Mycophenolate mofetil, (Cellcept) start with 250 mg PO bid x 5 days, then 500 mg PO bid x 5 days, then 1 gm PO bid, onset of action: 2-4 mo, max effect 5-6 mo

Mechanism of action:

• Inhibits lymphocyte purine synthesis by selective inhibition of enzyme inosine-5 monophosphate dehydrogenase.

• This is an essential step with the de novo synthesis of the guanosine mononucleotide.  Because B and T cells, like many other cells, rely almost exclusively on de novo synthesis, mycophenolate can selectively interfere with lymphocyte function.

• Axonal G1 and S phases of cell cycle.T and B cell suppression by interfering with purine biosynthesis and disrupt the antigen processing and presentation (RNA synthesis dependent), as well as proliferation and differentiation of immunocompetent cells (DNA and RNA synthesis dependent).

Uses:

• In a large, double-blind, placebo controlled trials in prednisone treated patients MMF did not show efficacy at 3 months and 9 months respectively.  Still other data indicate that mycophenolate may be an effective treatment for MG.  A larger retrospective study showed that the steroid sparing effect became most evident in the second and third years of treatment, a finding that may explain the lack of a steroid sparing effect in the randomized trial. 

• Mycophenolate is used as an adjunct therapy for resistant inflammatory myopathy, likely due to its overall ease of use.  It is also been used with some success as an adjunct therapy and CIDP.

• Mycophenolate mofetil is considered a third line agent and MG, CIDP, dermatomyositis, polymyositis, and IMNM (as an add-on to prednisone, when methotrexate is not tolerated).Myasthenia gravis, systemic and nonsystemic vasculitic neuropathy, sarcoid neuropathy, myositis, immune mediated necrotizing myopathy, and Isaac's syndrome.

AE: 

• Diarrhea, abdominal pain and discomfort, nausea, fever, leukopenia, peripheral edema, little or no renal and hepatotoxicity.  

• Increased risk of lymphoma, immunosuppression, teratogenicity risk, pancytopenia. 

• Adverse hematological effects seen in doses exceeding 2000 mg a day.  Rare reports of lymphoma or lymphoproliferative.  PML reported in patients on MMF for SLE and organ transplantation

Treatment regimen:

• Several recent, uncontrolled studies have reported efficacy, and some also suggest that mycophenolate mofetil has a quicker mode of onset than azathioprine, particularly at 1 g bid. Begin with 500 mg bid, and if the drug is tolerated, increase the dose to 1 g bid after 4 weeks. If diarrhea occurs, try 1 to 1.5 g/day. Other side effects include gastrointestinal hemorrhage and perforation; increased susceptibility to infection is a consideration with all of these agents, particularly in combination with corticosteroids. Neutropenia is generally associated with doses of 2 g/day or greater. Mycophenolate mofetil eventually may replace azathioprine as the first-line immunosuppressive drug in patients with MG, but further studies are required.

• It should be taken 1 hour before meals or 2-3 hours following meals in order to maximize absorption. 

• Therapeutic latency and myasthenia gravis: 9 to 11 weeks with maximal effect seen in 6 months to 1 year.

• It is renally excreted and and renal insufficiency dose must be reduced but not less than 1 g a day.

• Monitor blood tests weekly for the first month of treatment, twice monthly for the second and third months, and then monthly thereafter.

• Used sometimes as an adjuvant drug in combination with cyclosporine and prednisone.

• Preferred drug for elderly myasthenics.

• Randomized trials of mycophenolate mofetil did not show improved clinical outcomes when the drug was added to prednisone in patients with myasthenia gravis.

• Myfortic .  Mycophenolic acid or mycophenolate sodium (Myfortic) is an alternative preparation.  182 - 360 mg enteric-coated tablets to lessen GI side effects.  Daily dose: 720 -1440 mg/day in 2 divided doses.  The conversion ratio of CellCept to Myfortic is 1000mg: 720 mg.   

• Tapering MMF: Tapering mycophenolate mofetil appears safe after years of disease stability. Hobson-Webb and colleagues showed a success rate of 67%, with greater success in those with greater than 5 years of medical stability and those that underwent a slow taper of approximately 500 mg/year. There were no differences related to antibody status, duration of myasthenia gravis (MG) before treatment, severity of MG before treatment, previous thymectomy, or rates of previous immunosuppressive failure. Taper failures were most commonly noted approximately 10 months after dose reduction and when reducing the daily dose to less than 1000 mg.

Initial: 500 mg twice daily; maintenance: 1-1.5 gm twice daily

2-12 mo 

Diarrhea, nausea, abdominal pain; myelosuppression, peripheral edema, fever, infection, malignancy, and teratogenicity

CBC: weekly × 4, then monthly for 1 year and semiannually thereafter; consider skin cancer screening exam annually