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These highlights do not include all the information needed to use MYCOPHENOLATE MOFETIL CAPSULES safely and effectively. See full prescribing information for MYCOPHENOLATE MOFETIL CAPSULES. MYCOPHENOLATE MOFETIL capsules, for oral use Initial U.S. Appr | Mycophenolate Mofetil [Teva Pharmaceuticals USA, Inc.] | BioPortfolio

13:40 EST 27th January 2019 | BioPortfolio
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WARNING: EMBRYOFETAL TOXICITY, MALIGNANCIES and SERIOUS INFECTIONS

Mycophenolate mofetil capsules (MMF) are indicated for the prophylaxis of organ rejection, in recipients 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.

Mycophenolate Mofetil Capsules

Mycophenolate mofetil capsules should not be used interchangeably with mycophenolic acid delayed-release tablets without supervision of a physician with experience in immunosuppressive therapy because the rates of absorption following the administration of mycophenolate mofetil capsules and mycophenolic acid delayed-release tablets are not equivalent.

Mycophenolate mofetil capsules should not be opened or crushed. Patients should avoid inhalation or contact of the skin or mucous membranes with the powder contained in mycophenolate mofetil capsules. If such contact occurs, they must wash the area of contact thoroughly with soap and water. In case of ocular contact, rinse eyes with plain water.

The initial oral dose of mycophenolate mofetil capsules should be given as soon as possible following kidney, heart or liver transplant. It is recommended that mycophenolate mofetil capsules be administered on an empty stomach. In stable transplant patients, however, mycophenolate mofetil capsules may be administered with food if necessary [see Clinical Pharmacology (12.3)].

Patients should be instructed to take a missed dose as soon as they remember, except if it is closer than 2 hours to the next scheduled dose; in this case, they should continue to take mycophenolate mofetil capsules at the usual times.

Adults

The recommended dose for adult kidney transplant patients is 1 g orally, twice daily (daily dose of 2 g).

Pediatrics (3 months and older)

Pediatric dosing is based on body surface area (BSA). The recommended dose of mycophenolate mofetil oral suspension for pediatric kidney transplant patients 3 months and older is 600 mg/m, administered twice daily (maximum daily dose of 2g or 10 mL of the oral suspension). Pediatric patients with BSA ≥ 1.25 m may be dosed with capsules or tablets as follows:

Table 1.          Pediatric Dosing Using Capsules or Tablets for Pediatric Kidney Transplant

Body Surface Area Dosing
1.25 m2 to <1.5 m2 Mycophenolate mofetil capsule 750 mg twice daily (1.5 g daily dose)
≥ 1.5 m2 Mycophenolate mofetil capsules or tablets 1 g twice daily (2 g daily dose)

The recommended dose of mycophenolate mofetil for adult heart transplant patients is 1.5 g orally administered twice daily (daily dose of 3 g).

The recommended dose of mycophenolate mofetil for adult liver transplant patients is 1.5 g administered orally twice daily (daily dose of 3 g).

Renal Impairment

No dose adjustments are needed in kidney transplant patients with delayed graft function postoperatively [see Clinical Pharmacology (12.3)]. In kidney transplant patients with severechronic impairment of the graft (GFR <25 mL/min/1.73 m), do not administer doses of mycophenolate mofetil greater than 1 g twice a day. These patients should be carefully monitored [see Clinical Pharmacology (12.3)].

Neutropenia

If neutropenia develops (ANC <1.3 x 10/mL), dosing with mycophenolate mofetil should be interrupted or reduced, appropriate diagnostic tests performed, and the patient managed appropriately [see Warnings and Precautions (5.4) and Adverse Reactions (6.1].

Mycophenolate Mofetil Capsules USP are available in the following strength:

250 mg hard gelatin capsules with a light blue opaque cap and a bright orange opaque body, filled with a white to off-white powder with small agglomerates; imprinted with "TEVA" on the cap and "7334" on the body

Allergic reactions to mycophenolate mofetil capsules have been observed; therefore, mycophenolate mofetil capsules are contraindicated in patients with a hypersensitivity to mycophenolate mofetil (MMF), mycophenolic acid (MPA) or any component of the drug product.

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)].

Patients receiving immunosuppressants, including mycophenolate mofetil capsules, 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 sunscreen with a high protection factor.

Post-transplant lymphoproliferative disorder (PTLD) developed in 0.4% to 1% of patients receiving mycophenolate mofetil capsules (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)]. In pediatric patients, no other malignancies besides PTLD were observed in clinical trials [see Adverse Reactions (6.1)].

Patients receiving immunosuppressants, including mycophenolate mofetil capsules, 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 reducing immunosuppression 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.

Severe neutropenia [absolute neutrophil count (ANC) <0.5 x 10/mL] developed in transplant patients receiving mycophenolate mofetil capsules 3 g daily [see Adverse Reactions (6.1)]. Patients receiving mycophenolate mofetil capsules 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 x 10/mL), dosing with mycophenolate mofetil capsules 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 capsules 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 capsules in combination with other immunosuppressive agents. In some cases, PRCA was found to be reversible with dose reduction or cessation of mycophenolate mofetil capsule therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk.

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 capsules to patients with a gastrointestinal disease.

Mycophenolate mofetil capsules are 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.

During treatment with mycophenolate mofetil capsules, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Advise patients to discuss with the physician before seeking any immunizations.

Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of mycophenolate mofetil capsules because their blood or blood products might be administered to a female of reproductive potential or a pregnant woman.

Based on animal data, men should not donate semen during therapy and for 90 days following discontinuation of mycophenolate mofetil capsules [see Use In Specific Populations (8.3)].

The following adverse reactions are discussed in greater detail in other sections of the label:

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.

The data described below primarily derive from five randomized, active-controlled double- blind 12-month trials of mycophenolate mofetil capsules in de novo kidney (3) heart (1) and liver (1) transplant patients [see Clinical Studies (14.1, 14.2 and 14.3)].

Mycophenolate Mofetil Oral

The incidence of adverse reactions for mycophenolate mofetil was determined in five randomized, comparative, double-blind trials in the prevention of rejection in kidney, heart and liver transplant patients (two active- and one placebo-controlled trials, one active-controlled trial, and one active-controlled trial, respectively) [see Clinical Studies ( 14.1 , 14.2  and 14.3 )].

The three de novo kidney studies with 12-month duration compared two dose levels of oral mycophenolate mofetil (1 g twice daily and 1.5 g twice daily) with azathioprine (2 studies) or placebo (1 study) when administered in combination with cyclosporine (Sandimmune) and corticosteroids to prevent acute rejection episodes. One study also included anti-thymocyte globulin (ATGAM) induction therapy.

In the de novo heart transplantation study with 12-month duration, patients received mycophenolate mofetil 1.5 g twice daily (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.

In the de novo liver transplantation study with 12-month duration, 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 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 total number of patients enrolled was 565.

Approximately 53% of the kidney transplant patients, 65% of the heart transplant patients, and 48% of the liver transplant patients were treated for more than 1 year. Adverse reactions reported in ³ 20% of patients in the mycophenolate mofetil treatment groups are presented below. The safety data of three kidney transplantation studies are pooled together.

Table 3.    Adverse Reactions in Controlled Studies of De Novo Kidney, Heart or Liver Transplantation (Reported in ³20% of Patients in the Mycophenolate Mofetil Group)

In the three de novo kidney studies, patients receiving 2 g/day of mycophenolate mofetil had an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil.

Post-transplant lymphoproliferative disease (PTLD) 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 kidney, heart and liver transplant patients followed for at least 1 year [see Warnings and Precautions (5.2)]. 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 kidney and heart transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. In pediatric patients, PTLD was observed in 1.35% (2/148) by 12 months post-transplant.

Severe neutropenia (ANC <0.5 x 10/mL) developed in up to 2.0% of kidney transplant patients, up to 2.8% of heart transplant patients and up to 3.6% of liver transplant patients receiving mycophenolate mofetil 3 g daily [see Warnings and Precautions (5.4) and Dosage and Administration (2.5)].

Table 4 shows the incidence of opportunistic infections that occurred in the kidney, heart, and liver transplant populations in the azathioprine-controlled prevention trials:

Table 4.  Opportunistic Viral and Fungal Infections in Controlled Studies of De Novo Kidney, Heart or Liver Transplantation

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 and tissue invasive disease; Cryptococcosis; Aspergillus/Mucor; Pneumocystis jirovecii.

In patients receiving mycophenolate mofetil (2 g or 3 g) in controlled studies for prevention of kidney, heart or liver rejection, fatal infection/sepsis occurred in approximately 2% of kidney and heart patients and in 5% of liver patients [see Warnings and Precautions (5.3)].

The following adverse reactions were reported with 3% to <20% incidence in kidney, heart, and liver transplant patients treated with mycophenolate mofetil, in combination with cyclosporine and corticosteroids.

Table 5.          Adverse Reactions Reported in 3% to <20% of Patients Treated with Mycophenolate Mofetil in Combination with Cyclosporine and Corticosteroids

Pediatric Study

The type and frequency of adverse events in a clinical study for prevention of kidney allograft rejection in 100 pediatric patients 3 months to 18 years of age dosed with mycophenolate mofetil oral suspension 600 mg/m twice daily (up to 1 g twice daily) were generally similar to those observed in adult patients dosed with mycophenolate mofetil capsules at a dose of 1 g twice daily 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.

Geriatrics

Elderly patients (³65 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 Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

Mycophenolate Mofetil Intravenous

The safety profile of mycophenolate mofetil intravenous was determined from a single, double-blind, controlled comparative study of the safety of 2 g/day of intravenous and oral mycophenolate mofetil in kidney transplant patients in the immediate post-transplant period (administered for the first 5 days).

The potential venous irritation of mycophenolate mofetil intravenous was evaluated by comparing the adverse reactions attributable to peripheral venous infusion of mycophenolate mofetil intravenous with those observed in the intravenous placebo group; patients in the placebo group received active medication by the oral route.

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

Kidney Studies Heart Study L iver Study
Mycophenolate Mofetil
2 g/day
Mycophenolate Mofetil
3 g/day
Azathioprine
1 to 2 mg/kg/day or
10 0 to 150 m g / day
Mycophenolate Mofetil
3 g/day
Azathioprine 1 .5 to 3 mg/kg/day Mycophenolate Mofetil
3 g/day
Azathioprine
1 to 2 mg/kg/day
(n=336) (n=330) (n=326) (n=289) (n=289) (n=277) (n=287)
% % % % % % %
Bo dy as a Whole
Infection 18.2 20.9 19.9 25.6 19.4 27.1 25.1
Sepsis 27.4 26.5
Ascites 24.2 22.6
Hematologic and L y m phatic
Anemia 25.6 25.8 23.6 42.9 43.9 43.0 53.0
Leukopenia 23.2 34.5 24.8 30.4 39.1 45.8 39.0
Thrombocytopenia 23.5 27.0 38.3 42.2
Leukocytosis 40.5 35.6 22.4 21.3
Urogenital
Urinary tract infection 37.2 37.0 33.7
Cardiovascular
Hypertension 32.4 28.2 32.2 77.5 72.3 62.1 59.6
Hypotension 32.5 36.0
Tachycardia 20.1 18.0 22.0 15.7
M e tabolic and Nutritional
Peripheral edema 28.6 27.0 28.2 64.0 53.3 48.4 47.7
Hyper­ cholesterolemia 41.2 38.4
Edema 26.6 25.6 28.2 28.2
Hypokalemia 31.8 25.6 37.2 41.1
Hyperkalemia 22.0 23.7
Hyperglycemia 46.7 52.6 43.7 48.8
Creatinine increased 39.4 36.0
BUN increased 34.6 32.5
Lactic dehydrogenase increased 23.2 17.0
Hypomagnesemia 39.0 37.6
Hypocalcemia 30.0 30.0
Digestive
Diarrhea 31.0 36.1 20.9 45.3 34.3 51.3 49.8
Constipation 22.9 18.5 22.4 41.2 37.7 37.9 38.3
Nausea 19.9 23.6 24.5 54.0 54.3 54.5 51.2
Dyspepsia 22.4 20.9
Vomiting 33.9 28.4 32.9 33.4
Anorexia 25.3 17.1
Liver function tests abnormal 24.9 19.2
Respiratory
Infection 22.0 23.9 19.6 37.0 35.3
Dyspnea 36.7 36.3 31.0 30.3
Cough increased 31.1 25.6
Sinusitis 26.0 19.0
Pleural effusion 34.3 35.9
S k in and Appendages
Rash 22.1 18.0
Nervous System
Tremor 24.2 23.9 33.9 35.5
Insomnia 40.8 37.7 52.3 47.0
Dizziness 28.7 27.7
Anxiety 28.4 23.9
Paresthesia 20.8 18.0
Kidney Studies Heart Study L iver Study
Mycophenolate Mofetil
2 g/day
Mycophenolate Mofetil
3 g/day
Azathioprine 1 to 2 mg/kg/day o r 100 to 150 mg/day Mycophenolate Mofetil
3 g/day
Azathioprine 1 .5 to 3 mg/kg/day Mycophenolate Mofetil
3 g/day
Azathioprine
1 to 2 mg/kg/day
(n=336) (n=330) (n=326) (n=289) (n=289) (n=277) (n=287)
% % % % % % %
Herpes simplex 16.7 20.0 19.0 20.8 14.5 10.1 5.9
Cytomegalovirus
– Viremia/syndrome 13.4 12.4 13.8 12.1 10.0 14.1 12.2
– Tissue invasive disease 8.3 11.5 6.1 11.4 8.7 5.8 8.0
Herpes zoster 6.0 7.6 5.8 10.7 5.9 4.3 4.9
– Cutaneous disease 6.0 7.3 5.5 10.0 5.5 4.3 4.9
Candida 17.0 17.3 18.1 18.7 17.6 22.4 24.4
– Mucocutaneous 15.5 16.4 15.3 18.0 17.3 18.4 17.4
Body System Adverse Reactions
Body as a Whole Abscess, cellulitis, chills occurring with fever, malaise, peritonitis
Hematologic and Lymphatic coagulation disorder, ecchymosis, pancytopenia, petechia, polycythemia, prothrombin time increased, thromboplastin time increased
Urogenital acute kidney failure, albuminuria, dysuria, , hematuria, kidney failure, kidney tubular necrosis, pain, pyelonephritis, scrotal edema
Cardiovascular angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, congestive heart failure, extrasystole, heart failure, hypotension, palpitation, pericardial effusion, pulmonary hypertension, supraventricular tachycardia, supraventricular extrasystoles, syncope, tachycardia, ventricular extrasystole, ventricular tachycardia
Metabolic and Nutritional acidosis, hypercholesteremia, hyperlipemia
Digestive anorexia, esophagitis, flatulence, gastritis, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, gum hyperplasia, hepatitis, ileus, jaundice, melena, mouth ulceration, nausea and vomiting, oral moniliasis, stomach ulcer, stomatitis
Respiratory bronchitis, epistaxis, hemoptysis, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory moniliasis, rhinitis, sinusitis
Skin and Appendages acne, fungal dermatitis, hemorrhage, hirsutism , pruritus, rash, skin benign neoplasm, skin carcinoma, vesiculobullous rash

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:

-Facial malformations: cleft lip, cleft palate, micrognathia, hypertelorism of the orbits

-Abnormalities of the ear and eye: abnormally formed or absent external/middle ear, coloboma, microphthalmos

-Malformations of the fingers: polydactyly, syndactyly, brachydactyly

-Cardiac abnormalities: atrial and ventricular septal defects

-Esophageal malformations: esophageal atresia

-Nervous system malformations: such as spina bifida.

Table 6.          Drug Interactions with Mycophenolate Mofetil Capsules that Affect Mycophenolic Acid (MPA) Exposure

Antacids with Magnesium or Aluminum Hydroxide
Clinical Impact Concomitant use with an antacid containing magnesium or aluminum hydroxide decreases MPA systemic exposure [see Clinical Pharmacology (12.3)], which may reduce mycophenolate mofetil efficacy.
Prevention or Management Administer magnesium or aluminum hydroxide containing antacids at least 2h after mycophenolate mofetil capsules administration.
Proton Pump Inhibitors (PPIs)
Clinical Impact Concomitant use with PPIs decreases MPA systemic exposure [see Clinical Pharmacology (12.3)], which may reduce mycophenolate mofetil efficacy.
Prevention or Management Monitor patients for alterations in efficacy when PPIs are co- administered with mycophenolate mofetil capsules.
Examples Lansoprazole, pantoprazole
Drugs that Interfere with Enterohepatic Recirculation
Clinical Impact Concomitant use with drugs that directly interfere with enterohepatic recirculation, or indirectly interfere with enterohepatic recirculation by altering the gastrointestinal flora, can decrease MPA systemic exposure [see Clinical Pharmacology (12.3)], which may reduce mycophenolate mofetil efficacy.
Prevention or Management Monitor patients for alterations in efficacy or mycophenolate mofetil related adverse reactions when these drugs are co-administered with mycophenolate mofetil capsules.
Examples Trimethoprim/sulfamethoxazole, bile acid sequestrants (cholestyramine), rifampin as well as aminoglycoside, cephalosporin, fluoroquinolone and penicillin classes of antimicrobials
Drugs Modulating Glucuronidation
Clinical Impact Concomitant use with drugs inducing glucuronidation decreases MPA systemic exposure, potentially reducing mycophenolate mofetil efficacy, while use with drugs inhibiting glucuronidation increases MPA systemic exposure [see Clinical Pharmacology (12.3)], which may increase the risk of mycophenolate mofetil related adverse reactions.
Prevention or Management Monitor patients for alterations in efficacy or mycophenolate mofetil related adverse reactions when these drugs are co-administered with mycophenolate mofetil capsules.
Examples Telmisartan (induces glucuronidation); isavuconazole (inhibits glucuronidation).
Calcium Free Phosphate Binders
Clinical Impact Concomitant use with calcium free phosphate binders decrease MPA systemic exposure [see Clinical Pharmacology (12.3)], which may reduce mycophenolate mofetil efficacy.
Prevention or Management Administer calcium free phosphate binders at least 2 hours after mycophenolate mofetil capsules.
Examples Sevelamer

Table 7.          Drug Interactions with Mycophenolate Mofetil Capsules that Affect Other Drugs

Drugs that Undergo Renal Tubular Secretion
Clinical Impact When concomitantly used with mycophenolate mofetil capsules, its metabolite MPAG, may compete with drugs eliminated by renal tubular secretion which may increase plasma concentrations and/or adverse reactions associated with these drugs.
Prevention or Management Monitor for drug-related adverse reactions in patients with renal impairment.
Examples Acyclovir, ganciclovir, probenecid, valacyclovir, valganciclovir
Combination Oral Contraceptives
Clinical Impact Concomitant use with mycophenolate mofetil capsules decreased the systemic exposure to levonorgestrel, but did not affect the systemic exposure to ethinylestradiol [see Clinical Pharmacology (12.3)], which may result in reduced combination oral contraceptive effectiveness.
Prevention or Management Use additional barrier contraceptive methods.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to mycophenolate during pregnancy and those becoming pregnant within 6 weeks of discontinuing mycophenolate mofetil capsule treatment. To report a pregnancy or obtain information about the registry, visit www.mycophenolateREMS.com or call 1-800-617-8191.

Risk Summary

Use of mycophenolate mofetil (MMF) during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of multiple congenital malformations in multiple organ systems [see Human Data].  Oral administration of mycophenolate to rats and rabbits during the period of organogenesis produced congenital malformations and pregnancy loss at doses less than the recommended clinical dose (0.02 to 0.1 times the recommended clinical doses in kidney and heart transplant patients) [see Animal Data].

Consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of mycophenolate mofetil capsules should be discussed with the pregnant woman.

The estimated background risk of pregnancy loss and congenital malformations in organ transplant populations is not clear. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Human Data

A spectrum of congenital malformations (including multiple malformations in individual newborns) has been reported in 23 to 27% of live births in MMF exposed pregnancies, based on published data from pregnancy registries. Malformations that have been documented include external ear, eye, and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney, and nervous system.

Based on published data from pregnancy registries, the risk of first trimester pregnancy loss has been reported at 45 to 49% following MMF exposure.

Animal Data

In animal reproductive toxicology studies, there were increased rates of fetal resorptions and malformations in the absence of maternal toxicity. Oral administration of MMF to pregnant rats from Gestational Day 7 to Day 16 produced increased embryofetal lethality and fetal malformations including anophthalmia, agnathia, and hydrocephaly at doses equivalent to

0.03 and 0.02 times the recommended human doses for renal and cardiac transplant patients,

respectively, when corrected for BSA. Oral administration of MMF to pregnant rabbits from Gestational Day 7 to Day 19 produced increased embryofetal lethality and fetal malformations included ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia at dose equivalents as low as 0.1 and 0.06 times the recommended human doses for renal and cardiac transplant patients, respectively, when corrected for BSA.

Risk Summary

There are no data on the presence of mycophenolate in human milk, or the effects on milk production. There are limited data in the National Transplantation Pregnancy Registry on the effects of mycophenolate on a breastfed child [see Data]. Studies in rats treated with MMF have shown mycophenolic acid (MPA) to be present in milk. Because available data are limited, it is not possible to exclude potential risks to a breastfeeding infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mycophenolate mofetil capsules and any potential adverse effects on the breastfed infant from mycophenolate mofetil capsules or from the underlying maternal condition.

Data

Limited information is available from the National Transplantation Pregnancy Registry. Of seven infants reported by the National Transplantation Pregnancy Registry to have been breastfed while the mother was taking mycophenolate, all were born at 34 to 40 weeks gestation, and breastfed for up to 14 months. No adverse events were reported.

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.

Pregnancy Planning

For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity whenever possible. Risks and benefits of mycophenolate mofetil capsules should be discussed with the patient.

Pregnancy Testing

To prevent unplanned exposure during pregnancy, all females of reproductive potential should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL immediately before starting mycophenolate mofetil capsules. Another pregnancy test with the same sensitivity should be done 8 to 10 days later. Repeat pregnancy tests should be performed during routine follow-up visits. Results of all pregnancy tests should be discussed with the patient. In the event of a positive pregnancy test, consider alternative immunosuppressants with less potential for embryofetal toxicity whenever possible.

Contraception

Female Patients

Females of reproductive potential taking mycophenolate mofetil capsules must receive contraceptive counseling and use acceptable contraception (see Table 8 for acceptable contraception methods). Patients must use acceptable birth control during the entire mycophenolate mofetil capsule therapy, and for 6 weeks after stopping mycophenolate mofetil capsules, unless the patient chooses abstinence.

Patients should be aware that mycophenolate mofetil capsules reduce blood levels of the hormones from the oral contraceptive pill and could theoretically reduce its effectiveness [see Drug Interactions (7.2)].

Table 8.           Acceptable Contraception Methods For Females Of Reproductive Potential

Pick from the following birth control options:

Male Patients

Genotoxic effects have been observed in animal studies at exposures exceeding the human therapeutic exposures by approximately 2.5 times. Thus, the risk of genotoxic effects on sperm cells cannot be excluded. Based on this potential risk, sexually active male patients and/or their female partners are recommended to use effective contraception during treatment of the male patient and for at least 90 days after cessation of treatment. Also, based on the potential risk of genotoxic effects, male patients should not donate sperm during treatment with mycophenolate mofetil capsules and for at least 90 days after cessation of treatment [see Use in Special Populations (8.1), Nonclinical Toxicology (13.1), Patient Counseling Information (17.9)].

Safety and effectiveness of mycophenolate mofetil capsules have been established in pediatric patients 3 months and older for the prophylaxis of kidney rejection after allogeneic kidney transplant. Use of mycophenolate mofetil capsules in this population is supported by evidence from adequate and well-controlled studies of mycophenolate mofetil capsules in adults with additional data from one open-label, pharmacokinetic and safety study of mycophenolate mofetil capsules in pediatric patients after receiving allogeneic kidney transplant [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)].

Safety and effectiveness in pediatric patients receiving allogeneic heart or liver transplants have not been established.

Clinical studies of mycophenolate mofetil capsules 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 the elderly and younger patients. In general, dose selection for an elderly 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)].

Patients with Kidney Transplant

No dose adjustments are needed in kidney transplant patients experiencing delayed graft function postoperatively but patients should be carefully monitored [see Clinical Pharmacology (12.3)]. In kidney transplant patients with severe chronic impairment of the graft (GFR <25 mL/min/1.73 m), no dose adjustments are necessary; however, doses greater than 1 g administered twice a day should be avoided.

Patients with Heart and Liver Transplant

No data are available for heart or liver transplant patients with severe chronic renal impairment. Mycophenolate mofetil capsules may be used for heart or liver transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.

Patients with Kidney Transplant

No dose adjustments are recommended for kidney transplant 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 (12.3)]. 

Patients with Heart Transplant

No data are available for heart transplant patients with severe hepatic parenchymal disease.

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 capsules 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)].

Treatment and Management

MPA and the phenolic glucuronide metabolite of MPA (MPAG) are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 mg/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 (12.3)].

Mycophenolate mofetil, USP is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor.

The chemical name for mycophenolate mofetil, USP (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 the following structural formula:

CHNO      M.W. 433.50

Mycophenolate mofetil, USP is a white to almost white crystalline powder. It is slightly soluble in water (43 mcg/mL at pH 7.4), freely soluble in acetone, soluble in methanol, sparingly soluble in anhydrous ethanol, and practically insoluble in water. No polymorphic form was found. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for mycophenolate mofetil, USP are 5.6 for the morpholino group and 8.5 for the phenolic group.

Mycophenolate mofetil, USP is available for oral administration as capsules containing 250 mg of mycophenolate mofetil, USP.

Inactive ingredients in Mycophenolate Mofetil Capsules USP, 250 mg include: black iron oxide, croscarmellose sodium, D&C red #28, D&C yellow #10, FD&C blue #1, FD&C red #40, gelatin, magnesium stearate, povidone, pregelatinized corn starch, propylene glycol, shellac glaze, and titanium dioxide.

Mycophenolate mofetil (MMF) is absorbed following oral administration and hydrolyzed to mycophenolic acid (MPA), the active metabolite. MPA is a 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. MMF 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.

There is a lack of information regarding the pharmacodynamic effects of MMF.

Absorption

Following oral and intravenous administration, MMF undergoes complete conversion to MPA, the active metabolite. In 12 healthy volunteers, the mean absolute bioavailability of oral MMF relative to intravenous MMF was 94%. Two 500 mg mycophenolate mofetil tablets have been shown to be bioequivalent to four 250 mg mycophenolate mofetil capsules. Five mL of the 200 mg/mL constituted mycophenolate mofetil oral suspension have been shown to be bioequivalent to four 250 mg capsules.

The mean (±SD) pharmacokinetic parameters estimates for MPA following the administration of MMF given as single doses to healthy volunteers, and multiple doses to kidney, heart, and liver transplant patients, are shown in Table 9. The area under the plasma- concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in kidney transplant patients receiving multiple oral doses of MMF up to a daily dose of 3 g (1.5g twice daily) (see Table 9).

Table 9.          Pharmacokinetic Parameters for MPA [mean (±SD)] Following Administration of MMF to Healthy Volunteers (Single Dose), and Kidney, Heart, and Liver Transplant Patients (Multiple Doses)

AUC(0-12h) values quoted are extrapolated from data from samples collected over 4 hours.

In the early post-transplant period (less than 40 days post-transplant), kidney, heart, and liver transplant patients had mean MPA AUCs approximately 20% to 41% lower and mean C approximately 32% to 44% lower compared to the late transplant period (i.e., 3 to 6 months post-transplant) (non-stationarity in MPA pharmacokinetics).

Mean MPA AUC values following administration of 1 g twice daily intravenous mycophenolate mofetil over 2 hours to kidney transplant patients for 5 days were about 24% higher than those observed after oral administration of a similar dose in the immediate post-transplant phase.

In liver transplant patients, administration of 1 g twice daily intravenous mycophenolate mofetil followed by 1.5 g twice daily oral mycophenolate mofetil resulted in mean MPA AUC estimates similar to those found in kidney transplant patients administered 1 g mycophenolate mofetil twice daily.

Effect of Food

Food (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of MMF when administered at doses of 1.5 g twice daily to kidney transplant patients. However, MPA C was decreased by 40% in the presence of food [see Dosage and Administration (2.1)].

Distribution

The mean (±SD) apparent volume of distribution of MPA in 12 healthy volunteers was approximately 3.6 (±1.5) L/kg. At clinically relevant concentrations, MPA is 97% bound to plasma albumin. The phenolic glucuronide metabolite of MPA (MPAG) is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable kidney transplant patients; however, at higher MPAG concentrations (observed in patients with kidney impairment or delayed kidney 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 human serum albumin) and MPAG (at ≥ 460 mcg/mL with plasma proteins) increased 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%.

Elimination

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.

Metabolism

The parent drug, MMF, can be measured systemically during the intravenous infusion; however, approximately 5 minutes after the infusion is stopped or after oral administration, MMF concentrations are below the limit of quantitation (0.4 mcg/mL).

Metabolism to MPA occurs pre-systemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form MPAG, which is not pharmacologically active. In vivo, MPAG is converted to MPA during enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of MMF to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.

Due to the enterohepatic recirculation of MPAG/MPA, secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to 12 hours post-dose. Bile sequestrants, such as cholestyramine, reduce MPA AUC by interfering with this enterohepatic recirculation of the drug [see Overdose (10 ) and Drug Interaction Studies below].

Excretion

Negligible amount of drug is excreted as MPA (less than 1% of dose) in the urine. Orally administered radiolabeled MMF 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.

Increased plasma concentrations of MMF metabolites (MPA 50% increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal insufficiency [see Specific Populations].

Specific Populations

Patients with Renal Impairment

The mean (±SD) pharmacokinetic parameters for MPA following the administration of oral MMF given as single doses to non-transplant subjects with renal impairment are presented in Table 10.

In a single-dose study, MMF was administered as a capsule or as an intravenous infusion over 40 minutes. Plasma MPA AUC observed after oral dosing to volunteers with severe chronic renal impairment (GFR < 25 mL/min/1.73 m) was about 75% higher relative to that observed in healthy volunteers (GFR > 80 mL/min/1.73 m). 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 m) was 62.4 mcg•h/mL (±19.3). Multiple dosing of MMF in patients with severe chronic renal impairment has not been studied.

Patients with Delayed Graft Function or Nonfunction

In patients with delayed renal graft function post-transplant, mean MPA AUC(0-12h) was comparable to that seen in post-transplant 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(0-12h) was 2-fold to 3-fold higher than in post-transplant patients without delayed renal graft function [see Dosage and Administration (2.5)].

In eight patients with primary graft non-function following kidney 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 MMF 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.

Patients with Hepatic Impairment

The mean (± SD) pharmacokinetic parameters for MPA following the administration of oral MMF given as single doses to non-transplant subjects with hepatic impairment is presented in Table 10.

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. 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).

Table 10.        Pharmacokinetic Parameters for MPA [mean (±SD)] Following Single Doses of MMF Capsules in Chronic Renal and Hepatic Impairment

Pediatric Patients

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/m twice daily (up to a maximum of 1 g twice daily) after allogeneic kidney transplantation. The pharmacokinetic data for MPA is provided in Table 11.

Table 11.         Mean (±SD) Computed Pharmacokinetic Parameters for MPA by Age and Time after Allogeneic Kidney Transplantation

adjusted to a dose of 600 mg/m n=20 n=16 a subset of 1 to <6 yr

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

Male and Female Patients

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 32.0 (±14.5) and for females (n=41) was 36.5 (±18.8) mcg•h/mL while mean (±SD) MPA C 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.

Geriatric Patients

The pharmacokinetics of mycophenolate mofetil and its metabolites have not been found to be altered in elderly transplant patients when compared to younger transplant patients.

Drug Interaction Studies

Acyclovir

Coadministration of MMF (1 g) and acyclovir (800 mg) to 12 healthy volunteers resulted in no significant change in MPA AUC and C. However, MPAG and acyclovir plasma AUCs were increased 10.6% and 21.9%, respectively.

Antacids with Magnesium and Aluminum Hydroxides

Absorption of a single dose of MMF (2 g) was decreased when administered to 10 rheumatoid arthritis patients also taking Maalox TC (10 mL qid). The C and AUC(0-24h) for MPA were 33% and 17% lower, respectively, than when MMF was administered alone under fasting conditions.

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 capsules has been reported to reduce the exposure to MPA. An approximate reduction of 30 to 70% in the C 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.

Cholestyramine

Following single-dose administration of 1.5 g MMF to 12 healthy volunteers pretreated with 4 g three times a day 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.

Cyclosporine

Cyclosporine (Sandimmune) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 g twice daily of MMF in 10 stable kidney

transplant patients. The mean (±SD) AUC(0-12h) and C of cyclosporine after 14 days of multiple doses of MMF 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, 1 week before administration of MMF.

Cyclosporine A interferes with MPA enterohepatic recirculation.  In kidney transplant patients, mean MPA exposure (AUC(0-12h)) was approximately 30 to 50% greater when MMF was administered without cyclosporine compared with when MMF was 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.

Drugs Affecting Glucuronidation

Concomitant administration of drugs inhibiting glucuronidation of MPA may increase MPA exposure (e.g., increase of MPA AUC(0-∞) by 35% was observed with concomitant administration of isavuconazole).

Concomitant administration of telmisartan and mycophenolate mofetil capsules resulted in an approximately 30% decrease in MPA concentrations. Telmisartan changes MPA’s elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results in an enhanced UGT1A9 expression and glucuronidation activity.

Ganciclovir

Following single-dose administration to 12 stable kidney transplant patients, no pharmacokinetic interaction was observed between MMF (1.5 g) and intravenous ganciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and C (n=10) were 54.3 (±19.0) mcg•h/mL and 11.5 (±1.8) mcg/mL, respectively, after coadministration of the two drugs, compared to 51.0 (±17.0) mcg•h/mL and 10.6 (±2.0) mcg/mL, respectively, after administration of intravenous ganciclovir alone. The mean (±SD) AUC and C 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) mg•h/mL and 30.9 (±11.2) mcg/mL, respectively, after administration of MMF alone.

Oral Contraceptives

A study of coadministration of mycophenolate mofetil capsules (1 g twice daily) 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 3 consecutive menstrual cycles. Mean serum levels of LH, FSH and progesterone were not significantly affected. 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.

Sevelamer

Concomitant administration of sevelamer and MMF in adult and pediatric patients decreased the mean MPA C and AUC(0-12h) by 36% and 26% respectively.

Antimicrobials

Antimicrobials eliminating beta-glucuronidase-producing bacteria in the intestine (e.g. aminoglycoside, cephalosporin, fluoroquinolone, and penicillin classes of antimicrobials) may interfere with the MPAG/MPA enterohepatic recirculation thus leading to reduced systemic MPA exposure. Information concerning antibiotics is as follows:

Healthy Volunteers Dose/Route T m a x (h) C m a x ( m cg/mL) T o tal AUC (mcg•h/mL)
Single dose 1 g/oral 0.80 24.5 63.9
(±0.36) (±9.5) (±16.2)
(n=129) (n=129) (n=117)
Kidney Transplant Patients (twice daily dosing) Time After Transplantation Dose/Route T m a x (h) C m a x ( m cg/mL) I nterdosing Interval
AUC(0- 12h)
( m cg•h/mL)
5 days 1 g/iv 1.58 12.0 40.8
(±0.46) (±3.82) (±11.4)
(n=31) (n=31) (n=31)
6 days 1 g/oral 1.33 10.7 32.9
(±1.05) (±4.83) (±15.0)
(n=31) (n=31) (n=31)
Early (Less than 40 days) 1 g/oral 1.31 8.16 27.3
(±0.76) (±4.50) (±10.9)
(n=25) (n=25) (n=25)
Early (Less than 40 days) 1.5 g/oral 1.21 13.5 38.4
(±0.81) (±8.18) (±15.4)
(n=27) (n=27) (n=27)
Late (Greater than 3 1.5 g/oral 0.90 24.1 65.3
months) (±0.24) (±12.1) (±35.4)
(n=23) (n=23) (n=23)
Heart transplant Patients (twice daily dosing) Time After Transplantation Dose/Route T m a x (h) C m a x ( m cg/mL) I nterdosing Interval
AUC(0- 12h)
( m cg•h/mL)
Early 1.5 g/oral 1.8 11.5 43.3
(Day before discharge) (±1.3) (±6.8) (±20.8)
(n=11) (n=11) (n=9)
Late (Greater than 6 1.5 g/oral 1.1 20.0 54.1a
months) (±0.7) (±9.4) (±20.4)
(n=52) (n=52) (n=49)
L iver transplant Patients (twice daily dosing) Time After Transplantation Dose/Route T m a x (h) C m a x ( m cg/mL) I nterdosing Interval
AUC(0- 12h)
( m cg•h/mL)
4 to 9 days 1 g/iv 1.50 17.0 34.0
(±0.517) (±12.7) (±17.4)
(n=22) (n=22) (n=22)
Early (5 to 8 days) 1.5 g/oral 1.15 13.1 29.2
(±0.432) (±6.76) (±11.9)
(n=20) (n=20) (n=20)
Late (Greater than 6 1.5 g/oral 1.54 19.3 49.3
months) (±0.51) (±11.7) (±14.8)
(n=6) (n=6) (n=6)
Pharmacokinetic Parameters for Renal Impairment
Dose T m a x (h) C m a x ( m cg/mL) AUC(0-96h) ( m cg•h/mL)
Healthy Volunteers 1 g 0.75 25.3 45.0
GFR greater than 80 mL/min/1.73 m2 (±0.27) (±7.99) (±22.6)
(n=6)
Mild Renal Impairment 1 g 0.75 26.0 59.9
GFR 50 to 80 mL/min/1.73 m2 (±0.27) (±3.82) (±12.9)
(n=6)
Moderate Renal Impairment 1 g 0.75 19.0 52.9
GFR 25 to 49 mL/min/1.73 m2 (±0.27) (±13.2) (±25.5)
(n=6)
Severe Renal Impairment 1 g 1.00 16.3 78.6
GFR less than 25 mL/min/1.73 m2 (±0.41) (±10.8) (±46.4)
(n=7)
Pharmacokinetic Parameters for Hepatic Impairment
Dose T m a x (h) C m a x ( m cg/mL) AUC(0-48h) ( m cg•h/mL)
Healthy Volunteers 1 g 0.63 24.3 29.0
(n=6) (±0.14) (±5.73) (±5.78)
Alcoholic Cirrhosis 1 g 0.85 22.4 29.8
(n=18) (±0.58) (±10.1) (±10.7)

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 0.4 times the recommended clinical dose (2 g/day) in renal transplant patients and 0.3 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 0.07 times the recommended clinical dose in kidney transplant patients and 0.05 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 vivo mouse 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 0.1 times the recommended clinical dose in renal transplant patients and 0.06 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 0.02 times the recommended clinical dose in renal transplant patients and 0.01 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.

Adults

The three de novo kidney transplantation studies compared two dose levels of oral mycophenolate mofetil (1 g twice daily and 1.5 g twice daily) with azathioprine (2 studies) or placebo (1 study) to prevent acute rejection episodes. One of the two studies with azathioprine (AZA) control arm also included anti-thymocyte globulin (ATGAM) induction therapy. The geographic location of the investigational sites of these studies are included in Table 12.

In all three de novo kidney transplantation studies, the primary efficacy endpoint was the proportion of patients in each treatment group who experienced treatment failure within the first 6 months after transplantation. Treatment failure was 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, 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 12). 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 combined are summarized in Table 13. Patients who prematurely discontinued treatment were not followed for the occurrence of acute rejection after termination.

Table 12.        Treatment Failure in De Novo Kidney Transplantation Studies

*Does not include death and graft loss as reason for early termination.

No advantage of mycophenolate mofetil at 12 months with respect to graft loss or patient death (combined) was established (Table 13). 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 1 year.

Table 13.        De Novo Kidney Transplantation Studies Cumulative Incidence of Combined Graft Loss or Patient Death at 12 Months

Pediatrics- De Novo Kidney transplantation PK Study with Long Term Follow-Up

One open-label, safety and pharmacokinetic study of mycophenolate mofetil oral suspension 600 mg/m2 twice daily (up to 1 g twice daily) in combination with cyclosporine and corticosteroids was performed at centers in the United States (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 (6.1)], and the pharmacokinetics profile was similar to that seen in adult patients dosed with 1 g twice daily mycophenolate mofetil capsules [see Clinical Pharmacology (12.3)]. 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 kidney transplant patients.

USA Study a
(N=499 patients)
Mycophenolate Mofetil

2 g/day
(n=167 patients)
Mycophenolate Mofetil

3 g/day
(n=166 patients)
AZA 1 to 2 mg/kg/day
(n=166 patients)
All 3 groups received anti-thymocyte globulin induction, cyclosporine and corticosteroids
All treatment failures 31.1% 31.3% 47.6%
Early termination without prior acute rejectionb 9.6% 12.7% 6.0%
Biopsy-proven rejection episode on treatment 19.8% 17.5% 38.0%
Europe/Canada/Australia
Study c
(N=503 patients)
Mycophenolate Mofetil

2 g/day
(n=173 patients)
Mycophenolate Mofetil

3 g/day
(n=164 patients)
AZA 100 to 150 mg/day
(n=166 patients)
No induction treatment administered; all 3 groups received cyclosporine and corticosteroids.
All treatment failures 38.2% 34.8% 50.0%
Early termination without prior acute rejectionb 13.9% 15.2% 10.2%
Biopsy-proven rejection episode on treatment 19.7% 15.9% 35.5%
Europe Study d
(N=491 patients)
Mycophenolate Mofetil
2 g/day
(n=165 patients)
Mycophenolate Mofetil
3 g/day
(n=160 patients)
Placebo (n=166 patients)
No induction treatment administered; all 3 groups received cyclosporine and corticosteroids.
All treatment failures 30.3% 38.8% 56.0%
Early termination without prior acute rejectionb 11.5% 22.5% 7.2%
Biopsy-proven rejection episode on treatment 17.0% 13.8% 46.4%
Study Mycophenolate Mofetil 2 g/day Mycophenolate Mofetil 3 g/day Control (AZA or Placebo)
USA 8.5% 11.5% 12.2%
Europe/Canada/Australia 11.7% 11.0% 13.6%
Europe 8.5% 10.0% 11.5%

A double-blind, randomized, comparative, parallel-group, multicenter study in primary de novo heart 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:

Table 14.        De Novo Heart Transplantation Study Rejection at 6 Months/Death or Re-transplantation at 1 Year

 Hemodynamic  compromise  occurred  if  any  of  the  following  criteria  were  met:  pulmonary capillary wedge pressure ³20 mm or a 25% increase; cardiac index <2.0 L/min/m  or a 25% decrease; ejection fraction £30%; pulmonary artery oxygen saturation £60% or a 25% decrease; presence of new S gallop; fractional shortening was £20% or a 25% decrease; inotropic support required to manage the clinical condition.

All Patients (ITT) Treated Patients
AZA
N = 323
Mycophenolate Mofetil
N = 327
AZA
N = 289
Mycophenolate Mofetil
N = 289
Biopsy-proven rejection with hemodynamic compromise at 6 monthsa 121 (38%) 120 (37%) 100 (35%) 92 (32%)
Death or re-transplantation at 1 year 49 (15.2%) 42 (12.8%) 33 (11.4%) 18 (6.2%)

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 15).

Table 15.        De Novo Liver Transplantation Study Rejection at 6 Months/Death or Retransplantation at 1 Year

AZA
N = 287
Mycophenolate Mofetil
N = 278
Biopsy-proven, treated rejection at 6 months (includes death or re- transplantation) 137 (47.7%) 107 (38.5%)
Death or re-transplantation at 1 year 42 (14.6%) 41 (14.7%)

1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Mycophenolate mofetil (MMF) has demonstrated teratogenic effects in humans [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Mycophenolate Mofetil Capsules USP should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in Mycophenolate Mofetil Capsules USP. Follow applicable special handling and disposal procedures.

Mycophenolate Mofetil Capsules USP are available as follows:

250 mg – hard gelatin capsules with a light blue opaque cap and a bright orange opaque body, filled with a white to off-white powder with small agglomerates; imprinted with "TEVA" on the cap and "7334" on the body. They are available in bottles of 100 and 500 capsules. (NDC 0093-7334-01 and NDC 0093-7334-05)

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, with a child-resistant closure (as required).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Information for Patients

See FDA-approved patient labeling (Medication Guide and Instructions for Use).

Pregnancy loss and malformations

Inform females of reproductive potential and pregnant women that use of mycophenolate mofetil capsules during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations. Advise that they must use an acceptable form of contraception [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)].

Encourage pregnant women to enroll in the Pregnancy Exposure Registry. This registry monitors pregnancy outcomes in women exposed to mycophenolate [see Use in Specific Populations (8.1)].

Contraception

Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential [see Use in Specific Populations (8.3)].

Females of reproductive potential must use an acceptable form of birth control during the entire mycophenolate mofetil capsule therapy and for 6 weeks after stopping mycophenolate mofetil capsules, unless the patient chooses abstinence. Mycophenolate mofetil capsules may reduce effectiveness of oral contraceptives. Use of additional barrier contraceptive methods is recommended [see Use in Specific Populations (8.3)].

For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of mycophenolate mofetil capsules should be discussed with the patient.

Advise sexually active male patients and/or their partners to use effective contraception during the treatment of the male patient and for at least 90 days after cessation of treatment. This recommendation is based on findings of animal studies [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

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.

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)].

Inform patients that mycophenolate mofetil capsules 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)].

Inform patients that mycophenolate mofetil capsules 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 (5.7)].

Advise patients not to donate blood during therapy and for at least 6 weeks following discontinuation of mycophenolate mofetil capsules.

Advise males of childbearing potential not to donate semen during therapy and for 90 days following discontinuation of mycophenolate mofetil capsules.

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA, Inc.

Manufactured In Czech Republic By: Teva Czech Industries, s.r.o. Opava-Komarov, Czech Republic

Manufactured For: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454

Rev. M 9/2018

M E DICATION GUIDE
Mycophenolate Mofetil (MYE-koe-FEN-oh-late MOE-fe-til) Capsules, 250 mg
Read the Medication Guide that comes with mycophenolate mofetil capsules 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 treatment.
W hat is the most important information I should know about mycophenolate mofetil capsules? Mycophenolate mofetil capsules can cause serious side effects, including: Increased risk of loss of a pregnancy (miscarriage) and higher risk of birth defects. Females who take mycophenolate mofetil capsules 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 capsules. You should have 1 pregnancy test immediately before starting mycophenolate mofetil capsules 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 capsule treatment and for 6 weeks after stopping mycophenolate mofetil capsules, unless at any time you choose to avoid sexual intercourse (abstinence) with a man completely. Mycophenolate mofetil capsules decrease 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 capsules, and you could become pregnant. If you take birth control pills while using mycophenolate mofetil capsules 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 capsules. If you are a sexually active male whose female partner can become pregnant while you are taking mycophenolate mofetil capsules, use effective contraception during treatment and for at least 90 days after stopping mycophenolate mofetil capsules. 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 capsules, do not stop taking mycophenolate mofetil capsules. Call your doctor right away. You and your doctor may decide that other medicines to prevent rejection may be right for you. You and your doctor should report your pregnancy to the Mycophenolate Pregnancy Registry either: By phone at 1-800-617-8191 or By visiting the REMS website at: w w w .m y cophenola t eR E M S .com The purpose of this registry is to gather information about the health of you and your baby. Increased risk of getting certain cancers. People who take mycophenolate mofetil capsules 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·a change in the size and color of a mole or lymph node swelling·a new skin lesion or bump a brown or black skin lesion with uneven borders,·any other changes to your health or one part of the lesion does not look like the other Increased risk of getting serious infections. Mycophenolate mofetil capsules weaken the body’s immune system and affect your ability to fight infections. Serious infections can happen with mycophenolate mofetil capsules and can lead to hospitalizations and death. These serious infections can include: V iral 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 capsules 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 capsules 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. Call 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 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 capsules and can cause serious tissue and blood infections (See “What are the possible side effects of mycophenolate mofetil capsules?”).
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 See “What are the possible side effects of mycophenolate mofetil capsules?” for information about other serious side effects.
W hat are mycophenolate mofetil capsules? Mycophenolate mofetil capsules are 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 capsules are used with other medicines containing cyclosporine and corticosteroids.
W ho should not take mycophenolate mofetil capsules? Do not take mycophenolate mofetil capsules if you are allergic to mycophenolate mofetil or any of the ingredients in mycophenolate mofetil capsules. See the end of this Medication Guide for a complete list of ingredients in mycophenolate mofetil capsules.
W hat should I tell my doctor before taking mycophenolate mofetil capsules? T ell your doctor about all of your medical conditions, including if you: have any digestive problems, such as ulcers. have Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, or another rare inherited deficiency hypoxanthine-guanine phosphoribosyl-transferase (HGPRT). You should not take mycophenolate mofetil capsules if you have one of these disorders. plan to receive any vaccines. People taking mycophenolate mofetil capsules should not receive live vaccines. Some vaccines may not work as well during treatment with mycophenolate mofetil capsules. are pregnant or plan to become pregnant. See “What is the most important information I should know about mycophenolate mofetil capsules?” are breastfeeding or plan to breastfeed. It is not known if mycophenolate mofetil passes into breast milk. You and your doctor will decide if you will take mycophenolate mofetil capsules or breastfeed. T ell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Some medicines may affect the way mycophenolate mofetil capsules work, and mycophenolate mofetil capsules 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 capsules?” sevelamer (Renagel®, Renvela). These products should be taken at least 2 hours after taking mycophenolate mofetil capsules. acyclovir (Zovirax®), valacyclovir (Valtrex®), ganciclovir (CYTOVENE®-IV, Vitrasert®), valganciclovir (VALCYTE®). rifampin (Rifater®, Rifamate®, Rimactane®, Rifadin®). antacids that contain magnesium and aluminum (mycophenolate mofetil capsules and the antacid should not be taken at the same time). proton pump inhibitors (PPIs) (Prevacid®, Protonix®). sulfamethoxazole/trimethoprim (BACTRIMä, BACTRIM DSä). ·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 capsules? Take mycophenolate mofetil capsules exactly as prescribed. Do not stop taking mycophenolate mofetil capsules or change the dose unless your doctor tells you to. If you miss a dose of mycophenolate mofetil capsules, or you are not sure when you took your last dose, take your prescribed dose of mycophenolate mofetil capsules as soon as you remember. If your next dose is less than 2 hours away, 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. Take mycophenolate mofetil capsules on an empty stomach, unless your doctor tells you otherwise. Do not open or crush mycophenolate mofetil capsules.
If you are not able to swallow mycophenolate mofetil capsules, your doctor may prescribe mycophenolate mofetil oral suspension. This is a liquid form of mycophenolate mofetil capsules. Your pharmacist will mix the medicine before you pick it up from a pharmacy. Do not breathe in (inhale) or let mycophenolate mofetil capsules powder come in contact with your skin or mucous membranes. If you accidentally get the powder on the skin, wash the area well with soap and water. If you accidentally get the powder in your eyes or other mucous membranes, flush with plain water. If you take too many mycophenolate mofetil capsules, call your doctor or the poison control center right away.
These are not all of the possible side effects of mycophenolate mofetil capsules. 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. You may also report side effects to Teva at 1-888-838-2872.
How should I store mycophenolate mofetil capsules? Store mycophenolate mofetil capsules at room temperature, between 68°F to 77°F (20°C to 25°C). Keep the container closed tightly. Keep mycophenolate mofetil capsules and all medicines out of the reach of children.
General Information about the safe and effective use of mycophenolate mofetil capsules. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use mycophenolate mofetil capsules for a condition for which they were not prescribed. Do not give mycophenolate mofetil capsules to other people, even if they have the same symptoms that you have. They may harm them. This Medication Guide summarizes the most important information about mycophenolate mofetil capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about mycophenolate mofetil capsules that is written for health professionals.
W hat are the ingredients in mycophenolate mofetil capsules? A ctive Ingredient: mycophenolate mofetil Inactive Ingredients: Mycophenolate mofetil capsules, 250 mg: black iron oxide, croscarmellose sodium, D&C red #28, D&C yellow #10, FD&C blue #1, FD&C red #40, gelatin, magnesium stearate, povidone, pregelatinized corn starch, propylene glycol, shellac glaze, and titanium dioxide. Manufactured In Czech Republic By:
Teva Czech Industries, s.r.o.
Opava-Komarov, Czech Republic
Manufactured For:
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454
All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA, Inc. For more information, call 1-888-838-2872 or visit www.tevagenerics.com.
This Medication Guide has been approved by the U.S. Food and Drug Administration.                                                                                 Rev. J 9/2018

NDC 0093-7334-05

Mycophenolate

Mofetil

Capsules USP 

250 mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.  

500 CAPSULES

TEVA

Manufacturer

Teva Pharmaceuticals USA, Inc.

Active Ingredients

Source

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