.1)], heart [see Clinical Studies (14.2)] or liver transplants [see Clinical Studies (14.3)] , in combination with other immunosuppressants.
^ Mechanism Of Action
Mycophenolate mofetil (MMF) is absorbed following oral administration and hydrolyzed to mycophenolic acid (MPA), the active metabolite. MPA is a selective uncompetitive inhibitor of the two isoforms (type I and type II) of inosine monophosphate dehydrogenase (IMPDH) leading to inhibition of the de novopathway of guanosine nucleotide synthesis and blocks DNA synthesis. The mechanism of action of MPA is multifaceted and includes effects on cellular checkpoints responsible for metabolic programming of lymphocytes. MPA shifts transcriptional activities in lymphocytes from a proliferative state to catabolic processes. In vitro studies suggest that MPA modulates transcriptional activities in human CD4 +T-lymphocytes by suppressing the Akt/mTOR and STAT5 pathways that are relevant to metabolism and survival, leading to an anergic state of T-cells whereby the cells become less responsive to antigenic stimulation. Additionally, MPA enhanced the expression of negative co-stimulators such as CD70, PD-1, CTLA-4, and transcription factor FoxP3 as well as decreased the expression of positive co-stimulators CD27 and CD28.
MPA decreases proliferative responses of T- and B-lymphocytes to both mitogenic and allo-antigenic stimulation, antibody responses, as well as the production of cytokines from lymphocytes and monocytes such as GM-CSF, IFN-ɣ, IL-17, and TNF-α. Additionally, 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.
Overall, the effect of MPA is cytostatic and reversible.