Mycophenolate Mofetil Injection

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 (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 a molecular formula of C23H31NO7, a molecular weight of 433.50, and the following structural formula:

Mycophenolate mofetil, USP is a white or almost white crystalline powder. It is slightly soluble in water and freely soluble in acetone and sparingly soluble in 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 hydrochloride has a solubility of 65.8 mg/mL in 5 % Dextrose Injection USP (D5W). The pH of the reconstituted solution is 2.7 to 4.1.

Mycophenolate mofetil for injection is the hydrochloride salt of mycophenolate mofetil. The chemical name for the hydrochloride salt of mycophenolate mofetil is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate hydrochloride. It has a molecular formula of C23H31NO7 HCl and a molecular weight of 469.96.

Mycophenolate mofetil for injection is available as a sterile white to off-white lyophilized powder in vials containing mycophenolate mofetil hydrochloride for administration by intravenous infusion only. Each vial of mycophenolate mofetil for injection contains the equivalent of 500 mg mycophenolate mofetil as the hydrochloride salt. The inactive ingredients are polysorbate 80, 25 mg, and citric acid, 5 mg. Sodium hydroxide may have been used in the manufacture of mycophenolate mofetil for injection to adjust the pH. Reconstitution and dilution with 5 % Dextrose Injection USP yields a clear colorless to slightly yellow color solution of mycophenolate mofetil, 6 mg/mL. (For detailed method of preparation, see DOSAGE AND ADMINISTRATION).

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.

Pharmacokinetics

Following oral and intravenous administration, mycophenolate mofetil undergoes rapid and complete metabolism to MPA, the active metabolite. Oral absorption of the drug is rapid and essentially complete. MPA is metabolized to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. The parent drug, mycophenolate mofetil, can be measured systemically during the intravenous infusion; however, shortly (about 5 minutes) after the infusion is stopped or after oral administration, MMF concentration is below the limit of quantitation (0.4 mcg/mL).

Absorption

In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil (based on MPA AUC) was 94 %. The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in renal transplant patients receiving multiple doses of mycophenolate mofetil up to a daily dose of 3 g (see Table 1).

Food (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g bid to renal transplant patients. However, MPA Cmax was decreased by 40 % in the presence of food (see DOSAGE AND ADMINISTRATION).

Distribution

The mean (±SD) apparent volume of distribution of MPA in 12 healthy volunteers is approximately 3.6 (±1.5) and 4 (±1.2) L/kg following intravenous and oral administration, respectively. MPA, at clinically relevant concentrations, is 97 % bound to plasma albumin. MPAG is 82 % bound to plasma albumin at MPAG concentration ranges that are normally seen in stable renal transplant patients; however, at higher MPAG concentrations (observed in patients with renal impairment or delayed renal graft function), the binding of MPA may be reduced as a result of competition between MPAG and MPA for protein binding. Mean blood to plasma ratio of radioactivity concentrations was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into the cellular fractions of blood.

In vitro studies to evaluate the effect of other agents on the binding of MPA to human serum albumin (HSA) or plasma proteins showed that salicylate (at 25 mg/dL with HSA) and MPAG (at ≥ 460 mcg/mL with plasma proteins) increased the free fraction of MPA. At concentrations that exceeded what is encountered clinically, cyclosporine, digoxin, naproxen, prednisone, propranolol, tacrolimus, theophylline, tolbutamide, and warfarin did not increase the free fraction of MPA. MPA at concentrations as high as 100 mcg/mL had little effect on the binding of warfarin, digoxin or propranolol, but decreased the binding of theophylline from 53 % to 45 % and phenytoin from 90 % to 87 %.

Metabolism

Following oral and intravenous dosing, mycophenolate mofetil undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo, MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.

Secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to 12 hours postdose. The coadministration of cholestyramine (4 g tid) resulted in approximately a 40 % decrease in the MPA AUC (largely as a consequence of lower concentrations in the terminal portion of the profile). These observations suggest that enterohepatic recirculation contributes to MPA plasma concentrations.

Increased plasma concentrations of mycophenolate mofetil metabolites (MPA 50 % increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal insufficiency (see CLINICAL PHARMACOLOGY: Special Populations).

Excretion

Negligible amount of drug is excreted as MPA (< 1 % of dose) in the urine. Orally administered radiolabeled mycophenolate mofetil resulted in complete recovery of the administered dose, with 93 % of the administered dose recovered in the urine and 6 % recovered in feces. Most (about 87 %) of the administered dose is excreted in the urine as MPAG. At clinically encountered concentrations, MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations                     (> 100 mcg/mL), small amounts of MPAG are removed. Bile acid sequestrants, such as cholestyramine, reduce MPA AUC by interfering with enterohepatic circulation of the drug (see OVERDOSAGE).

Mean (±SD) apparent half-life and plasma clearance of MPA are 17.9 (±6.5) hours and 193 (±48) mL/min following oral administration and 16.6 (±5.8) hours and                    177 (±31) mL/min following intravenous administration, respectively.

Pharmacokinetics in Healthy Volunteers, Renal, Cardiac, and Hepatic Transplant Patients

Shown below are the mean (±SD) pharmacokinetic parameters for MPA following the administration of mycophenolate mofetil given as single doses to healthy volunteers and multiple doses to renal, cardiac, and hepatic transplant patients. In the early posttransplant period (< 40 days posttransplant), renal, cardiac, and hepatic transplant patients had mean MPA AUCs approximately 20 % to 41 % lower and mean Cmax approximately 32 % to 44 % lower compared to the late transplant period (3 to 6 months posttransplant).

Mean MPA AUC values following administration of 1 g bid intravenous mycophenolate mofetil over 2 hours to renal transplant patients for 5 days were about 24 % higher than those observed after oral administration of a similar dose in the immediate posttransplant phase. In hepatic transplant patients, administration of 1 g bid intravenous mycophenolate mofetil followed by 1.5 g bid oral mycophenolate mofetil resulted in mean MPA AUC values similar to those found in renal transplant patients administered 1 g mycophenolate mofetil bid.

Special Populations

Shown below are the mean (±SD) pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil given as single doses to non-transplant subjects with renal or hepatic impairment.

Renal Insufficiency

In a single-dose study, MMF was administered as capsule or intravenous infusion over 40 minutes. Plasma MPA AUC observed after oral dosing to volunteers with severe chronic renal impairment [glomerular filtration rate (GFR) < 25 mL/min/1.73 m2] was about 75 % higher relative to that observed in healthy volunteers (GFR > 80 mL/min/1.73 m2). In addition, the single-dose plasma MPAG AUC was 3-fold to 6-fold higher in volunteers with severe renal impairment than in volunteers with mild renal impairment or healthy volunteers, consistent with the known renal elimination of MPAG. No data are available on the safety of long-term exposure to this level of MPAG.

Plasma MPA AUC observed after single-dose (1 g) intravenous dosing to volunteers (n=4) with severe chronic renal impairment (GFR < 25 mL/min/1.73 m2) was 62.4 mcg•h/mL (±19.3). Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied (see PRECAUTIONS: Patients with Renal Impairment and DOSAGE AND ADMINISTRATION).

In patients with delayed renal graft function posttransplant, mean MPA AUC(0 to12h) was comparable to that seen in posttransplant patients without delayed renal graft function. There is a potential for a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. However, dose adjustment does not appear to be necessary in patients with delayed renal graft function. Mean plasma MPAG AUC(0 to 12h) was 2-fold to 3-fold higher than in posttransplant patients without delayed renal graft function (see PRECAUTIONS: Patients with Renal Impairment and DOSAGE AND ADMINISTRATION).

In 8 patients with primary graft non-function following renal transplantation, plasma concentrations of MPAG accumulated about 6-fold to 8-fold after multiple dosing for 28 days. Accumulation of MPA was about 1-fold to 2-fold.

The pharmacokinetics of mycophenolate mofetil are not altered by hemodialysis. Hemodialysis usually does not remove MPA or MPAG. At high concentrations of MPAG (> 100 mcg/mL), hemodialysis removes only small amounts of MPAG.

Hepatic Insufficiency 

In a single-dose (1 g oral) 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 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 as compared to healthy volunteers in other studies, thus making comparisons between volunteers with alcoholic cirrhosis and healthy volunteers difficult. Effects of hepatic disease on this process probably depend on the particular disease. Hepatic disease with other etiologies, such as primary biliary cirrhosis, may show a different effect. In a single-dose (1 g intravenous) study of 6 volunteers with severe hepatic impairment (aminopyrine breath test less than 0.2 % of dose) due to alcoholic cirrhosis, MMF was rapidly converted to MPA. MPA AUC was 44.1 mcg•h/mL (±15.5).

Pediatrics 

The pharmacokinetic parameters of MPA and MPAG have been evaluated in 55 pediatric patients (ranging from 1 year to 18 years of age) receiving mycophenolate mofetil oral suspension at a dose of 600 mg/m2 bid (up to a maximum of 1 g bid) after allogeneic renal transplantation. The pharmacokinetic data for MPA is provided in Table 3.

The mycophenolate mofetil oral suspension dose of 600 mg/m2 bid (up to a maximum of 1 g bid) achieved mean MPA AUC values in pediatric patients similar to those seen in adult renal transplant patients receiving mycophenolate mofetil capsules at a dose of 1 g bid in the early posttransplant period. There was wide variability in the data. As observed in adults, early posttransplant MPA AUC values were approximately 45 % to 53 % lower than those observed in the later posttransplant period (> 3 months). MPA AUC values were similar in the early and late posttransplant period across the 1 year to 18 year age range.

Gender

Data obtained from several studies were pooled to look at any gender-related differences in the pharmacokinetics of MPA (data were adjusted to 1 g oral dose). Mean (±SD) MPA AUC(0-12h) for males (n=79) was 32 (±14.5) and for females (n=41) was 36.5 (±18.8) mcg•h/mL while mean (±SD) MPA Cmax was 9.96 (±6.19) in the males and 10.6 (±5.64) mcg/mL in the females. These differences are not of clinical significance.

Geriatrics

Pharmacokinetics in the elderly have not been studied.

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.

Mycophenolate mofetil for injection is an alternative dosage form to mycophenolate mofetil capsules, tablets and oral suspension. Mycophenolate mofetil for injection should be administered within 24 hours following transplantation. Mycophenolate mofetil for injection can be administered for up to 14 days; patients should be switched to oral mycophenolate mofetil as soon as they can tolerate oral medication.

Allergic reactions to mycophenolate mofetil have been observed; therefore, mycophenolate mofetil is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product. Mycophenolate mofetil for injection is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN).

The principal adverse reactions associated with the administration of mycophenolate mofetil include diarrhea, leukopenia, sepsis, vomiting, and there is evidence of a higher frequency of certain types of infections eg, opportunistic infection (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections). The adverse event profile associated with the administration of mycophenolate mofetil for injection has been shown to be similar to that observed after administration of oral dosage forms of mycophenolate mofetil.

Mycophenolate mofetil Oral

The incidence of adverse events for mycophenolate mofetil was determined in randomized, comparative, double-blind trials in prevention of rejection in renal (2 active, 1 placebo-controlled trials), cardiac (1 active-controlled trial), and hepatic (1 active-controlled trial) transplant patients.

Geriatrics

Elderly patients (≥ 65 years), particularly those who are receiving mycophenolate mofetil as part of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus [CMV] tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema, compared to younger individuals (see PRECAUTIONS).

Safety data are summarized below for all active-controlled trials in renal (2 trials), cardiac (1 trial), and hepatic (1 trial) transplant patients. Approximately 53 % of the renal patients, 65 % of the cardiac patients, and 48 % of the hepatic patients have been treated for more than 1 year. Adverse events reported in ≥ 20 % of patients in the mycophenolate mofetil treatment groups are presented below.

The placebo-controlled renal transplant study generally showed fewer adverse events occurring in ≥ 20 % of patients. In addition, those that occurred were not only qualitatively similar to the azathioprine-controlled renal transplant studies, but also occurred at lower rates, particularly for infection, leukopenia, hypertension, diarrhea and respiratory infection.

The above data demonstrate that in three controlled trials for prevention of renal rejection, patients receiving 2 g/day of mycophenolate mofetil had an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil.

The above data demonstrate that the types of adverse events observed in multicenter controlled trials in renal, cardiac, and hepatic transplant patients are qualitatively similar except for those that are unique to the specific organ involved.

Sepsis, which was generally CMV viremia, was slightly more common in renal transplant patients treated with mycophenolate mofetil compared to patients treated with azathioprine. The incidence of sepsis was comparable in mycophenolate mofetil and in azathioprine-treated patients in cardiac and hepatic studies.

In the digestive system, diarrhea was increased in renal and cardiac transplant patients receiving mycophenolate mofetil compared to patients receiving azathioprine, but was comparable in hepatic transplant patients treated with mycophenolate mofetil or azathioprine.

Patients receiving mycophenolate mofetil alone or as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see WARNINGS: Lymphoma and Malignancy). The incidence of malignancies among the 1483 patients treated in controlled trials for the prevention of renal allograft rejection who were followed for ≥ 1 year was similar to the incidence reported in the literature for renal allograft recipients.

Lymphoproliferative disease or lymphoma developed in 0.4 % to 1 % of patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and hepatic transplant patients followed for at least 1 year (see WARNINGS: Lymphoma and Malignancy). Non-melanoma skin carcinomas occurred in 1.6 % to 4.2 % of patients, other types of malignancy in 0.7 % to 2.1 % of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1 year data.

In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed.

Severe neutropenia (ANC < 0.5 x 103/μL) developed in up to 2 % of renal transplant patients, up to 2.8 % of cardiac transplant patients and up to 3.6 % of hepatic transplant patients receiving mycophenolate mofetil 3 g daily (see WARNINGS: Neutropenia, PRECAUTIONS: Laboratory Tests and DOSAGE AND ADMINISTRATION).

All transplant patients are at increased risk of opportunistic infections. The risk increases with total immunosuppressive load (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections).

Table 10 shows the incidence of opportunistic infections that occurred in the renal, cardiac, and hepatic transplant populations in the azathioprine-controlled prevention trials:

The following other opportunistic infections occurred with an incidence of less than 4 % in mycophenolate mofetil patients in the above azathioprine-controlled studies: Herpes zoster, visceral disease; Candida, urinary tract infection, fungemia/disseminated disease, tissue invasive disease; Cryptococcosis; Aspergillus/Mucor; Pneumocystis carinii.

In the placebo-controlled renal transplant study, the same pattern of opportunistic infection was observed compared to the azathioprine-controlled renal studies, with a notably lower incidence of the following: Herpes simplex and CMV tissue-invasive disease.

In patients receiving mycophenolate mofetil (2 g or 3 g) in controlled studies for prevention of renal, cardiac or hepatic rejection, fatal infection/sepsis occurred in approximately 2 % of renal and cardiac patients and in 5 % of hepatic patients (see WARNINGS: Serious Infections).

In cardiac transplant patients, the overall incidence of opportunistic infections was approximately 10 % higher in patients treated with mycophenolate mofetil than in those receiving azathioprine, but this difference was not associated with excess mortality due to infection/sepsis among patients treated with mycophenolate mofetil.

The following adverse events were reported with 3 % to < 20 % incidence in renal, cardiac, and hepatic transplant patients treated with mycophenolate mofetil, in combination with cyclosporine and corticosteroids.

Pediatrics

The type and frequency of adverse events in a clinical study in 100 pediatric patients 3 months to 18 years of age dosed with mycophenolate mofetil oral suspension 600 mg/m2 bid (up to 1 g bid) were generally similar to those observed in adult patients dosed with mycophenolate mofetil capsules at a dose of 1 g bid with the exception of abdominal pain, fever, infection, pain, sepsis, diarrhea, vomiting, pharyngitis, respiratory tract infection, hypertension, leukopenia, and anemia, which were observed in a higher proportion in pediatric patients.

Mycophenolate Mofetil for Injection

The adverse event profile of mycophenolate mofetil for injection was determined from a single, doubleblind, controlled comparative study of the safety of 2 g/day of intravenous and oral mycophenolate mofetil in renal transplant patients in the immediate posttransplant period (administered for the first 5 days). The potential venous irritation of mycophenolate mofetil for injection was evaluated by comparing the adverse events attributable to peripheral venous infusion of mycophenolate mofetil for injection with those observed in the intravenous placebo group; patients in this group received active medication by the oral route.

Adverse events attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4 % in patients treated with mycophenolate mofetil for injection.

In the active controlled study in hepatic transplant patients, 2 g/day of mycophenolate mofetil for injection were administered in the immediate posttransplant period (up to 14 days). The safety profile of intravenous mycophenolate mofetil was similar to that of intravenous azathioprine.

Postmarketing Experience

Congenital Disorders

Embryofetal Toxicity

Congenital malformations, including ear, facial, cardiac and nervous system malformations and an increased incidence of first trimester pregnancy loss have been reported following exposure to mycophenolate mofetil during pregnancy (see PRECAUTIONS: Pregnancy).

Digestive

Colitis (sometimes caused by cytomegalovirus), pancreatitis, isolated cases of intestinal villous atrophy.

Hematologic and Lymphatic

Cases of pure red cell aplasia (PRCA) and hypogammaglobulinemia have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents.

Infections (see WARNINGS: Serious Infections, New or Reactivated Viral Infections)

•   Serious life-threatening infections such as meningitis and infectious endocarditis have been reported occasionally.
•   There is evidence of a higher frequency of certain types of serious infections such as tuberculosis and atypical mycobacterial infection.
•   Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with mycophenolate mofetil. The reported cases generally had risk factors for PML, including treatment with immunosuppressant therapies and impairment of immune function.
•   Polyomavirus associated neuropathy (PVAN), especially due to BK virus infection, has been observed in patients receiving immunosuppressants, including mycophenolate mofetil. This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss.
•   Viral reactivation has been reported in patients infected with HBV or HCV.

Respiratory

Interstitial lung disorders, including fatal pulmonary fibrosis, have been reported rarely and should be considered in the differential diagnosis of pulmonary symptoms ranging from dyspnea to respiratory failure in posttransplant patients receiving mycophenolate mofetil.

Mycophenolate Mofetil for Injection, USP

Supplied in a 20 mL, sterile vial containing the equivalent of 500 mg mycophenolate mofetil as the hydrochloride salt in cartons of 4 vials:

NDC Number

NDC 68382-669-08

Storage

Store powder and reconstituted/infusion solutions at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]; excursions permitted to 15° to 30°C (59° to 86°F).

*Brands mentioned are trademarks of their respective owners.

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India.

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Rev.: 03/2017

MEDICATION GUIDE

Mycophenolate Mofetil for Injection, USP

(MYE-koe-FEN-oh-late MOE-fe-til)

Read the Medication Guide that comes with mycophenolate mofetil before you start taking it and each time you refill your prescription. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about mycophenolate mofetil? Mycophenolate mofetil can cause serious side effects:

•   Increased risk of loss of a pregnancy (miscarriage) and higher risk of birth defects. Females who take mycophenolate mofetil during pregnancy have a higher risk of miscarriage during the first 3 months (first trimester), and a higher risk that their baby will be born with birth defects

If you are a female who can become pregnant

• your doctor must talk with you about acceptable birth control methods (contraceptive counseling) to use while taking mycophenolate mofetil.
• you should have one pregnancy test immediately before starting mycophenolate mofetil and another pregnancy test 8 to 10 days later. Pregnancy tests should be repeated during routine follow-up visits with your doctor. Talk to your doctor about the results of all of your pregnancy tests.
• you must use acceptable birth control during your entire mycophenolate mofetil therapy and for 6 weeks after stopping mycophenolate mofetil, unless at any time you choose to avoid sexual intercourse (abstinence) with a man completely. Mycophenolate mofetil decreases blood levels of the hormones in birth control pills that you take by mouth. Birth control pills may not work as well while you take mycophenolate mofetil, and you could become pregnant. If you take birth control pills while using mycophenolate mofetil you must also use another form of birth control. Talk to your doctor about other birth control methods that you can use while taking mycophenolate mofetil.

If you plan to become pregnant, talk with your doctor. Your doctor will decide if other medicines to prevent rejection may be right for you.

If you become pregnant while taking mycophenolate mofetil, do not stop taking mycophenolate mofetil. Call your doctor right away. In certain situations, you and your doctor may decide that taking mycophenolate mofetil is more important to your health than the possible risks to your unborn baby.

• You and your doctor should report your pregnancy to
• Mycophenolate Pregnancy Registry (1-800-617-8191).
• The purpose of this registry is to gather information about the health of you and your baby.
• Increased risk of getting serious infections. Mycophenolate mofetil weakens the body's immune system and affects your ability to fight infections. Serious infections can happen with mycophenolate mofetil and can lead to death. These serious infections can include:
• Viral infections. Certain viruses can live in your body and cause active infections when your immune system is weak. Viral infections that can happen with mycophenolate mofetil include:
• Shingles, other herpes infections, and cytomegalovirus (CMV). CMV can cause serious tissue and blood infections.
• BK virus. BK virus can affect how your kidney works and cause your transplanted kidney to fail.
• Hepatitis B and C viruses. Hepatitis viruses can affect how your liver works. Talk to your doctor about how hepatitis viruses may affect you.
• A brain infection called Progressive Multifocal Leukoencephalopathy (PML).

In some patients, mycophenolate mofetil may cause an infection of the brain that may cause death. You are at risk for this brain infection because you have a weakened immune system. You should tell your doctor right away if you have any of the following symptoms:

•   Weakness on one side of the body
•   You do not care about things that you usually care about (apathy)
•   You are confused or have problems thinking
•   You cannot control your muscles
•   Fungal infections. Yeasts and other types of fungal infections can happen with mycophenolate mofetil and can cause serious tissue and blood infections (see "What are the possible side effects of mycophenolate mofetil?" )

Call your doctor right away if you have any of the following signs and symptoms of infection:

• Temperature of 100.5°F or greater
• Cold symptoms, such as a runny nose or sore throat
• Flu symptoms, such as an upset stomach, stomach pain, vomiting or diarrhea
• Earache or headache
• Pain during urination
• White patches in the mouth or throat
• Unexpected bruising or bleeding
• Cuts, scrapes or incisions that are red, warm and oozing pus
• Increased risk of getting certain cancers. People who take mycophenolate mofetil have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Tell your doctor if you have:
• unexplained fever, prolonged tiredness, weight loss or lymph node swelling
• a brown or black skin lesion with uneven borders, or one part of the lesion does not look like the other
• a change in the size and color of a mole
• a new skin lesion or bump
• any other changes to your health

See the section "What are the possible side effects of mycophenolate mofetil?" for information about other serious side effects.

What is mycophenolate mofetil?

Mycophenolate mofetil is a prescription medicine to prevent rejection (antirejection medicine) in people who have received a kidney, heart or liver transplant. Rejection is when the body's immune system perceives the new organ as a "foreign" threat and attacks it.

Mycophenolate mofetil is used with other medicines called cyclosporine (Sandimmune®#, Gengraf®#, Neoral®#) and corticosteroids. 

Mycophenolate mofetil has been used safely and works in children who received a kidney transplant as it does in adults. It is not known if mycophenolate mofetil is safe and works in children who receive a heart or liver transplant.

Who should not take mycophenolate mofetil?

Do not take mycophenolate mofetil if you are allergic to mycophenolate mofetil or any of the ingredients in mycophenolate mofetil. See the end of this Medication Guide for a complete list of ingredients in mycophenolate mofetil.

What should I tell my doctor before taking mycophenolate mofetil?

Tell your doctor about all of your medical conditions, if you:

•   have any digestive problems, such as ulcers.
•   have Lesch-Nyhan or Kelley-Seegmiller syndrome or another rare inherited deficiency hypoxanthine-guanine phosphoribosyl-transferase (HGPRT). You should not take mycophenolate mofetil if you have one of these disorders.
•   plan to receive any vaccines.People taking mycophenolate mofetil should not take live vaccines . Some vaccines may not work as well during treatment with mycophenolate mofetil.
•   are pregnant or are planning to become pregnant. See "What is the most important information I should know about mycophenolate mofetil?"
•   are breastfeeding or plan to breastfeed. It is not known if mycophenolate mofetil passes into breastmilk. You and your doctor will decide if you will take mycophenolate mofetil or breastfeed.

Tell your healthcare provider about all of the medicines you are taking including prescription and nonprescription medicines, vitamins and herbal supplements. Some medicines may affect the way mycophenolate mofetil works, and mycophenolate mofetil may affect how some medicines work. Especially tell your doctor if you take:

•   birth control pills (oral contraceptives). See "What is the most important information I should know about mycophenolate mofetil?"
•   sevelamer (Renagel®#, Renvela™#). These products should be taken 2 hours after taking mycophenolate mofetil
•   acyclovir (Zovirax®#), valacyclovir (Valtrex®#), ganciclovir (Cytovene®#-IV, Vitrasert®#), valganciclovir (Valcyte®#)
•   rifampin (Rifater®#, Rifamate®#, Rimactane®#, Rifadin®#)
•   antacids that contain magnesium and aluminum (mycophenolate mofetil and the antacid should not be taken at the same time)
•   proton pump inhibitors (PPIs) (Prevacid®#, Protonix®#)
•   sulfamethoxazole/trimethoprim (Bactrim™#, Bactrim DS™#)
•   norfloxacin (Noroxin®#) and metronidazole (Flagyl®#, Flagyl®#ER, Flagyl®#IV, Metro IV, Helidac®#, Pylera™#)
•   ciprofloxacin (Cipro®#, Cipro®#XR, Ciloxan®#, Proquin®#XR) and amoxicillin plus clavulanic acid (Augmentin®#, Augmentin XR™#)
•   azathioprine (Azasan®#, Imuran®#)
•   cholestyramine (Questran Light®#, Questran®#, Locholest Light, Locholest, Prevalite®#)

Know the medicines you take. Keep a list of them to show to your doctor or nurse and pharmacist when you get a new medicine. Do not take any new medicine without talking with your doctor.

How should I take mycophenolate mofetil?

• Take mycophenolate mofetil exactly as prescribed.
• Do not stop taking mycophenolate mofetil or change the dose unless your doctor tells you to.
• If you miss a dose of mycophenolate mofetil, or are not sure when you took your last dose, take the regular amount of mycophenolate mofetil prescribed as soon as you remember. If it is time for your next dose, skip the missed dose and take your next dose at your normal scheduled time. Do not take 2 doses at the same time. Call your doctor if you are not sure what to do.
• If you take too much mycophenolate mofetil, call your doctor or the poison control center right away.

What should I avoid while taking mycophenolate mofetil?

•   Avoid pregnancy. See "What is the most important information I should know about mycophenolate mofetil?"
•   Limit the amount of time you spend in sunlight. Avoid using tanning beds or sunlamps. People who take mycophenolate mofetil have a higher risk of getting skin cancer. (See "What is the most important information I should know about mycophenolate mofetil?" ) Wear protective clothing when you are in the sun and use a sunscreen with a high protection factor (SPF 30 and above). This is especially important if your skin is very fair or if you have a family history of skin cancer

What are the possible side effects of mycophenolate mofetil? Mycophenolate mofetil can cause serious side effects:

•   See "What is the most important information I should know about mycophenolate mofetil?"
•   Low blood cell counts. People taking high doses of mycophenolate mofetil each day may have a decrease in blood counts, including
•   white blood cells, especially neutrophils. Neutrophils fight against bacterial infections. You have a higher chance of getting an infection when your white blood cell count is low. This is most common from 3 months to 6 months after your transplant.
•   red blood cells. Red blood cells carry oxygen to your body tissues. You have a higher chance of getting severe anemia when your red blood cell count is low.
•   platelets . Platelets help with blood clotting.

Your doctor will do blood tests before you start taking mycophenolate mofetil and during treatment with mycophenolate mofetil to check your blood cell counts.

Tell your doctor right away if you have any signs of infection (see "What is the most important information I should know about mycophenolate mofetil?"), or any unexpected bruising or bleeding. Also, tell your doctor if you have unusual tiredness, lack of energy, dizziness or fainting.

•   Stomach problems. Stomach and intestinal bleeding can happen in people who take high doses of mycophenolate mofetil. Bleeding can be severe and you may have to be hospitalized for treatment

Common side effects include:

•   diarrhea. Call your doctor right away if you have diarrhea. Do not stop taking mycophenolate mofetil without first talking with your doctor.
•   vomiting
•   pain
•   stomach area pain
•   swelling of the lower legs, ankles and feet
•   high blood pressure

Side effects that happen more often in children than in adults taking mycophenolate mofetil include:

•   stomach area pain
•   fever
•   infection
•   pain
•   blood infection (sepsis)
•   diarrhea
•   vomiting
•   sore throat
•   colds (respiratory tract infections)
•   high blood pressure
•   low white blood cell count
•   low red blood cell count

These are not all of the possible side effects of mycophenolate mofetil. Tell your doctor about any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store mycophenolate mofetil for injection?

• Store powder and reconstituted/infusion solutions at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]; excursions permitted to 15° to 30°C (59° to 86°F).
• Keep mycophenolate mofetil and all medicines out of the reach of children

General Information about mycophenolate mofetil

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use mycophenolate mofetil for a condition for which it was not prescribed. Do not give mycophenolate mofetil to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about mycophenolate mofetil. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about mycophenolate mofetil that is written for healthcare professionals.

Please address all medical inquiries to, (MedicalAffairs@zydususa.com) Tel.: 1-877-993-8779.

What are the ingredients in mycophenolate mofetil for injection, USP?

Active Ingredient: Mycophenolate mofetil, USP

Inactive Ingredients:

polysorbate 80, and citric acid. Sodium hydroxide may have been used in the manufacture of mycophenolate mofetil for injection to adjust the pH.

This Medication Guide has been approved by the US Food and Drug Administration.

#Brands mentioned are trademarks of their respective owners.

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India.

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Rev.: 03/2017