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    Pyrimidine Synthesis Inhibitors

    BOXED WARNING

    Fungal infection, herpes infection, immunosuppression, infection, progressive multifocal leukoencephalopathy, requires a specialized care setting, requires an experienced clinician, varicella, viral infection

    Immunosuppression may lead to increased susceptibility to infection. Bacterial infection, viral infection, protozoal infection, and fungal infection occur commonly during immunosuppressive therapy and can be fatal. Reactivation of a latent viral infection (e.g., hepatitis B, hepatitis C, herpes infection, or varicella) and opportunistic infections can occur with immunosuppressive therapy. Examples of opportunistic infections are JC virus-associated progressive multifocal leukoencephalopathy and polyomavirus-associated nephropathy associated with BK virus infection. Instruct patients to report signs of infection promptly. In patients who develop new infections or reactivation of viral infections, consider a dose reduction or discontinuation of mycophenolate while weighing the risk of reduced immunosuppression on the functioning allograft. Mycophenolate therapy requires an experienced clinician knowledgeable in immunosuppressant therapy and organ transplantation. The clinician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. A patient receiving mycophenolate requires a specialized care setting for medical management, acutely and chronically; facilities should be equipped and staffed with adequate laboratory and supportive medical services.[27985] [28149]

    Pregnancy

    Avoid mycophenolate use during pregnancy and use a safe, alternative treatment, if available. Use of mycophenolate during pregnancy is associated with an increased risk of first-trimester pregnancy loss (45% to 49% loss rate) and an increased risk of congenital malformations have been reported in 23% to 27% of live births. Documented congenital malformations include external ear and other facial abnormalities including cleft lip and palate and anomalies of the distal limbs, heart, esophagus, kidney, and nervous system. Educate females of reproductive potential about the reproductive risk associated with mycophenolate use and provide pregnancy prevention and planning counseling. Females of child-bearing potential should have pregnancy testing done immediately before beginning therapy and have a negative serum or urine pregnancy test (sensitivity of at least 25 milli-International Units/mL). Another pregnancy test with the same sensitivity should be done 8 to 10 days later. Additionally, discuss contraception requirements with the patient. Perform repeat pregnancy tests during routine follow-up visits. Discuss the results of all pregnancy tests with the patient. In the event of a positive pregnancy test, counsel females about whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations. For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Data on 33 mycophenolate-exposed pregnancies in 24 patients are available from the national transplantation pregnancy registry. Of the 33 pregnancies, 15 were spontaneously aborted (45%), and 18 were live births. Four of the 18 infants had structural malformations. Additional data are available from the voluntary reporting of events. Of 77 women who were exposed to mycophenolate during pregnancy, 25 had spontaneous abortions, and 14 (18%) had a malformed infant or fetus; 6 of the 14 malformed offspring had ear abnormalities. Of note, the background rate for congenital anomalies in the US is about 3%, and data from the national transplantation pregnancy registry show a rate of 4 to 5% among babies born to organ transplant recipients who use other immunosuppressive drugs. Recommended avoiding the use of mycophenolate during pregnancy and consider alternate immunosuppressive therapy. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to mycophenolate and those who become pregnant within 6 weeks of discontinuing therapy with mycophenolate; information about the registry can be obtained at www.Mycophenolatepregnancyregistry.com or by calling 1-800-617-8191.[27985] [63995] [63996]

    Lymphoma, new primary malignancy, post-transplant lymphoproliferative disorder (PTLD), skin cancer, sunlight (UV) exposure

    Patients receiving immunosuppressants are at increased risk for the development of a new primary malignancy, such as lymphoma or skin cancer. Risk of developing a malignancy appears to be related to the intensity and duration of immunosuppression rather than the specific immunosuppressant agent. Patients receiving mycophenolate should limit their sunlight (UV) exposure by wearing protective clothing, including hats, and using a broad-spectrum sunscreen with a high protection factor. Post-transplant lymphoproliferative disorder (PTLD) has been reported in 0.4% to 1% of patients who received combination immunosuppression with mycophenolate mofetil in clinical trials involving kidney, heart, and liver transplant. Majority of these cases were found to be related to an Epstein Barr Virus (EBV) infection with the greatest risk in those patients who are EBV seronegative; a population that includes young children.

    DEA CLASS

    Rx

    DESCRIPTION

    Immunosuppressant with mycophenolic acid (MPA) as active component; similar efficacy with mofetil or sodium formulas
    Used for organ rejection prophylaxis in conjunction with cyclosporine and corticosteroids
    May increase the risk of fetal harm (birth defects) and miscarriage in the first trimester of pregnancy; the Mycophenolate REMs program manages these risks

    COMMON BRAND NAMES

    CellCept, Myfortic

    HOW SUPPLIED

    CellCept/Mycophenolate Mofetil Intravenous Inj Pwd F/Sol: 500mg
    CellCept/Mycophenolate Mofetil Oral Cap: 250mg
    CellCept/Mycophenolate Mofetil Oral Pwd F/Recon: 1mL, 200mg
    CellCept/Mycophenolate Mofetil Oral Tab: 500mg
    Mycophenolate Sodium/Myfortic Oral Tab DR: 180mg, 360mg

    DOSAGE & INDICATIONS

    For kidney transplant rejection prophylaxis with or without antithymocyte induction.
    Intravenous dosage
    Adults

    1 g IV over at least 2 hours twice daily in combination with corticosteroids and cyclosporine is recommended. The initial dose should be administered within 24 hours of transplantation. There is no advantage of 3 g/day versus 2 g/day. In addition, patients receiving 2 g/day had an overall better safety profile than those patients receiving 3 g/day. According to renal transplant guidelines, mycophenolate is the suggested first-line antiproliferative agent to be used for initial maintenance immunosuppression with a calcineurin inhibitor such as tacrolimus plus or minus corticosteroids.

    Oral dosage (NOTE: The delayed-release tablets (mycophenolate sodium) and the capsules, oral suspension, and tablets (mycophenolate mofetil) are not interchangeable on a mg basis)
    Adults

    1 g PO mycophenolate mofetil or 720 mg PO mycophenolate sodium twice daily is recommended in combination with corticosteroids and cyclosporine. Doses of 3 g/day of mycophenolate mofetil did not show any advantage over 2 g/day. The initial dose should be administered as soon as possible following transplantation. According to renal transplant guidelines, mycophenolate is the suggested first-line antiproliferative agent to be used for initial maintenance immunosuppression with a calcineurin inhibitor such as tacrolimus plus or minus corticosteroids.

    Children

    600 mg/m2 PO twice daily of the oral suspension, not to exceed 2 g/day. Mycophenolate mofetil capsules may be given at dose of 750 mg PO twice daily for children with a body surface area (BSA) of 1.25 to 1.5 m2 or 1 g PO twice daily for children with a BSA > 1.5 m2. The dose for mycophenolate sodium delayed-release tablets is 400 mg/m2 PO twice daily to a maximum of 720 mg PO administered twice daily. Doses of mycophenolate sodium for children with a body surface area < 1.19 m2 cannot be given due to the limited tablet strengths available. According to renal transplant guidelines, mycophenolate is the suggested first-line antiproliferative agent to be used for initial maintenance immunosuppression with a calcineurin inhibitor such as tacrolimus plus or minus corticosteroids. Thirty-seven children were given mycophenolate mofetil for a mean of 11 months at dosages ranging from 8 to 30 mg/kg PO twice daily. All patients received cyclosporine and prednisone following sequential induction with antithymocyte globulin. The incidence of clinically significant acute rejection was 13%, which was lower than the incidence previously reported (26%—48%) at their institution. Pharmacokinetic studies suggest that pediatric doses adjusted to BSA as compared to doses adjusted for body weight result in AUCs that better approximate those of adults. In one pharmacokinetic study, concentration-time profiles of pediatric renal transplant recipients administered 600 mg/m2 PO twice daily were comparable to those in adults on 1 g PO twice daily.

    Infants >= 3 months of age

    600 mg/m2 PO twice daily of the oral suspension, not to exceed 2 g/day. Mycophenolate mofetil capsules may be given at dose of 750 mg PO twice daily for children with a body surface area (BSA) of 1.25 to 1.5 m2; the capsules or tablets may be given at a dose of 1 g PO twice daily for children with a BSA > 1.5 m2. According to renal transplant guidelines, mycophenolate is the suggested first-line antiproliferative agent to be used for initial maintenance immunosuppression with a calcineurin inhibitor such as tacrolimus plus or minus corticosteroids.

    For heart transplant rejection prophylaxis.
    NOTE: The safety and efficacy of mycophenolate in combination with sirolimus following withdrawal of initial calcineurin inhibitor therapy (cyclosporine or tacrolimus) have not been established. A study was stopped because of a higher than expected incidence of grade IIIA acute rejection in patients switched from calcineurin inhibitors in combination with mycophenolate to sirolimus in combination with mycophenolate 12 weeks after heart transplantation. Specifically, acute rejection occurred within 5 weeks of calcineurin inhibitor discontinuation in 4 of 7 patients randomized to get sirolimus, mycophenolate, and corticosteroids whereas none of the 8 patients randomized to continue getting a calcineurin inhibitor, mycophenolate, and corticosteroids had acute rejection. The study was designed to investigate whether renal function benefit could be achieved with sirolimus substitution of calcineurin inhibitor therapy.
    Intravenous dosage
    Adults

    1.5 g IV over at least 2 hours twice daily in combination with corticosteroids and cyclosporine. The first dose may be administered within 24 hours following transplantation. Guidelines state that mycophenolate or sirolimus, as tolerated, should be included in contemporary immunosuppressive regimens because of a reduced onset and progression of cardiac allograft vasculopathy as assessed by intravascular ultrasound.

    Oral dosage (mycophenolate mofetil)
    Adults

    1.5 g PO twice daily in combination with corticosteroids and cyclosporine. The initial oral dose should be administered as soon as possible following transplantation. Guidelines state that mycophenolate or sirolimus, as tolerated, should be included in contemporary immunosuppressive regimens because of a reduced onset and progression of cardiac allograft vasculopathy as assessed by intravascular ultrasound.

    For liver transplant rejection prophylaxis.
    Intravenous dosage
    Adults

    1 g IV over at least 2 hours twice daily in combination with corticosteroids and cyclosporine. The first dose may be administered within 24 hours following transplantation.

    Oral dosage (mycophenolate mofetil)
    Adults

    1.5 g PO twice daily in combination with corticosteroids and cyclosporine. The initial dose should be administered as soon as possible following transplantation.

    For the treatment of refractory acute kidney transplant rejection†.
    NOTE: The pharmacokinetic parameters of mycophenolic acid are unchanged in patients who have renal transplant rejection. No dosage change or cessation of mycophenolate is needed.
    Oral dosage (mycophenolate mofetil)
    Adults

    1.5 g PO twice daily. In patients with refractory acute renal allograft rejection, mycophenolate mofetil was compared to a 5-day course of intravenous methylprednisolone followed by a 5-day course of oral corticosteroids. Both groups also received cyclosporine and oral maintenance corticosteroids. Mycophenolate mofetil was clinically more effective than IV methylprednisolone in preserving renal allografts, however, statistical significance was not demonstrated.

    For the treatment of rheumatoid arthritis†.
    Oral dosage (mycophenolate mofetil)
    Adults

    Doses ranging from 250 mg to 2 g per day PO have been used in treating rheumatoid arthritis. Improvements in disease markers such as rheumatoid factor titers, immunoglobulin levels, and total number of T cells were all reported during therapy. The dose of 2 g/day was more effective than lower doses and pulse regimens.

    For the prophylaxis or treatment of acute graft-versus-host disease (GVHD)†.
    Oral dosage (mycophenolate mofetil)
    Adults

    In a preliminary study, 17 patients with acute GVHD after BMT and PBSCT were treated with mycophenolate 2 g/day PO in combination with cyclosporine and prednisolone. Overall grade improvement occurred in 65% of patients. Mycophenolate therapy resulted in significant dose reduction of prednisolone. Receipt of cyclosporine, methotrexate, and mycophenolate mofetil 1 g IV every 12 hours starting on day 10 after allogeneic transplantation resulted in 19 of 30 patients developing acute GVHD of grade 2 (n=14) or higher, and 9 and 2 developing limited or extensive chronic GVHD, respectively. All patients had advanced hematological cancer, and 26 received an unmanipulated PBSCT from matched unrelated donors. Over the follow-up period of 9 to 46 months, 14 patients died, 2 from acute GVHD. Most patients with positive CMV status had reactivation of their disease, but all received ganciclovir and none got an infection.

    For the treatment of lupus nephritis†.
    Oral dosage
    Adults

    2 to 3 g/day PO plus methylprednisolone 500 to 1000 mg/day IV for 3 days then prednisone 0.5 to 1 mg/kg/day (1 mg/kg/day recommended if crescents seen) tapered after a few weeks to lowest effective dose is recommended for class III/IV disease either for initial induction therapy or for induction therapy after lack of improvement with cyclophosphamide. Mycophenolate mofetil (MMF) and cyclophosphamide are considered equivalent for induction, but MMF is preferred for African Americans and Hispanics and for patients who express a major concern with fertility preservation; high-dose cyclophosphamide can cause permanent infertility in both women and men. For class V disease without proliferative changes but with nephrotic range proteinuria, MMF 2 to 3 g/day PO plus prednisone 0.5 mg/kg/day is recommended. Guidelines recommend that most patients be followed for 6 months after induction initiation before making major treatment changes unless >= 50% worsening of proteinuria or serum creatinine at 3 months exists. MMF and mycophenolic acid (MPA) are likely to be equivalent in inducing improvement with 1440 to 2160 mg total daily dose of MPA roughly equivalent to 2000 to 3000 mg total daily dose of MMF. MMF 1 to 2 g/day PO is a recommended option for maintenance therapy for those who respond to induction therapy. Fewer patients with active class III, IV, or V disease who had a clinical response to induction with either MMF or cyclophosphamide had treatment failure during maintenance therapy with MMF PO 2 g/day (16.4%) as compared with azathioprine 2 mg/kg/day PO recipients (32.4%) (HR, 0.44; 95% CI, 0.25—0.77, p = 0.003). Treatment failure was defined as death, end-stage renal disease, doubling of the serum creatinine concentration, renal flare, or rescue therapy need.

    For the treatment of atopic dermatitis†.
    Oral dosage (mycophenolate mofetil)
    Adults

    Limited data suggest 1 g PO twice daily for 4 weeks, then 500 mg PO twice daily for 4 weeks may be effective. In a pilot study, 8 patients with moderate-to-severe atopic dermatitis received mycophenolate 1 g PO twice daily for 4 weeks, then 500 mg PO twice daily for 4 weeks. Within 4 weeks, all patients experienced a significant improvement in their disease, which continued by 8 weeks. At 20 weeks of follow-up, no relapse of disease was noted in 6 of 7 patients who responded. One patient discontinued therapy after developing herpes retinitis.

    Children >= 2 years and Adolescents

    In a small trial, 30 to 50 mg/kg/day PO in 2 divided doses resulted in significant disease improvement in children and adolescents with severe, refractory atopic dermatitis. A retrospective analysis of 14 patients aged 2 to 16 years who were treated with mycophenolate mofetil (MMF) for 2 to 24 months was performed. All subjects had severe atopic dermatitis (i.e., extensive surface area affected with decreased quality of life including sleep disturbance, psychological distress, or impaired social functioning) refractory to topical therapy (i.e., potent corticosteroids and calcineurin inhibitors) and/or oral/IM corticosteroids and cyclosporine. The initial dose range was between 12 and 40 mg/kg/day PO in 2 divided doses. Upward dose titration was continued until patients achieved disease clearance or a dose of 75 mg/kg/day (maximum daily dose = 3 g) was reached. Of the 14 patients, 4 experienced complete clearance, 4 had > 90% improvement, 5 had 60% to 90% improvement, and 1 patient had < 60% improvement. The maximum benefit of therapy was achieved after 8 to 12 weeks at MMF doses of 40 to 50 mg/kg/day in younger children and 30 to 40 mg/kg/day in adolescents; these doses were representative of approximately 1200 mg/m2. Although topical therapies were continued as needed, 9 patients were able to discontinue topical corticosteroids or decrease use to <= 2 days per week within 6 weeks. Therapy was well tolerated with no reports of complications of infection and no significant changes in laboratory values.

    For the adjuvant treatment of pemphigus† (pemphigus vulgaris† and pemphigus foliaceus†).
    Oral dosage (mycophenolate mofetil)
    Adults

    35 to 45 mg/kg/day PO, or alternately, 1 gram PO twice daily. Use adjunctively with corticosteroids. Continue treatment until disease progression ceases and treatment goals are achieved. The timeframe for cessation of disease activity and remission varied widely in clinical trials due to variations in treatment regimens and outcome definitions. Using mycophenolate and corticosteroid regimens, complete lesion healing was reported at an average of 30 +/- 7 days, and complete remission (defined as the absence of lesions for 4 weeks) was reported at median 9 months (range: 1 to 13 months). Mycophenolate may be discontinued using a slow taper. In 1 clinical study, mycophenolate was more effective than azathioprine in inducing disease control. Mycophenolate may have inferior steroid-sparing effects compared to azathioprine and cyclophosphamide.

    For the treatment of myasthenia gravis†.
    Oral dosage (mycophenolate mofetil)
    Adults

    Dosage not established. 1 gram PO twice daily has been used with adjunctive corticosteroids or other non-steroidal immunosuppressive medications. Data from randomized, controlled trials do not support use; however, mycophenolate mofetil is widely used for myasthenia gravis. Some experts suggest mycophenolate mofetil use in poorly responsive disease where azathioprine is not tolerated or has failed.

    For the treatment of uveitis†.
    Oral dosage (mycophenolate mofetil)
    Adults

    1 gram PO twice daily for 6 to 41 months has been found to be an effective steroid-sparing agent in the treatment of uveitis; initiating with 500 mg PO twice daily for 1 week may decrease adverse events. Therapy with mycophenolate mofetil (MMF) was introduced in patients intolerant to high-dose steroids (> 20 mg/day) administered over at least 6 months continuously, patients with arterial hypertension and renal impairment on cyclosporine, patients with significant alterations in the differential blood count while receiving methotrexate, or patients with refractory uveitis where prednisolone had been used in combination with cyclosporine or methotrexate or both. In 92 of 106 patients studied with anterior uveitis (n = 26), intermediate uveitis (n = 51), posterior uveitis (n = 23), or panuveitis (n = 6), the number of uveitis recurrences was limited to none or 1 during the treatment period. In 95 patients, MMF was combined with prednisolone 2.5 to 10 mg/day PO. Eight patients were able to use MMF as monotherapy; 3 patients required additional immunosuppression with cyclosporine (dose not reported). Adverse events reported in the study were generally mild with gastrointestinal side effects being the most frequently reported adverse effect.

    For the treatment of psoriasis†.
    Oral dosage
    Adults

    Limited data suggest 1 to 1.5 g PO twice daily may be effective. In an open-label study of 23 patients with moderate to severe psoriasis, administration of mycophenolate mofetil (MMF) in doses of 2 to 3 g/day PO resulted in a 47% reduction in the psoriasis area severity index (PASI) at 12 weeks. Another open-label study of 11 patients with severe stable plaque psoriasis treated with MMF 1 g twice daily PO showed a 40% to 70% reduction in PASI within 3 weeks of initiating therapy.

    For the treatment of systemic lupus erythematosus (SLE)†.
    Oral dosage
    Adults

    Initially, 0.5 gram/day PO (i.e., 250 mg PO twice daily), then titrated as indicated/tolerated, is commonly used. Max: 2 grams/day PO. Consider immunosuppressive agents such as mycophenolate mofetil for patients unresponsive to antimalarials and/or glucocorticoids or for patients unable to reduce steroids below doses acceptable for chronic use.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    For mycophenolate mofetil tablets, capsules, or intravenous solution, maximum 3 g/day PO or IV. For mycophenolate sodium delayed-release tablets, maximum 1,440 mg/day PO.

    Geriatric

    For mycophenolate mofetil tablets, capsules, or intravenous solution, maximum 3 g/day PO or IV. For mycophenolate sodium delayed-release tablets, maximum 1,440 mg/day PO.

    Adolescents

    For the mycophenolate mofetil oral suspension, maximum is 1,200 mg/m2/day PO, not to exceed 2 g/day PO. For mycophenolate mofetil capsules, maximum is 1,500 mg/day PO for children with a BSA of 1.25 to less than 1.5 m2. For mycophenolate mofetil capsules and tablets, maximum is 2 g/day PO for children with a BSA of 1.5 m2 or greater. For mycophenolate sodium delayed-release tablets, maximum 800 mg/m2/day PO up to a maximum of 1,440 mg/day PO for children with a BSA greater than 1.19 m2. Delayed-release tablets are not used in children with a BSA of 1.19 m2 or less.

    Children

    For the mycophenolate mofetil oral suspension, maximum is 1,200 mg/m2/day PO, not to exceed 2 g/day PO. For mycophenolate mofetil capsules, maximum is 1,500 mg/day PO for children with a BSA of 1.25 to less than 1.5 m2. For mycophenolate mofetil capsules and tablets, maximum is 2 g/day PO for children with a BSA of 1.5 m2 or greater. For mycophenolate sodium delayed-release tablets, maximum 800 mg/m2/day PO up to a maximum of 1,440 mg/day PO for children with a BSA greater than 1.19 m2. Delayed-release tablets are not used in children with a BSA of 1.19 m2 or less.

    Infants

    3 months and older: For the mycophenolate mofetil oral suspension, maximum is 1,200 mg/m2/day PO, not to exceed 2 g/day PO. For mycophenolate mofetil capsules, maximum is 1,500 mg/day PO for children with a BSA of 1.25 to less than 1.5 m2. For mycophenolate mofetil capsules and tablets, maximum is 2 g/day PO for children with a BSA of 1.5 m2 or greater. For mycophenolate sodium delayed-release tablets, maximum 800 mg/m2/day PO up to a maximum of 1,440 mg/day PO for children with a BSA greater than 1.19 m2. Delayed-release tablets are not used in children with a BSA of 1.19 m2 or less.
    less than 3 months: Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. However, mycophenolic acid (MPA) is highly bound to albumin, and patients with severe hepatic impairment or hepatic encephalopathy may have increased free MPA concentrations.

    Renal Impairment

    CrCl < 25 ml/min: Do not exceed 1 g PO twice daily of mycophenolate mofetil if renal impairment occurs after the initial post-renal transplant period. No dosage adjustments are needed in renal transplant patients that develop delayed graft function postoperatively. There are no quantitative guidelines for mycophenolate sodium dose adjustment in patients with severe chronic renal impairment. Elevated free mycophenolic acid concentrations may be present (see Pharmacokinetics).

    ADMINISTRATION

    Only physicians experienced in the management of organ transplant recipients, including the use of immunosuppressant therapy should prescribe mycophenolate. Physician access to complete patient information for the appropriate patient follow-up during maintenance therapy is imperative.
    Complete blood count assessment is needed weekly during the first month of therapy, every other week during months 2 and 3, and monthly throughout the first year of treatment. Mycophenolate cessation or dosage reduction is needed if the ANC falls below 1300/mm3.
    NOTE regarding Females: Documentation of a negative pregnancy test should be obtained within 1 week of starting mycophenolate therapy in women of child-bearing potential. These women should use 2 effective forms of contraception before, during, and for 6 weeks following mycophenolate therapy.

    Oral Administration

    Administer on an empty stomach (i.e., 1 hour before or 2 hours after a meal). However, in stable renal transplant patients, mycophenolate mofetil (Cellcept) may be administered with food, if necessary.
    Care should be taken to avoid inhalation or direct contact with skin or mucous membranes of the dry powder from the capsules or oral suspension or reconstituted oral suspension. If such contact occurs, wash thoroughly with soap and water. If ocular contact occurs, rinse eyes thoroughly with plain water.

    Oral Solid Formulations

    Tablets and capsules: Do not crush or open mycophenolate capsules. Do not crush mycophenolate tablets.
    Delayed-release tablets: Do not crush, chew, or cut delayed-release tablets. Swallow delayed-release tablets whole to maintain the enteric coating.

    Oral Liquid Formulations

    Oral suspension:
    Shake well before each use. To ensure accurate dosage, administer with the oral dispenser provided with bottle.
    If needed, may be administered through a nasogastric tube with a minimum size of 8 French.
    Do not mix with other liquids or medications.
    During administration, avoid skin contact with the oral suspension. If contact occurs, wash the exposed area thoroughly with soap and water; if ocular contact occurs, rinse eyes with plain water.[27985]
     
    Reconstitution method for the oral suspension:
    Recommended to wear disposable gloves during reconstitution.
    Measure 94 mL of water. Add approximately half the total amount of water to the bottle and shake well for about 1 minute.
    Add remainder of the water and shake well for another minute.
    The final concentration of the oral suspension is 200 mg/mL.
    Remove the child-resistant cap and push the bottle adapter into the neck of the bottle.
    Close the bottle with the child-resistant cap. This will ensure the proper sealing to the bottle adapter in the bottle and the child-resistant status of the cap.
    Wipe the outer surface of the bottle and cap, as well as the preparation space following reconstitution of the suspension.
    Pharmacists: write the date of expiration of the constituted suspension on the bottle label. The shelf-life of the constituted suspension is 60 days.
    Storage of reconstituted suspension: Store the suspension at room temperature at 59 to 86 degrees F (15 to 30 degrees C) or under refrigeration, 36 to 46 degrees F (2 to 8 degrees C). Discard any unused portion 60 days after preparation. Do not freeze.[27985]

    Injectable Administration

    Visually inspect the solution for particulate matter or discoloration prior to administering. Discard solution if particulate matter or discoloration is observed.

    Intravenous Administration

    As an alternative to the oral formulation, intravenous mycophenolate mofetil is recommended in patients who are unable to tolerate oral medications.
    The intravenous mycophenolate mofetil may be administered for up to 14 days. Patients should be switched to the oral formulation as soon as possible.[27985]
     
    Reconstitution:
    Intravenous mycophenolate mofetil does not contain an antibacterial preservative; therefore, it should be prepared under aseptic conditions. Avoid direct contact with the prepared solution. Also, the product is vacuum-sealed and should retain a vacuum throughout its shelf life. Do not use a vial if a lack of vacuum is noted during diluent addition.
    Intravenous mycophenolate may ONLY be reconstituted and diluted with Dextrose 5% injection.
    Reconstitute each vial with 14 mL of Detrose 5% injection. Gently shake vial to dissolve the drug.
    Further dilute into Dextrose 5% injection to prepare the infusion.
    For 1 gram doses, remove the reconstituted solution from 2 vials and dilute in 140 mL Detrose 5% injection.
    For 1.5 grams doses, removed the reconstituted solution from 3 vials and dilute in 210 mL Detrose 5% injection.
    The final concentration is approximately 6 mg/mL.
    Storage of reconstituted/infusion solutions: Store at room temperature of 59 to 86 degrees F (15 to 30 degrees C). Administration should begin within 4 hours of reconstitution and dilution.[27985]
     
    Intravenous infusion:
    Administer via slow IV infusion of a period of not less than 2 hours by either a peripheral or central vein. Never administer as a rapid or bolus intravenous injection.
    During Y-site administration, mycophenolate is physically compatible and chemically stable with 0.9% sodium chloride injection for up to 4 hours.
    The infusion should not be mixed or administered concurrently via the same infusion catheter with other IV drugs or infusion admixtures. [27985] [33358]

    STORAGE

    CellCept:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Myfortic:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    GI bleeding, GI disease, GI perforation, peptic ulcer disease

    Mycophenolate should be used cautiously in patients with active gastrointestinal disease. Gastrointestinal (GI) ulceration, including gastric and duodenal ulcers, GI bleeding requiring hospitalization, and GI perforation were reported in clinical trials. Serious GI adverse effects associated with mycophenolate administration may aggravate or complicate GI disease, such as peptic ulcer disease; caution should be utilized when administering mycophenolate to this patient population.

    Renal failure, renal impairment

    Mycophenolate should be used with caution in patients with renal impairment or renal failure. Mycophenolate mofetil should not be given in doses greater than 1 gram twice daily to renal transplant patients with severe chronic impairment of the graft (GFR less than 25 mL/minute/1.73 m2). No dosage adjustments are needed in kidney transplant patients experiencing delayed graft function postoperatively, but patients should be carefully monitored. There are no data for mycophenolate mofetil use in heart or liver transplant patients with severe chronic renal impairment; use only if the potential benefits outweigh the potential risks.

    Fungal infection, herpes infection, immunosuppression, infection, progressive multifocal leukoencephalopathy, requires a specialized care setting, requires an experienced clinician, varicella, viral infection

    Immunosuppression may lead to increased susceptibility to infection. Bacterial infection, viral infection, protozoal infection, and fungal infection occur commonly during immunosuppressive therapy and can be fatal. Reactivation of a latent viral infection (e.g., hepatitis B, hepatitis C, herpes infection, or varicella) and opportunistic infections can occur with immunosuppressive therapy. Examples of opportunistic infections are JC virus-associated progressive multifocal leukoencephalopathy and polyomavirus-associated nephropathy associated with BK virus infection. Instruct patients to report signs of infection promptly. In patients who develop new infections or reactivation of viral infections, consider a dose reduction or discontinuation of mycophenolate while weighing the risk of reduced immunosuppression on the functioning allograft. Mycophenolate therapy requires an experienced clinician knowledgeable in immunosuppressant therapy and organ transplantation. The clinician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. A patient receiving mycophenolate requires a specialized care setting for medical management, acutely and chronically; facilities should be equipped and staffed with adequate laboratory and supportive medical services.[27985] [28149]

    Biliary cirrhosis, hepatic disease, hepatitis B exacerbation, hepatitis C infection

    Viral reactivation has been reported in patients with hepatitis B or hepatitis C infection. Monitoring infected patients for clinical and laboratory signs of active hepatitis B or C infection (e.g., hepatitis B exacerbation) is recommended. Patients with pre-existing hepatic disease should be approached with caution. No mycophenolate dosage adjustments are recommended for kidney transplant patients with severe hepatic parenchymal disease. However, it is not known whether dosage adjustments are needed for hepatic disease with other etiologies, such as biliary cirrhosis. No data are available for heart transplant patients with severe hepatic parenchymal disease.

    Anemia, bone marrow suppression, neutropenia, red cell aplasia

    Neutropenia and pure red cell aplasia (PRCA) can occur with the use of mycophenolate. Severe neutropenia [absolute neutrophil count (ANC) less than 500 cells/mcL] has been reported in patients who received mycophenolate mofetil 3 g daily. Onset of neutropenia with mycophenolate mofetil has been found to most frequently occur 31 to 180 days post-kidney, heart, and liver transplant. Neutropenia development may be due to mycophenolate therapy, concomitant medications, viral infections, or combination of causes. Cases of pure red cell aplasia (PRCA) have also been noted with combination therapy with mycophenolate and other immunosuppressive medications. Reversal of PRCA has occurred in some cases with dose reduction or discontinuation of mycophenolate; however, decreased immunosuppression may increase the risk of graft rejection. Patients with preexisting bone marrow suppression or anemia should be observed closely for exacerbation of these conditions. Complete blood counts should be obtained weekly during the first month, twice monthly for the second and third months, and then monthly throughout the first year of therapy. If neutropenia (i.e., ANC less than 1300 cells/mcL) or anemia develops, mycophenolate therapy should be interrupted or the dose reduced and appropriate diagnostic and patients support measures instituted. Patients should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding, or other signs of bone marrow suppression.[27985] [28149]

    Geriatric

    Geriatric patients, especially those who are receiving mycophenolate in a combination immunosuppressive regimen, may be at increased risk of certain infections (including CMV tissue disease) and possibly GI hemorrhage and pulmonary edema, as compared with younger patients. Dosage selection should be made in consideration of the patient's renal and hepatic function, which may be compromised in older patients.

    Children, infants

    Unlike for children ages 5 to 16 years of age undergoing a stable renal transplant, the safety and efficacy of mycophenolate sodium in de novo pediatric renal transplant patients have not been established. Furthermore, doses of mycophenolate sodium for children with a body surface area less than 1.19 m2 cannot be given due to the limited delayed-release tablet strengths available. Mycophenolate mofetil and mycophenolate sodium are not interchangeable on a mg-per-mg basis. Mycophenolate mofetil is indicated for allogenic kidney transplant rejection prophylaxis in infants at least 3 months of age and children. Safety and effectiveness of mycophenolate mofetil in pediatric patients following allogeneic heart or liver transplant have not been established.[28149] [27985]

    Pregnancy

    Avoid mycophenolate use during pregnancy and use a safe, alternative treatment, if available. Use of mycophenolate during pregnancy is associated with an increased risk of first-trimester pregnancy loss (45% to 49% loss rate) and an increased risk of congenital malformations have been reported in 23% to 27% of live births. Documented congenital malformations include external ear and other facial abnormalities including cleft lip and palate and anomalies of the distal limbs, heart, esophagus, kidney, and nervous system. Educate females of reproductive potential about the reproductive risk associated with mycophenolate use and provide pregnancy prevention and planning counseling. Females of child-bearing potential should have pregnancy testing done immediately before beginning therapy and have a negative serum or urine pregnancy test (sensitivity of at least 25 milli-International Units/mL). Another pregnancy test with the same sensitivity should be done 8 to 10 days later. Additionally, discuss contraception requirements with the patient. Perform repeat pregnancy tests during routine follow-up visits. Discuss the results of all pregnancy tests with the patient. In the event of a positive pregnancy test, counsel females about whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations. For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Data on 33 mycophenolate-exposed pregnancies in 24 patients are available from the national transplantation pregnancy registry. Of the 33 pregnancies, 15 were spontaneously aborted (45%), and 18 were live births. Four of the 18 infants had structural malformations. Additional data are available from the voluntary reporting of events. Of 77 women who were exposed to mycophenolate during pregnancy, 25 had spontaneous abortions, and 14 (18%) had a malformed infant or fetus; 6 of the 14 malformed offspring had ear abnormalities. Of note, the background rate for congenital anomalies in the US is about 3%, and data from the national transplantation pregnancy registry show a rate of 4 to 5% among babies born to organ transplant recipients who use other immunosuppressive drugs. Recommended avoiding the use of mycophenolate during pregnancy and consider alternate immunosuppressive therapy. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to mycophenolate and those who become pregnant within 6 weeks of discontinuing therapy with mycophenolate; information about the registry can be obtained at www.Mycophenolatepregnancyregistry.com or by calling 1-800-617-8191.[27985] [63995] [63996]

    Breast-feeding

    There are no data describing the presence of mycophenolate in human milk or the effect of the drug on milk production. No adverse events were reported among 7 infants who were breastfed for up to 14 months while the mother was taking mycophenolate. Due to the limited amount of data available regarding the use of mycophenolate during breast-feeding, an alternative drug may be considered. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for mycophenolate and any potential adverse effects on the breastfed infant from mycophenolate or the underlying maternal condition.[27985]

    Accidental exposure, ocular exposure

    Due to the potential teratogenic effects of mycophenolate, care should be taken by caregivers, health care workers, and patients to avoid accidental exposure via inhalation, skin, mucous membrane or ocular exposure. Mycophenolate tablets and capsules should not be opened or crushed. Use caution when handling and preparing oral suspensions or intravenous mycophenolate mofetil. If contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

    Phenylketonuria

    Mycophenolate mofetil oral suspension contains aspartame, a source of phenylalanine (0.56 mg/mL phenylalanine). Care should be taken if mycophenolate mofetil oral suspension is given to patients with phenylketonuria.

    Lymphoma, new primary malignancy, post-transplant lymphoproliferative disorder (PTLD), skin cancer, sunlight (UV) exposure

    Patients receiving immunosuppressants are at increased risk for the development of a new primary malignancy, such as lymphoma or skin cancer. Risk of developing a malignancy appears to be related to the intensity and duration of immunosuppression rather than the specific immunosuppressant agent. Patients receiving mycophenolate should limit their sunlight (UV) exposure by wearing protective clothing, including hats, and using a broad-spectrum sunscreen with a high protection factor. Post-transplant lymphoproliferative disorder (PTLD) has been reported in 0.4% to 1% of patients who received combination immunosuppression with mycophenolate mofetil in clinical trials involving kidney, heart, and liver transplant. Majority of these cases were found to be related to an Epstein Barr Virus (EBV) infection with the greatest risk in those patients who are EBV seronegative; a population that includes young children.

    Vaccination

    Vaccination with live or live-attenuated vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, bacillus calmette-guerin (BCG), yellow fever, varicella, and TY21a typhoid vaccines) is contraindicated during mycophenolate therapy. Patients should be advised that all vaccinations may be less effective and to discuss any vaccines with their physician before seeking any immunizations. Those undergoing immunosuppressive therapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of or in addition to vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    Activities requiring coordination and concentration, driving or operating machinery, hypotension, tremor

    Mycophenolate mofetil therapy may be associated with confusion, dizziness, somnolence, tremor, or hypotension and may impair the ability to drive or operate machinery. Patients should be cautioned to avoid driving or operating machinery or doing activities requiring coordination and concentration until they are aware of the effects of the medication.[27985]

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, prevention of pregnancy, reproductive risk, sperm donation

    Due to the increased risk of first-trimester pregnancy loss and congenital malformations, females of reproductive potential should be educated on the reproductive risk associated with mycophenolate use and prevention of pregnancy. Females of child-bearing potential should have pregnancy testing done immediately before beginning therapy and have a negative serum or urine pregnancy test (sensitivity of at least 25 milli-International Units/mL). Another pregnancy test with the same sensitivity should be done 8 to 10 days later. Additionally, discuss contraception requirements with the patient. Women of child-bearing potential who are sexually active must use effective contraception. Acceptable monotherapy options are IUD, tubal sterilization, or vasectomy of partner. Otherwise, 2 methods must be used such as 1 hormone and 1 barrier or 2 barrier methods, one of which is a male or female condom. Hormone methods include the birth control pill, transdermal patch, vaginal ring, injection, and implant. Mycophenolate may reduce the effectiveness of oral contraceptives. Contraceptive use must continue during mycophenolate receipt and for 6 weeks after stopping the drug unless the patient chooses abstinence (completely avoids heterosexual intercourse). Perform repeat pregnancy tests during routine follow-up visits. Discuss the results of all pregnancy tests with the patient. In the event of a positive pregnancy test, counsel females with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations. For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Strongly encourage women who are using mycophenolate at any time during pregnancy or who became pregnant within 6 weeks of discontinuing therapy to enroll in the Mycophenolate Pregnancy Registry by visiting www.mycophenolateREMS.com or calling 1-800-617-8191. Based on genotoxic effects observed in animal studies of mycophenolate mofetil at approximately 2.5 times human therapeutic exposures, there is a potential risk of male-mediated teratogenicity. Sexually active men with female partners should use effective, reliable contraception during treatment and for at least 90 days after treatment cessation; sperm donation should also be avoided for at least 90 days after treatment cessation.[27985] [28149]

    Gout, Lesch-Nyhan syndrome, nephrolithiasis

    Avoid use of mycophenolate in patients with hereditary deficiencies of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT), such as Lesch-Nyhan syndrome and Kelley-Seegmiller syndrome. Mycophenolate, an inosine monophosphate dehydrogenase (IMPDH) inhibitor, has been reported to cause hyperuricemia and may exacerbate symptoms associated with gout, such as acute arthritis, tophi, nephrolithiasis or urolithiasis, and renal disease including renal failure.[27985] [28149]

    Intravenous administration

    Avoid administration of mycophenolate mofetil injection by rapid or bolus intravenous administration. Rapid intravenous infusion increases the risk of local adverse reactions, including phlebitis and thrombosis.

    Blood donation

    Avoid blood donation during therapy and for at least 6 months following discontinuation of mycophenolate due to the potential administration of their blood or blood products to a pregnant woman or female of reproductive potential.

    Arthralgia, inflammation

    Acute inflammatory syndrome (AIS), a paradoxical inflammation reaction, has been reported with the use of mycophenolate products, and some cases have resulted in hospitalization. AIS is characterized by fever, arthralgia, arthritis, muscle pain and elevated inflammatory markers including, C-reactive protein and erythrocyte sedimentation rate, without evidence of infection or underlying disease recurrence. Symptoms occur within weeks to months of initiation of treatment or a dose increase. After discontinuation, improvement of symptoms and inflammatory markers are usually observed within 24 to 48 hours. Monitor patients for symptoms and laboratory parameters of AIS when starting treatment with mycophenolate products or when increasing the dosage. Discontinue treatment and consider other treatment alternatives based on the risk and benefit for the patient. Advise patients to contact their health care team if they develop fever, joint stiffness, joint pain, or muscle pains.

    ADVERSE REACTIONS

    Severe

    spontaneous fetal abortion / Delayed / 45.0-45.0
    azotemia / Delayed / 34.6-34.6
    pleural effusion / Delayed / 3.0-34.3
    ventricular tachycardia / Early / 3.0-22.0
    hyperkalemia / Delayed / 3.0-22.0
    teratogenesis / Delayed / 22.0-22.0
    ileus / Delayed / 3.0-19.9
    oliguria / Early / 3.0-19.9
    renal tubular necrosis / Delayed / 3.0-19.9
    renal failure (unspecified) / Delayed / 3.0-19.9
    coagulopathy / Delayed / 3.0-19.9
    pancytopenia / Delayed / 1.8-19.9
    pneumothorax / Early / 3.0-19.9
    pulmonary edema / Early / 3.0-19.9
    apnea / Delayed / 3.0-19.9
    pericardial effusion / Delayed / 3.0-19.9
    atrial flutter / Early / 3.0-19.9
    cardiac arrest / Early / 3.0-19.9
    pulmonary hypertension / Delayed / 3.0-19.9
    bradycardia / Rapid / 3.0-19.9
    atrial fibrillation / Early / 3.0-19.9
    arrhythmia exacerbation / Early / 3.0-19.9
    heart failure / Delayed / 3.0-19.9
    seizures / Delayed / 3.0-19.9
    hearing loss / Delayed / 3.0-19.9
    visual impairment / Early / 3.0-19.9
    ocular hemorrhage / Delayed / 3.0-19.9
    GI bleeding / Delayed / 1.0-5.4
    skin cancer / Delayed / 0.9-4.2
    thrombosis / Delayed / 4.0-4.0
    lymphoma / Delayed / 0-1.0
    post-transplant lymphoproliferative disorder (PTLD) / Delayed / 0.4-1.0
    esophageal ulceration / Delayed / Incidence not known
    hematemesis / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    red cell aplasia / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known

    Moderate

    hypertension / Early / 3.0-77.5
    peripheral edema / Delayed / 27.0-64.0
    hyperglycemia / Delayed / 3.0-46.7
    leukopenia / Delayed / 3.0-45.8
    anemia / Delayed / 3.0-43.0
    constipation / Delayed / 18.5-41.2
    hypomagnesemia / Delayed / 3.0-39.0
    thrombocytopenia / Delayed / 3.0-38.3
    hypokalemia / Delayed / 3.0-37.2
    dyspnea / Early / 3.0-36.7
    hypotension / Rapid / 3.0-32.5
    hypocalcemia / Delayed / 3.0-30.0
    chest pain (unspecified) / Early / 3.0-26.3
    elevated hepatic enzymes / Delayed / 3.0-24.9
    ascites / Delayed / 24.2-24.2
    candidiasis / Delayed / 0.6-22.4
    supraventricular tachycardia (SVT) / Early / 3.0-22.0
    sinus tachycardia / Rapid / 3.0-22.0
    melena / Delayed / 3.0-19.9
    gingival hyperplasia / Delayed / 3.0-19.9
    dysphagia / Delayed / 3.0-19.9
    esophagitis / Delayed / 3.0-19.9
    stomatitis / Delayed / 3.0-19.9
    gastritis / Delayed / 3.0-19.9
    cholangitis / Delayed / 3.0-19.9
    oral ulceration / Delayed / 3.0-19.9
    urinary incontinence / Early / 3.0-19.9
    dysuria / Early / 3.0-19.9
    hematuria / Delayed / 3.0-19.9
    bladder spasm / Early / 3.0-19.9
    urinary retention / Early / 3.0-19.9
    testicular swelling / Early / 3.0-19.9
    polycythemia / Delayed / 3.0-19.9
    lymphocele / Delayed / 3.0-19.9
    dysphonia / Delayed / 3.0-19.9
    hemoptysis / Delayed / 3.0-19.9
    hypoxia / Early / 3.0-19.9
    bullous rash / Early / 3.0-19.9
    skin ulcer / Delayed / 3.0-19.9
    orthostatic hypotension / Delayed / 3.0-19.9
    angina / Early / 3.0-19.9
    palpitations / Early / 3.0-19.9
    peripheral vasodilation / Rapid / 3.0-19.9
    jaundice / Delayed / 3.0-19.9
    cholestasis / Delayed / 3.0-19.9
    hepatitis / Delayed / 3.0-19.9
    hypervolemia / Delayed / 3.0-19.9
    hypochloremia / Delayed / 3.0-19.9
    hypercalcemia / Delayed / 3.0-19.9
    hyponatremia / Delayed / 3.0-19.9
    edema / Delayed / 3.0-19.9
    hypoglycemia / Early / 3.0-19.9
    hyperphosphatemia / Delayed / 3.0-19.9
    hypophosphatemia / Delayed / 3.0-19.9
    dehydration / Delayed / 3.0-19.9
    impaired wound healing / Delayed / 3.0-19.9
    hypercholesterolemia / Delayed / 3.0-19.9
    hyperbilirubinemia / Delayed / 3.0-19.9
    metabolic alkalosis / Delayed / 3.0-19.9
    hyperuricemia / Delayed / 3.0-19.9
    gout / Delayed / 3.0-19.9
    hyperlipidemia / Delayed / 3.0-19.9
    metabolic acidosis / Delayed / 3.0-19.9
    hypovolemia / Early / 3.0-19.9
    myasthenia / Delayed / 3.0-19.9
    osteoporosis / Delayed / 3.0-19.9
    impotence (erectile dysfunction) / Delayed / 3.0-19.9
    diabetes mellitus / Delayed / 3.0-19.9
    Cushing's syndrome / Delayed / 3.0-19.9
    hypothyroidism / Delayed / 3.0-19.9
    psychosis / Early / 3.0-19.9
    peripheral neuropathy / Delayed / 3.0-19.9
    depression / Delayed / 3.0-19.9
    hallucinations / Early / 3.0-19.9
    delirium / Early / 3.0-19.9
    hypertonia / Delayed / 3.0-19.9
    confusion / Early / 3.0-19.9
    cataracts / Delayed / 3.0-19.9
    amblyopia / Delayed / 3.0-19.9
    conjunctivitis / Delayed / 3.0-19.9
    phlebitis / Rapid / 4.0-4.0
    neutropenia / Delayed / 2.0-3.6
    colitis / Delayed / Incidence not known
    meningitis / Delayed / Incidence not known
    BK virus-associated nephropathy / Delayed / Incidence not known
    immunosuppression / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    blurred vision / Early / Incidence not known

    Mild

    abdominal pain / Early / 24.7-62.5
    nausea / Early / 19.0-54.5
    headache / Early / 16.1-54.3
    fever / Early / 21.4-52.3
    insomnia / Early / 23.5-52.3
    diarrhea / Early / 21.4-51.3
    back pain / Delayed / 3.0-46.6
    asthenia / Delayed / 35.4-43.3
    leukocytosis / Delayed / 22.4-40.5
    infection / Delayed / 0.6-37.2
    vomiting / Early / 20.0-33.9
    tremor / Early / 3.0-33.9
    cough / Delayed / 3.0-31.1
    dizziness / Early / 3.0-28.7
    anxiety / Delayed / 3.0-28.4
    sinusitis / Delayed / 3.0-26.0
    anorexia / Delayed / 25.3-25.3
    dyspepsia / Early / 19.0-22.5
    rash / Early / 3.0-22.1
    paresthesias / Delayed / 20.8-20.8
    gingivitis / Delayed / 3.0-19.9
    gastroesophageal reflux / Delayed / 3.0-19.9
    flatulence / Early / 3.0-19.9
    throat irritation / Early / 3.0-19.9
    increased urinary frequency / Early / 3.0-19.9
    nocturia / Early / 3.0-19.9
    rhinitis / Early / 3.0-19.9
    influenza / Delayed / 3.0-19.9
    pharyngitis / Delayed / 3.0-19.9
    chills / Rapid / 3.0-19.9
    hyperventilation / Early / 3.0-19.9
    epistaxis / Delayed / 3.0-19.9
    nasal congestion / Early / 3.0-19.9
    hiccups / Early / 3.0-19.9
    pruritus / Rapid / 3.0-19.9
    ecchymosis / Delayed / 3.0-19.9
    alopecia / Delayed / 3.0-19.9
    petechiae / Delayed / 3.0-19.9
    vesicular rash / Delayed / 3.0-19.9
    acne vulgaris / Delayed / 3.0-19.9
    pallor / Early / 3.0-19.9
    syncope / Early / 3.0-19.9
    weight loss / Delayed / 3.0-19.9
    polydipsia / Early / 3.0-19.9
    weight gain / Delayed / 3.0-19.9
    arthralgia / Delayed / 3.0-19.9
    drowsiness / Early / 3.0-19.9
    myalgia / Early / 3.0-19.9
    pelvic pain / Delayed / 3.0-19.9
    fatigue / Early / 3.0-19.9
    muscle cramps / Delayed / 3.0-19.9
    malaise / Early / 3.0-19.9
    hirsutism / Delayed / 3.0-19.9
    vertigo / Early / 3.0-19.9
    emotional lability / Early / 3.0-19.9
    agitation / Early / 3.0-19.9
    xerostomia / Early / 3.0-19.9
    tinnitus / Delayed / 3.0-19.9
    lacrimation / Early / 3.0-19.9
    otalgia / Early / 3.0-19.9

    DRUG INTERACTIONS

    Acyclovir: (Moderate) Coadministration of mycophenolate mofetil and acyclovir to healthy volunteers resulted in no significant change in mycophenolic acid concentrations or AUC. However, the glucuronide metabolite of mycophenolate (MPAG) and acyclovir AUCs were increased 10.6% and 21.9%, respectively. Because MPAG and acyclovir concentrations are increased in the presence of renal impairment, the potential exists for the two drugs to compete for tubular secretion, further increasing the concentration of both drugs in patients renal dysfunction.
    Amoxicillin: (Moderate) Drugs that alter the gastrointestinal flora may interact with mycophenolate by disrupting enterohepatic recirculation. Amoxicillin;Clavulanic Acid may decrease normal GI flora levels and thus lead to less free mycophenolate available for absorption. The effect of amoxicillin without clavulantic acid on mycophenolate kinetics is unclear.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Drugs that alter the gastrointestinal flora may interact with mycophenolate by disrupting enterohepatic recirculation. Amoxicillin;Clavulanic Acid may decrease normal GI flora levels and thus lead to less free mycophenolate available for absorption. The effect of amoxicillin without clavulantic acid on mycophenolate kinetics is unclear.
    Amoxicillin; Clavulanic Acid: (Moderate) Drugs that alter the gastrointestinal flora may interact with mycophenolate by disrupting enterohepatic recirculation. Amoxicillin;Clavulanic Acid may decrease normal GI flora levels and thus lead to less free mycophenolate available for absorption. The effect of amoxicillin without clavulantic acid on mycophenolate kinetics is unclear.
    Antacids: (Major) Coadministration of mycophenolate mofetil with antacids decreases the bioavailability of mycophenolate mofetil. Aluminum/magnesium hydroxide antacids decrease the AUC of mycophenolic acid by about 17% when given as mycophenolate mofetil. Decreased absorption of mycophenolate (possible chelation) is the likely etiology for reduced systemic exposure. If antacids and mycophenolate need to be used together, separate administration times are recommended (do not give simultaneously).
    Anticoagulants: (Moderate) Mycophenolate may causes thrombocytopenia and increase the risk for bleeding. Agents which may lead to an increased incidence of bleeding in patients with thrombocytopenia include anticoagulants.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Coadministration of mycophenolate mofetil with antacids decreases the bioavailability of mycophenolate mofetil. Aluminum or magnesium hydroxide antacids decrease AUC of mycophenolic acid by about 17%. Avoid administration of mycophenolate mofetil with agents that may decrease its absorption.
    Azathioprine: (Major) Concomitant use of mycophenolate and azathioprine is not recommended, as both drugs inhibit purine metabolism. Because azathioprine is an immunosuppressant with myelosuppressive actions, additive affects may be seen with other immunosuppressant agents (e.g., mycophenolate). Also, the drug combination has not been studied clinically.
    Basiliximab: (Minor) Because mycophenolate mofetil is an immunosuppressant, additive effects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies including lymphoma and leukemia, myelodysplastic syndromes, and lymphoproliferative disorders. The risk is related to the intensity and duration of immunosuppression rather than the specific agents.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Coadministration of mycophenolate mofetil, norfloxacin, and metronidazole is not recommended. Administration of all 3 drugs significantly reduced the systemic exposure of mycophenolic acid. Specifically, as compared with the value obtained with mycophenolate mofetil monotherapy, the mean mycophenolic acid AUC (0 to 48 h) was decreased by 33% when 1 gram of mycophenolate mofetil was administered to healthy patients who had received 4 days of both norfloxacin and metronidazole. The mycophenolic acid systemic exposure was slightly reduced when mycophenolate mofetil was coadministered with either norfloxacin or metronidazole. The mean (+/-SD) mycophenolic acid AUC (0 to 48 h) was 56.2 (+/-24) mcgh/ml after mycophenolate mofetil monotherapy, 48.3 (+/-24) mcgh/ml after coadministration with norfloxacin, and 42.7 (+/-23) mcgh/ml after coadministration with metronidazole. Addtionally, potential QT prolongation has been reported in limited case reports with metronidazole; therefore, it should be used cautiously when adminstered with norfloxacin, which has a possible risk for QT prolongation and TdP.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Coadministration of mycophenolate mofetil, norfloxacin, and metronidazole is not recommended. Administration of all 3 drugs significantly reduced the systemic exposure of mycophenolic acid. Specifically, as compared with the value obtained with mycophenolate mofetil monotherapy, the mean mycophenolic acid AUC (0 to 48 h) was decreased by 33% when 1 gram of mycophenolate mofetil was administered to healthy patients who had received 4 days of both norfloxacin and metronidazole. The mycophenolic acid systemic exposure was slightly reduced when mycophenolate mofetil was coadministered with either norfloxacin or metronidazole. The mean (+/-SD) mycophenolic acid AUC (0 to 48 h) was 56.2 (+/-24) mcgh/ml after mycophenolate mofetil monotherapy, 48.3 (+/-24) mcgh/ml after coadministration with norfloxacin, and 42.7 (+/-23) mcgh/ml after coadministration with metronidazole. Addtionally, potential QT prolongation has been reported in limited case reports with metronidazole; therefore, it should be used cautiously when adminstered with norfloxacin, which has a possible risk for QT prolongation and TdP.
    Calcium Carbonate: (Major) Coadministration of mycophenolate mofetil with antacids decreases the bioavailability of mycophenolate mofetil. Aluminum or magnesium hydroxide antacids decrease AUC of mycophenolic acid by about 17%. Avoid administration of mycophenolate mofetil with agents that may decrease its absorption.
    Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Coadministration of mycophenolate mofetil with antacids decreases the bioavailability of mycophenolate mofetil. Aluminum or magnesium hydroxide antacids decrease AUC of mycophenolic acid by about 17%. Avoid administration of mycophenolate mofetil with agents that may decrease its absorption.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Coadministration of mycophenolate mofetil with antacids decreases the bioavailability of mycophenolate mofetil. Aluminum or magnesium hydroxide antacids decrease AUC of mycophenolic acid by about 17%. Avoid administration of mycophenolate mofetil with agents that may decrease its absorption.
    Calcium Carbonate; Risedronate: (Major) Coadministration of mycophenolate mofetil with antacids decreases the bioavailability of mycophenolate mofetil. Aluminum or magnesium hydroxide antacids decrease AUC of mycophenolic acid by about 17%. Avoid administration of mycophenolate mofetil with agents that may decrease its absorption.
    Calcium Carbonate; Simethicone: (Major) Coadministration of mycophenolate mofetil with antacids decreases the bioavailability of mycophenolate mofetil. Aluminum or magnesium hydroxide antacids decrease AUC of mycophenolic acid by about 17%. Avoid administration of mycophenolate mofetil with agents that may decrease its absorption.
    Carboplatin: (Contraindicated) Concurrent use of carboplatin with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Cefuroxime: (Minor) Drugs that alter the gastrointestinal flora may interact with mycophenolate by disrupting enterohepatic recirculation. Cefuroxime may decrease normal GI flora levels and thus lead to less free mycophenolate available for absorption.
    Charcoal: (Major) Activated charcoal binds bile acids and can interrupt enterohepatic recirculation of mycophenolic acid and thus, reduce mycophenolic acid systemic exposure. Concurrent use of any drug that may interfere with enterohepatic recirculation of MPA such as activated charcoal is not recommended.
    Chlorambucil: (Minor) Chlorambucil is known to cause myelosuppression, which may lead to neutropenia related side effects. Concurrent use of chlorambucil with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cholestyramine: (Major) Avoid administration of mycophenolate mofetil with cholestyramine. Coadministration of mycophenolate mofetil with cholestyramine decreases the bioavailability of mycophenolate mofetil. Cholestyramine decreases the AUC of mycophenolate by about 40%.
    Ciprofloxacin: (Moderate) Drugs that alter the gastrointestinal flora such as ciprofloxacin may interact with mycophenolate by disrupting enterohepatic recirculation. Mycophenolic acid (MPA) is converted to an inactive phenolic glucuronide, MPA glucuronide (MPAG), which undergoes enterohepatic recirculation. Bacteria that express beta-glucuronidase cleave the glucuronide conjugate, which results in liberation of MPA. Normally, two peaks of MPA occur after administration. The first peak occurs after absorption of MPA, and the second peak occurs after cleavage of MPAG by beta-glucuronidase producing bacteria. Antibiotics with activity against such bacteria can reduce the second peak in MPA serum concentrations; interference of MPAG hydrolysis may lead to less MPA available for absorption. A reduction in predose MPA concentrations was noted after ciprofloxacin (500 mg PO twice daily) was administered to 24 patients taking mycophenolate mofetil and tacrolimus for renal transplant prophylaxis. The predose concentration was obtained before the morning dose and 12 hours after the evening mycophenolate dose. The mean MPA predose concentration at baseline was 2.3 mg/L. After 3 days of ciprofloxacin, the mean concentration was 1.5 mg/L. With 7 days of ciprofloxacin, the predose concentration was 1.2 mg/L, and 3 days after the 7-day course, the mean concentration was not significantly different from baseline (2.6 mg/L). A reduction in the MPA predose concentration was also noted among 21 patients who took a 14-day course of ciprofloxacin. Interestingly, the predose concentration rose with continued ciprofloxacin use. The mean predose concentration was 2.3 mg/L at baseline, 1.4 mg/L after 3 days of the antibiotic, 1.5 mg/L after 7 days of the antibiotic, and 1.9 mg/L after 14 days of the antibiotic. In addition to a rise in predose concentrations with continued antibiotic use, some patients did not have a large reduction in their predose concentration. Nine of 44 patients who got a 7-day course of ciprofloxacin or another antibiotic, and 7 of 38 patients who got a 14-day course with either ciprofloxacin or another antibiotic had MPA concentrations on day 3 of antibiotics that were greater than 80% of baseline values. Also, the predose MPA concentration may not accurately represent changes in overall MPA exposure. No deaths, graft losses, acute rejection episodes, or gastrointestinal disturbances were noted throughout the study. A mycophenolate dose increase in response to reduced MPA predose concentrations could cause toxicity in some patients. Of note, the impact of an antibiotic that reduces enterohepatic recirculation of MPA on patients also taking cyclosporine needs investigation; cyclosporine also reduces the enterohepatic recirculation of MPA.
    Colesevelam: (Major) Bile acid sequestrants can interrupt enterohepatic recirculation and thus, reduce mycophenolic acid systemic exposure. Concurrent use of colesevelaml and mycophenolate mofetil is not recommended.
    Colestipol: (Major) Bile acid sequestrants, such as colestipol can interrupt enterohepatic recirculation and thus, reduce mycophenolic acid systemic exposure. The AUC of mycophenolic acid when given as mycophenolate mofetil is decreased by about 40% when take with cholestyramine. Concurrent use of a bile acid sequestrant, such as colestipol, or any drug that may interfere with enterohepatic recirculation of MPA is not recommended.
    Cyclosporine: (Moderate) Because mycophenolate mofetil is an immunosuppressant, additive affects may be seen with other immunosuppressives, such as cyclosporine.
    Daclizumab: (Minor) Because mycophenolate mofetil is an immunosuppressant, additive effects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies including lymphoma and leukemia, myelodysplastic syndromes, and lymphoproliferative disorders. The risk is related to the intensity and duration of immunosuppression rather than the specific agents. Of note, tacrolimus is a potent inhibitor of UDP-glucuronosyl transferase (UDPGT). As mycophenolic acid is metabolized by UDPGT, increased concentrations of mycophenolic acid would be anticipated (see Mechanism of Action).
    Daunorubicin: (Major) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Desogestrel; Ethinyl Estradiol: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and mycophenolate together with caution as both drugs can cause metabolic acidosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Doxorubicin: (Major) Concurrent use of doxorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Drospirenone; Ethinyl Estradiol: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs like mycophenolate. Although documentation is lacking, use of echinacea with immunosuppressants is not recommended by some resources. Additionally, a variety of substances may alter mycophenolate concentrations, and it is unclear if Echinacea would alter mycophenolate exposure. While the overall effect on mycophenolate concentrations is not known, if combined use is necessary, monitoring of mycophenolate concentrations may be prudent.
    Ethinyl Estradiol: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Ethinyl Estradiol; Norgestrel: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Etonogestrel; Ethinyl Estradiol: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Ferric Maltol: (Major) Conflicting information has been reported regarding coadministration of mycophenolate and iron salts. Due to the discrepant findings and study differences, additional data are needed to clarify the potential interaction between iron salts and MMF. Until more information is available, avoid concurrent administration of mycophenolate mofetil and oral iron salts, including polysaccharide-iron complex, if possible.
    Food: (Minor) Administration of mycophenolate with food can affect absorption of the drug. The extent of absorption is not affected, but the maximum serum concentration is lowered as compared with the fasting state. Patients need to be told to take mycophenolate either 1 hour before or 2 hours after eating.
    Fosphenytoin: (Moderate) The pharmacokinetics of mycophenolate mofetil, an immunosuppressive agent, are not affected by phenytoin. However, mycophenolate decreases the protein binding of phenytoin by roughly 3%, which may increase unbound phenytoin concentrations.
    Ganciclovir: (Moderate) The systemic concentration of ganciclovir and the glucuronide metabolite of mycophenolate are increased in the presence of renal impairment. Concomitant use may result in competition for tubular secretion, which could further increase the systemic exposures. Thus, adverse effects from increased serum concentrations may be anticipated; blood cell count monitoring is recommended.
    Infliximab: (Moderate) Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
    Iron Salts: (Major) Conflicting information has been reported regarding coadministration of mycophenolate and iron salts. Due to the discrepant findings and study differences, additional data are needed to clarify the potential interaction between iron salts and MMF. Until more information is available, avoid concurrent administration of mycophenolate mofetil and oral iron salts, including polysaccharide-iron complex, if possible.
    Iron: (Major) Conflicting information has been reported regarding coadministration of mycophenolate and iron salts. Due to the discrepant findings and study differences, additional data are needed to clarify the potential interaction between iron salts and MMF. Until more information is available, avoid concurrent administration of mycophenolate mofetil and oral iron salts, including polysaccharide-iron complex, if possible.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with mycophenolate results in elevated mycophenolate serum concentrations. Patients receiving this drug combination should be closely monitored for mycophenolate-related adverse reactions and toxicities. The mechanism of the interaction is not completely understood, but is expected to be due to UDP-glucosyltransferase (UGT) metabolism; both isavuconazole, the active moiety of isavuconazonium, and mycophenolate are substrates for UGT, and isavuconazole may also inhibit UGT.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Use of both rifampin and mycophenolate mofetil is not recommended unless the benefit outweighs the risk. Concurrent administration to a heart-lung transplant patient led to a a 67% decrease in mycophenolic acid exposure after correction for dose.
    Isoniazid, INH; Rifampin: (Major) Use of both rifampin and mycophenolate mofetil is not recommended unless the benefit outweighs the risk. Concurrent administration to a heart-lung transplant patient led to a a 67% decrease in mycophenolic acid exposure after correction for dose.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Drugs that alter the gastrointestinal flora may interact with mycophenolate by disrupting enterohepatic recirculation. Amoxicillin;Clavulanic Acid may decrease normal GI flora levels and thus lead to less free mycophenolate available for absorption. The effect of amoxicillin without clavulantic acid on mycophenolate kinetics is unclear.
    Lanthanum Carbonate: (Major) Oral compounds known to interact with antacids, like mycophenolate, should not be taken within 2 hours of dosing with lanthanum carbonate. If these agents are used concomitantly, space the dosing intervals appropriately. Monitor serum concentrations and clinical condition.
    Levonorgestrel; Ethinyl Estradiol: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Live Vaccines: (Contraindicated) Do not administer live vaccines to mycophenolate recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving mycophenolate. At least 2 weeks before initiation of mycophenolate therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Mycophenolate recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Melphalan Flufenamide: (Minor) Bone marrow suppression is the most significant toxicity associated with melphalan in most patients. The bone marrow depressant effects of melphalan can be potentiated by concurrent or sequential administration of other bone marrow depressants and immunosuppressives.
    Melphalan: (Minor) Bone marrow suppression is the most significant toxicity associated with melphalan in most patients. The bone marrow depressant effects of melphalan can be potentiated by concurrent or sequential administration of other bone marrow depressants and immunosuppressives.
    Mestranol; Norethindrone: (Moderate) Anti-infectives which disrupt the normal GI flora, including mycophenolate, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    Metronidazole: (Moderate) Coadministration of mycophenolate mofetil, norfloxacin, and metronidazole is not recommended. Administration of all 3 drugs significantly reduced the systemic exposure of mycophenolic acid. Specifically, as compared with the value obtained with mycophenolate mofetil monotherapy, the mean mycophenolic acid AUC (0 to 48 h) was decreased by 33% when 1 gram of mycophenolate mofetil was administered to healthy patients who had received 4 days of both norfloxacin and metronidazole. The mycophenolic acid systemic exposure was slightly reduced when mycophenolate mofetil was coadministered with either norfloxacin or metronidazole. The mean (+/-SD) mycophenolic acid AUC (0 to 48 h) was 56.2 (+/-24) mcgh/ml after mycophenolate mofetil monotherapy, 48.3 (+/-24) mcgh/ml after coadministration with norfloxacin, and 42.7 (+/-23) mcgh/ml after coadministration with metronidazole. Addtionally, potential QT prolongation has been reported in limited case reports with metronidazole; therefore, it should be used cautiously when adminstered with norfloxacin, which has a possible risk for QT prolongation and TdP.
    Micafungin: (Moderate) Leukopenia, neutropenia, anemia, and thrombocytopenia have been associated with micafungin. In theory, patients who are taking immunosuppressive agents such as mycophenolate concomitantly with micafungin may have additive risks for infection or other side effects. However, the manufacturer has listed no particular precautions for co-use of micafungin with these medications. Concurrent administration of micafungin and mycophenolate mofetil did not alter the pharmacokinetic parameters of micafungin. Furthermore, there was no effect of a single or multiple doses of micafungin on mycophenolate mofetil pharmacokinetic parameters.
    Natalizumab: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with mycophenolate.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Conflicting information has been reported regarding coadministration of mycophenolate and iron salts. Due to the discrepant findings and study differences, additional data are needed to clarify the potential interaction between iron salts and MMF. Until more information is available, avoid concurrent administration of mycophenolate mofetil and oral iron salts, including polysaccharide-iron complex, if possible. (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Norethindrone; Ethinyl Estradiol: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Conflicting information has been reported regarding coadministration of mycophenolate and iron salts. Due to the discrepant findings and study differences, additional data are needed to clarify the potential interaction between iron salts and MMF. Until more information is available, avoid concurrent administration of mycophenolate mofetil and oral iron salts, including polysaccharide-iron complex, if possible. (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Norfloxacin: (Moderate) Coadministration of mycophenolate mofetil, norfloxacin, and metronidazole is not recommended. Administration of all 3 drugs significantly reduces the systemic exposure of mycophenolic acid.
    Norgestimate; Ethinyl Estradiol: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Drugs that alter the gastrointestinal flora may interact with mycophenolate by disrupting enterohepatic recirculation. Amoxicillin;Clavulanic Acid may decrease normal GI flora levels and thus lead to less free mycophenolate available for absorption. The effect of amoxicillin without clavulantic acid on mycophenolate kinetics is unclear.
    Omeprazole; Sodium Bicarbonate: (Major) Coadministration of mycophenolate mofetil with antacids decreases the bioavailability of mycophenolate mofetil. Aluminum or magnesium hydroxide antacids decrease AUC of mycophenolic acid by about 17%. Avoid administration of mycophenolate mofetil with agents that may decrease its absorption.
    Phenytoin: (Moderate) Mycophenolic acid is more than 98% bound to albumin. Administration of mycophenolate mofetil decreased the protein binding of phenytoin by 3%. Monitor patients receiving mycophenolate with highly protein bound drugs, such as phenytoin for changes in clinical status.
    Platelet Inhibitors: (Moderate) Platelet Inhibitors inhibit platelet aggregation and should be used cautiously in patients with thrombocytopenia, as mycophenolate can also cause thrombocytopenia.
    Polysaccharide-Iron Complex: (Major) Conflicting information has been reported regarding coadministration of mycophenolate and iron salts. Due to the discrepant findings and study differences, additional data are needed to clarify the potential interaction between iron salts and MMF. Until more information is available, avoid concurrent administration of mycophenolate mofetil and oral iron salts, including polysaccharide-iron complex, if possible.
    Probenecid: (Minor) Probenecid is a known inhibitor of renal tubular secretion, and the inactive metabolite, MPAG undergoes tubular secretion. Increased MPAG concentrations can cause increased mycophenolic acid systemic exposure and thus, adverse effects. Patients receiving both drugs should be monitored carefully.
    Probenecid; Colchicine: (Minor) Probenecid is a known inhibitor of renal tubular secretion, and the inactive metabolite, MPAG undergoes tubular secretion. Increased MPAG concentrations can cause increased mycophenolic acid systemic exposure and thus, adverse effects. Patients receiving both drugs should be monitored carefully.
    Proton pump inhibitors: (Moderate) Concomitant administration of proton pump inhibitors (PPIs) with mycophenolate mofetil (Cellcept) appears to reduce MPA exposure AUC-12h (25.8 +/- 6.4 mg/L x h with omeprazole vs. 33.3 +/- 11.5 mg//L x h without omeprazole); however, the interaction does not appear to exist with mycophenolate sodium delayed-release tablets (Myfortic). Reduced systemic exposure of MPA after mycophenolate mofetil in the presence of a PPI appears to be due to impaired absorption of mycophenolate mofetil which may occur because of incomplete dissolution of mycophenolate mofetil in the stomach at elevated pH. The clinical significance of reduced MPA exposure is unknown; however patients should be evaluated periodically if mycophenolate mofetil is administered with a PPI. Of note, MPA concentrations appear to be reduced in the initial hours after mycophenolate mofetil receipt but increase later in the dosing interval because of enterohepatic recirculation. A second peak in the concentration-time profile of MPA is observed 612 hours after dosing due to enterohepatic recirculation. For example, the 12-hour plasma concentrations of MPA were similar among patients who received mycophenolate mofetil with or without omeprazole. The biphasic plasma concentration-time course of MPA due to extensive enterohepatic circulation hampers therapeutic drug monitoring of MPA. Drug exposure as measured by AUC-12h is the best estimator for the clinical effectiveness of mycophenolate, but measurement of full-dose interval MPA AUC-12h requires collection of multiple samples over a 12-hour period; MPA predose concentrations correlate poorly with MPA AUC-12h. The interaction does not appear to exist with Mycophenolate sodium (Myfortic).
    Rifampin: (Major) Use of both rifampin and mycophenolate mofetil is not recommended unless the benefit outweighs the risk. Concurrent administration to a heart-lung transplant patient led to a a 67% decrease in mycophenolic acid exposure after correction for dose.
    Salicylates: (Moderate) Mycophenolic acid is more than 98% bound to albumin. Concurrent use of mycophenolate with salicylates can decrease the protein binding of mycophenolic acid resulting in an increase in the free fraction of MPA. Patients should be observed for increased clinical effects from mycophenolate as well as additive adverse effects.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Mycophenolate mofetil may not have any influence on the ovulation suppressing action of ethinyl estradiol. However, it is recommended that hormonal contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.
    Sevelamer: (Major) Do not administer sevelamer simultaneously with mycophenolate mofetil. The mean mycophenolic acid Cmax was decreased by 36%, and the mean mycophenolic acid AUC(0-12h) was decreased by 26% when sevelamer and mycophenolate mofetil were coadministered in adult and pediatric patients. If sevelamer and mycophenolate are needed, administer sevelamer 2 hours after mycophenolate mofetil intake in order to minimize the impact on the absorption of mycophenolic acid.
    Sirolimus: (Minor) Because mycophenolate mofetil is an immunosuppressant, additive effects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies including lymphoma and leukemia, myelodysplastic syndromes, and lymphoproliferative disorders. The risk is related to the intensity and duration of immunosuppression rather than the specific agents. Of note, tacrolimus is a potent inhibitor of UDP-glucuronosyl transferase (UDPGT). As mycophenolic acid is metabolized by UDPGT, increased concentrations of mycophenolic acid would be anticipated (see Mechanism of Action).
    Sodium Bicarbonate: (Major) Coadministration of mycophenolate mofetil with antacids decreases the bioavailability of mycophenolate mofetil. Aluminum or magnesium hydroxide antacids decrease AUC of mycophenolic acid by about 17%. Avoid administration of mycophenolate mofetil with agents that may decrease its absorption.
    Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Major) Conflicting information has been reported regarding coadministration of mycophenolate and iron salts. Due to the discrepant findings and study differences, additional data are needed to clarify the potential interaction between iron salts and MMF. Until more information is available, avoid concurrent administration of mycophenolate mofetil and oral iron salts, including polysaccharide-iron complex, if possible.
    Sulfinpyrazone: (Minor) Concomitant use of sulfinpyrazone and mycophenolate mofetil theoretically may lead to severe adverse effects from mycophenolate including vomiting, abdominal pain, and pyrosis. Competition for renal tubular secretion may have resulted in increased MPAG concentrations and thus, increased MPA systemic exposure
    Tacrolimus: (Minor) Tacrolimus is a potent inhibitor of UDP-glucuronosyl transferase. As mycophenolic acid is metabolized by UDPGT, increased concentrations of mycophenolic acid would be anticipated.
    Telmisartan: (Moderate) Concommitant administration of telmisartan and mycophenolate resulted in a 30% decrease in mycophenolic acid (MPA) concentration. Telmisartan enhances PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which results in enhanced UGT1A9 expression and activity. MPA is primarily metabolized by glucuronyl transferase to the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. Monitor patients receiving these drugs concurrently for signs or symptoms of organ rejection.
    Telmisartan; Amlodipine: (Moderate) Concommitant administration of telmisartan and mycophenolate resulted in a 30% decrease in mycophenolic acid (MPA) concentration. Telmisartan enhances PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which results in enhanced UGT1A9 expression and activity. MPA is primarily metabolized by glucuronyl transferase to the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. Monitor patients receiving these drugs concurrently for signs or symptoms of organ rejection.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Concommitant administration of telmisartan and mycophenolate resulted in a 30% decrease in mycophenolic acid (MPA) concentration. Telmisartan enhances PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which results in enhanced UGT1A9 expression and activity. MPA is primarily metabolized by glucuronyl transferase to the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. Monitor patients receiving these drugs concurrently for signs or symptoms of organ rejection.
    Temozolomide: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Theophylline, Aminophylline: (Minor) Mycophenolic acid is highly protein bound. Administration of mycophenolate mofetil decreases the protein binding of aminophylline. Monitor patients receiving mycophenolate with highly protein bound drugs, such as aminophylline for changes in clinical status. (Minor) Mycophenolic acid is highly protein bound. Administration of mycophenolate mofetil decreases the protein binding of theophylline. Monitor patients receiving mycophenolate with highly protein bound drugs, such as theophylline for changes in clinical status.
    Tobramycin: (Minor) Drugs that alter the gastrointestinal flora may interact with mycophenolate by disrupting enterohepatic recirculation. Tobramycin may decrease normal GI flora levels and thus lead to less free mycophenolate available for absorption.
    Valacyclovir: (Moderate) Valacyclovir, a prodrug of acyclovir, when added to a regimen of MMF, cyclosporine, and prednisolone caused neutropenia. The acyclovir trough concentration was 4.5 mg/L, which is in the upper range of the EC(50) for antiviral activity. Cessation of valacyclovir led to immediate recovery of the neutrophil count and an increased concentration of mycophenolic acid (from 0.85 to 1.93 mg/L). Coadministration of mycophenolate mofetil (MMF) and acyclovir to healthy volunteers resulted in no significant change in mycophenolic acid concentrations or AUC. However, the systemic exposure of the glucuronide metabolite of mycophenolate (MPAG) and of acyclovir was increased 10.6% and 21.9%, respectively. Blood cell count monitoring is recommended. The risk of adverse effects (e.g., leukopenia) from concomitant use may be greater in patients with renal impairment, as MPAG and acyclovir concentrations undergo renal tubular secretion. The potential exists for the two drugs to compete for tubular secretion, which could further increase the concentration of both drugs in patients with renal dysfunction.
    Valganciclovir: (Moderate) Because the glucuronide metabolite of mycophenolate and ganciclovir concentrations are increased in the presence of renal impairment, the potential exists for the two drugs to compete for tubular secretion, further increasing the concentration of both drugs.

    PREGNANCY AND LACTATION

    Pregnancy

    Avoid mycophenolate use during pregnancy and use a safe, alternative treatment, if available. Use of mycophenolate during pregnancy is associated with an increased risk of first-trimester pregnancy loss (45% to 49% loss rate) and an increased risk of congenital malformations have been reported in 23% to 27% of live births. Documented congenital malformations include external ear and other facial abnormalities including cleft lip and palate and anomalies of the distal limbs, heart, esophagus, kidney, and nervous system. Educate females of reproductive potential about the reproductive risk associated with mycophenolate use and provide pregnancy prevention and planning counseling. Females of child-bearing potential should have pregnancy testing done immediately before beginning therapy and have a negative serum or urine pregnancy test (sensitivity of at least 25 milli-International Units/mL). Another pregnancy test with the same sensitivity should be done 8 to 10 days later. Additionally, discuss contraception requirements with the patient. Perform repeat pregnancy tests during routine follow-up visits. Discuss the results of all pregnancy tests with the patient. In the event of a positive pregnancy test, counsel females about whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations. For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Data on 33 mycophenolate-exposed pregnancies in 24 patients are available from the national transplantation pregnancy registry. Of the 33 pregnancies, 15 were spontaneously aborted (45%), and 18 were live births. Four of the 18 infants had structural malformations. Additional data are available from the voluntary reporting of events. Of 77 women who were exposed to mycophenolate during pregnancy, 25 had spontaneous abortions, and 14 (18%) had a malformed infant or fetus; 6 of the 14 malformed offspring had ear abnormalities. Of note, the background rate for congenital anomalies in the US is about 3%, and data from the national transplantation pregnancy registry show a rate of 4 to 5% among babies born to organ transplant recipients who use other immunosuppressive drugs. Recommended avoiding the use of mycophenolate during pregnancy and consider alternate immunosuppressive therapy. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to mycophenolate and those who become pregnant within 6 weeks of discontinuing therapy with mycophenolate; information about the registry can be obtained at www.Mycophenolatepregnancyregistry.com or by calling 1-800-617-8191.[27985] [63995] [63996]

    Due to the increased risk of first-trimester pregnancy loss and congenital malformations, females of reproductive potential should be educated on the reproductive risk associated with mycophenolate use and prevention of pregnancy. Females of child-bearing potential should have pregnancy testing done immediately before beginning therapy and have a negative serum or urine pregnancy test (sensitivity of at least 25 milli-International Units/mL). Another pregnancy test with the same sensitivity should be done 8 to 10 days later. Additionally, discuss contraception requirements with the patient. Women of child-bearing potential who are sexually active must use effective contraception. Acceptable monotherapy options are IUD, tubal sterilization, or vasectomy of partner. Otherwise, 2 methods must be used such as 1 hormone and 1 barrier or 2 barrier methods, one of which is a male or female condom. Hormone methods include the birth control pill, transdermal patch, vaginal ring, injection, and implant. Mycophenolate may reduce the effectiveness of oral contraceptives. Contraceptive use must continue during mycophenolate receipt and for 6 weeks after stopping the drug unless the patient chooses abstinence (completely avoids heterosexual intercourse). Perform repeat pregnancy tests during routine follow-up visits. Discuss the results of all pregnancy tests with the patient. In the event of a positive pregnancy test, counsel females with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations. For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Strongly encourage women who are using mycophenolate at any time during pregnancy or who became pregnant within 6 weeks of discontinuing therapy to enroll in the Mycophenolate Pregnancy Registry by visiting www.mycophenolateREMS.com or calling 1-800-617-8191. Based on genotoxic effects observed in animal studies of mycophenolate mofetil at approximately 2.5 times human therapeutic exposures, there is a potential risk of male-mediated teratogenicity. Sexually active men with female partners should use effective, reliable contraception during treatment and for at least 90 days after treatment cessation; sperm donation should also be avoided for at least 90 days after treatment cessation.[27985] [28149]

    MECHANISM OF ACTION

    Mechanism of Action: Mycophenolic acid (MPA) inhibits lymphocyte purine synthesis by reversibly and noncompetitively inhibiting the enzyme, inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo synthesis of purines and is the rate-limiting step in converting inosine monophosphate (IMP) to guanosine monophosphate (GMP), an important intermediate in the synthesis of lymphocyte DNA, RNA, proteins, and glycoproteins. T- and B-lymphocytes, unlike other cells, can not synthesize GMP sufficiently through the salvage pathway. The cytostatic effect on lymphocytes is thus, greater than the effect on other cell types. Mycophenolic acid's inhibition of IMPDH prevents the formation of GMP, which decreases guanosine triphosphate (GTP) and deoxy-GTP that are necessary substrates for DNA, RNA, and protein synthesis. Subsequently, MPA inhibits lymphocyte proliferation and the formation of adhesion molecules in response to antigenic or mitogenic stimulation. Adhesion molecules are usually present on the surface of activated T cells.In comparison with other immunosuppressive agents, MPA has several potential advantages. First, in vitro studies show that MPA blocks the secondary antibody responses mediated by memory B cells. Secondly, in contrast to azathioprine and methotrexate which have a nonselective effect on DNA synthesis in all cell types, MPA has a selective effect on lymphocyte proliferation. Next, MPA is not incorporated into DNA and does not cause chromosome breaks. Lastly, MPA inhibits the proliferation of human B lymphocyte cell lines transformed by the Epstein-Barr virus (EBV); cyclosporine inhibits T-cell mediated surveillance of EBV-transformed B lymphocytes but does not block B-lymphocyte replication. The overall effects of MPA as revealed by clinical studies show that MPA is at least as potent as azathioprine when used in combination with cyclosporine and corticosteroids for immunosuppression.

    PHARMACOKINETICS

    Mycophenolate mofetil (MMF) is administered orally or intravenously whereas mycophenolate sodium is only administered orally. After both intravenous and oral administration, MMF is immediately hydrolyzed to form free mycophenolic acid (MPA), the active compound. The principal route of MPA metabolism is glucoronyl transferase to form the primary, inactive metabolite, mycophenolic acid glucuronide (MPAG). The minor acyl glucuronide metabolite has similar pharmacologic activity as compared with MPA. At steady state, the AUC ratio of MPA:MPAG:acyl glucuronide is approximately 1:24:0.28. During enterohepatic recirculation, MPAG is converted to MPA, which results in a secondary peak in plasma MPA concentration 6 to 12 hours post-dose. MPA is 97%, and MPAG is 82% bound to plasma albumin. Patients with kidney impairment or delayed kidney graft function may have higher MPAG concentrations resulting in decreased protein binding and increased free MPA due to competition for binding sites between MPAG and MPA. An increase in free MPA concentrations may occur under conditions of decreased protein binding, such as uremia, hepatic failure, and hypoalbuminemia.[27985] [28149]
     
    Therapeutic drug monitoring (TDM) for mycophenolate is not currently recommended, as there is an absence of needed data. Data from 1 study suggest the possible utility of TDM. Patients received cyclosporine, prednisone, and MMF to a predefined target MPA AUC concentrations (16.1, 32.2, or 60.6 mcg*hr/mL) for 6 months after renal transplantation. The number of patients with biopsy-proven acute rejection in the low, intermediate, and high target MPA AUC groups was 14 of 51, 7 of 47, and 6 of 52, respectively. The numbers of patients with premature withdrawal from the study due to adverse events in the 3 respective groups were 4 of 51, 11 of 47, and 23 of 52.[28143]

    Oral Route

    Mycophenolate is available as mycophenolate mofetil (MMF) capsules, tablets, and oral suspension and mycophenolic acid (MPA) delayed-release tablets.
    MMF capsules, tablets, and oral suspension: After oral administration, MMF is immediately hydrolyzed to form free MPA, the active compound. Mean peak plasma concentrations of MPA were found to occur within approximately 0.5 to 2 hours following single-dose administration to healthy volunteers and after multiple dose administration to kidney, heart, or liver transplant patients. Compared to intravenous MMF, oral MMF had a mean absolute oral bioavailability of 94%. Four 250 mg MMF capsules have been shown to be bioequivalent to two 500 mg MMF tablets. Also, 5 mL of MMF oral suspension (200 mg/mL) is bioequivalent to four 250 mg MMF capsules. The mean MPA AUC was 20% to 41% lower and Cmax was 32% to 44% lower during the early post-transplant period (less than 40 days post-transplant) compared to the late transplant period (i.e., 3 to 6 months post-transplant). Presence of food decreased the MPA Cmax by 40% but did not affect the AUC at doses of 1.5 g twice daily in kidney transplant patients. In healthy volunteers, the mean volume of distribution was 3.6 L/kg. Mean elimination half-life is 17.9 hours. Ninety-three percent of the orally administered dose is excreted in the urine, 87% of which is as MPAG, and 6% in the feces.[27985]
    MPA delayed-release tablets: The release of MPA from enteric-coated mycophenolate sodium does not occur under acidic conditions (pH less than 5) but in the neutral pH conditions of the intestines. Peak plasma concentrations of MPA are attained between 1.5 and 2.75 hours after administration of mycophenolate sodium. Gastrointestinal absorption of MPA following administration to stable renal transplant patients on cyclosporine was 93%, and MPA had an absolute bioavailability of 72%. Myfortic displays linear and dose-proportional pharmacokinetics over a dosage range of 360 mg to 2,160 mg. Mean elimination half-life for MPA is 8 to 16 hours and MPAG is 13 to 17 hours. Approximately 3% of the MPA dose is eliminated unchanged in the urine and over 60% of the dose as MPAG. Although the systemic exposure of MPA is similar when taken with or without food, peak concentrations are decreased by 33% and Tmax delayed by 5 hours.[28149]

    Intravenous Route

    After intravenous administration, mycophenolate mofetil (MMF) is immediately hydrolyzed to form free mycophenolic acid (MPA), the active compound. During intravenous infusions, the parent drug MMF can be measured; however, 5 minutes after the infusion is stopped the MMF concentration is not detectable. The mean elimination half-life of MPA is approximately 16.6 hours following intravenous administration. Compared to oral administration, the mean AUC was 24% higher following intravenous administration of 1 g twice daily for 5 days in kidney transplant patients.