Version May 2024
INTRODUCTION — Mycophenolate (also known as mycophenolic acid [MPA]), a powerful inhibitor of lymphocyte proliferation, has been used since the early 1990s for the prevention of acute allograft rejection. Mycophenolate is also widely used as a glucocorticoid-sparing agent for the treatment of patients with a variety of rheumatic diseases, including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory myopathies, and some systemic vasculitides.
General principles regarding the use of mycophenolate for the treatment of rheumatic diseases and the side effects associated with its use are discussed in this topic review. The use of mycophenolate in specific autoimmune disorders, organ transplantation, and other conditions with presumed immunologic bases (eg, Crohn disease) is presented separately. (See appropriate topic reviews.)
PHARMACOLOGY
Pharmacokinetics — Mycophenolic acid (MPA) is available in two formulations: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). MMF is a prodrug that was developed to improve the bioavailability of MPA. EC-MPS has the potential to reduce the incidence of adverse gastrointestinal (GI) effects, principally diarrhea, by delaying release of MPA into the small intestine instead of the stomach. Both formulations are rapidly hydrolyzed to the active metabolite MPA [1,2].
The bioavailability of both formulations is approximately 90 percent but is significantly reduced when taken with a high-fat meal. Accordingly, both formulations should be taken on an empty stomach to increase absorption. Alternatively, to improve GI tolerability, the MMF formulation may instead be taken with meals at consistent times each day.
A dose of 720 mg EC-MPS is therapeutically equivalent to 1000 mg of MMF [2-4]. However, the two formulations should not be interchanged indiscriminately because the rate and extent of absorption of these two products is not equivalent. In some patients, it is necessary to convert from MMF (CellCept) to EC-MPS (Myfortic) to improve GI tolerability. When this occurs, added monitoring of clinical effect is warranted.
Additional information on the efficacy and safety of the different formulations can be found elsewhere. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
Only free MPA is believed to be pharmacologically active [5]. In general, 97 percent of MPA is bound to albumin. This percentage is also decreased in the setting of hyperbilirubinemia [6]. Levels of free MPA, therefore, may be increased in patients with hepatic dysfunction or hypoalbuminemia.
More than 90 percent of active MPA is metabolized by glucuronidation to 7-O-glucuronide (MPAG), an inactive metabolite that is excreted in the urine and feces [7]. The mean serum half-life of MPA when given as MMF is approximately 18 hours; MPA half-life when delivered as EC-MPS is approximately 12 hours [8,9].
It is uncertain whether MMF dose adjustments are necessary in patients with liver dysfunction [10]. Measurement of free and total MPA in the serum as a guide to dose adjustment has been advocated by some investigators [11,12] but is not a common practice.
Dose adjustments are necessary in the setting of severe chronic renal failure. Renal failure prolongs the half-life of the inactive metabolite MPAG but not of MPA itself, and accumulation of MPAG may account for increased GI upset when MMF is used in patients on peritoneal- or hemodialysis [13].
Initial dose, dose titration, and dose adjustment in organ dysfunction is reviewed elsewhere. (See 'Drug dose' below.)
Mechanism of action — Activated lymphocytes are dependent upon the de novo synthesis of purine nucleotides. The conversion of inosine monophosphate (IMP) to guanosine monophosphate is catalyzed by IMP dehydrogenase. MPA reversibly inhibits IMP dehydrogenase, leading to decreased B- and T-cell proliferation and decreased antibody production. MPA may lead to immunosuppression through other mechanisms as well, including the induction of apoptosis of activated T lymphocytes and the inhibition of adhesion molecule expression and lymphocyte recruitment [14].
Two properties of MPA explain the relatively specific inhibition of lymphocyte proliferation. First, IMP dehydrogenase catalyzes the rate-limiting step in purine nucleotide synthesis in lymphocytes but not in other cell types. Second, MPA preferentially binds the type II isoform of IMP dehydrogenase, which is expressed by activated lymphocytes [15].
CONTRAINDICATIONS
Pregnancy — Mycophenolate increases the risk of first-trimester pregnancy loss and congenital malformations, including cleft lip and palate, as well as anomalies of the distal limbs, heart, esophagus, and kidneys. This medication should be avoided during pregnancy. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Mycophenolate mofetil'.)
Lactation — Mycophenolate is excreted into breast milk and is contraindicated in women who are breastfeeding. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Mycophenolate mofetil'.)
Active infection — Mycophenolate therapy should be avoided in the presence of active systemic or potentially life-threatening infection given the effects on the immune system, as well as the potential risk of causing neutropenia. (See 'Bone marrow suppression' below and 'Infection' below.)
PRETREATMENT CONSIDERATIONS
Drug interactions — Mycophenolate mofetil (MMF) is metabolized by cytochrome 3A4/5 and probably by cytochrome 2C8 [16]. There are, therefore, a number of significant drug interactions that should be considered prior to initiation of treatment with mycophenolate [17].
●Antacids, mineral supplements (eg, magnesium, calcium, iron), and sevelamer can decrease absorption of mycophenolate by 17 to 37 percent [17]. Separating these by at least two hours from the oral mycophenolate dose can minimize this interaction.
●Bile acid sequestrants (eg, cholestyramine) bind mycophenolate metabolites in the gastrointestinal (GI) tract and can decrease mycophenolic acid (MPA) levels by 40 percent. Use of bile acid sequestrants should be avoided in patients receiving mycophenolate [8,18].
●Proton pump inhibitors (eg, pantoprazole, lansoprazole) can decrease absorption of the MMF by formulation 25 percent or more [19]. Enteric-coated mycophenolate sodium (EC-MPS) appears less likely to interact.
●Rifampin use of several days leads to significant decreases (as much as twofold) in serum concentrations of MPA (active metabolite of MMF and EC-MPS) [20].
●Acyclovir, valacyclovir, and probenecid can increase serum concentrations of MPA.
●Mycophenolate may decrease serum concentrations of hormonal contraceptives, including pills, patches, and vaginal rings. Women of childbearing potential should use an alternative or additional form of contraception due to the risk of pregnancy loss and fetal malformations associated with use of mycophenolate during pregnancy [8,9].
The toxicity of other medications such as azathioprine (which also induces bone marrow suppression) can be increased when used with mycophenolate. Coadministration of these agents should be avoided when possible.
Specific interactions with other medications may be determined using the drug interactions program provided by UpToDate.
Immunization requirements — We advise that all patients receive appropriate immunizations prior to treatment with mycophenolate (table 1). (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
Laboratory and clinical testing — We typically perform the following studies prior to MMF therapy:
●Complete blood count (CBC) with differential
●Liver function tests, albumin
●Creatinine, urinalysis
●Serologic testing for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection
●Screening for latent tuberculosis with tuberculin skin test (TST) or interferon-gamma release assays (IGRAs)
There are case reports of reactivation of tuberculosis after transitioning from azathioprine to MMF [21,22], although, given the rarity of these reports, it is difficult to conclude that the risk of reactivation of tuberculosis with MMF is higher than the risk associated with comparable immunosuppression.
The data regarding the impact of MMF on the reactivation of viral hepatitis are even murkier. There is evidence that, in vitro, MPA suppresses both the expression of hepatitis B surface antigen and HBV viral replication [23]. An open-label cohort study indicated that treatment with MMF was associated with a lower risk of HBV reactivation than treatment with high-dose glucocorticoids alone [24], implying that MMF may exert a protective effect against HBV reactivation. Similarly, there are both in vitro [25] and in vivo [26] data indicating that MMF may inhibit HCV replication.
Prophylaxis for Pneumocystis jirovecii — It has been well established that MMF has antimicrobial properties against Pneumocystis jirovecii (P. jirovecii) pneumonia (formerly called Pneumocystis carinii pneumonia or PCP) [27] (see 'Pneumocystis jirovecii' below). Therefore, the use of PCP prophylaxis among patients who are receiving treatment with MMF is somewhat controversial and is largely driven by the underlying disease. Among patients who have received renal transplantation, for example, the use of PCP prophylaxis is not standard [28]. There are case reports, however, of patients who have received MMF in combination with low-dose glucocorticoids who have developed PCP, and, in patients who have an underlying rheumatic disease that has a predisposition towards developing PCP infections (eg, systemic lupus erythematosus [SLE], idiopathic inflammatory myopathies) or a history of other opportunistic infections (eg, cytomegalovirus [CMV]), the use of PCP prophylaxis may be prudent.
MYCOPHENOLATE DOSE AND ADMINISTRATION
Formulations — Oral mycophenolate is available in two different formulations: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). These formulations have different absorption characteristics and should not be used interchangeably (see 'Pharmacokinetics' above). Use of EC-MPS (Myfortic) results in delayed absorption but potentially improved gastrointestinal (GI) tolerability (less diarrhea). To convert from MMF (CellCept) 1000 mg every 12 hours, switch to EC-MPS (Myfortic) 720 mg every 12 hours [2].
We typically initiate therapy with MMF because of greater clinical experience with this compound. For patients who are intolerant of MMF, one could consider transitioning to EC-MPS, although many patients who are intolerant to MMF will also not tolerate EC-MPS and may need to be transitioned to another agent.
Drug dose — The target dose of MMF for the treatment of most rheumatic diseases is generally between 1.5 and 3 grams daily, in divided doses. Most patients will tolerate MMF if the total daily dose is divided in two doses. The maximum dose of MMF in patients with chronic renal failure (ie, a glomerular filtration rate less than 25 mL/minute) should not exceed 2 grams daily. Patients with end-stage kidney disease, already at risk for anemia because of erythropoietin deficiency, must be monitored closely [29]. No formal guidelines exist for dose adjustment of EC-MPS, although the same concerns apply.
Starting with lower doses at first (eg, 500 mg daily for several days) may improve a patient's GI tolerance of MMF. After several days, the dose of MMF may typically be increased to the target dose over a few weeks.
Monitoring — A complete blood count (CBC) should be performed one to two weeks after the start of therapy. If there is no evidence of bone marrow suppression at that time, it is our practice to check CBCs every six to eight weeks.
ADVERSE EFFECTS — With appropriate patient selection and monitoring, the side effect profile of mycophenolate mofetil (MMF) is generally at least as good as those of most immunomodulatory agents used in rheumatic disease. MMF is clearly safer than cyclophosphamide in most circumstances. Thiopurine methyltransferase deficiency, an important potential concern when prescribing azathioprine (see "Pharmacology and side effects of azathioprine when used in rheumatic diseases"), is not an issue with MMF. Gastrointestinal (GI) symptoms and dose-related bone marrow suppression are the most commonly observed adverse effects, but these usually resolve with dose adjustments.
Gastrointestinal — Persistent diarrhea is the most common adverse reaction to mycophenolate and is often the main reason some patients do not tolerate it. In one study of 85 patients receiving MMF for the treatment of psoriasis, nearly 75 percent initially had GI symptoms, including nausea, diarrhea, and abdominal cramping [30]. These symptoms were tolerated better with time and rarely required cessation of the drug. After several years of therapy, the prevalence of GI symptoms had declined to approximately 20 percent, and the symptoms were minor in these patients.
GI side effects are also frequent in patients being treated for systemic lupus erythematosus (SLE) and are responsible for drug discontinuation in up to 30 percent of patients [31]. Daily doses as low as 125 mg may cause intolerable symptoms. In some patients, complaints improve with increasing the number of divided daily doses (while maintaining the same total daily dose). Other patients may require reductions in the total dose. Enteric-coated mycophenolate sodium (EC-MPS) is another option for some patients [32].
The histopathologic changes associated with GI symptoms have not been characterized in rheumatic disease patients treated with MMF but have been studied in a retrospective series of solid organ transplant recipients who had undergone diagnostic colonic biopsies for such symptoms [33]. Abnormal findings were observed in 69 percent of 32 patients with GI symptoms on MMF (500 to 1000 mg twice daily), including changes suggestive of inflammatory bowel disease (28 percent), graft-versus-host disease (19 percent), ischemia (3 percent), or self-limited colitis (16 percent). By comparison, only one of eight patients not on MMF had significant changes, a mild graft-versus-host disease-like pattern.
Bone marrow suppression — Cytopenias are major potential concerns and require regular monitoring. Complete blood counts (CBCs) should be performed after the first one to two weeks of therapy and then once every six to eight weeks thereafter if no cytopenia is noted. (See 'Monitoring' above.)
Infection — There are no large studies examining the incidence of infections in patients with rheumatic illness treated with MMF. The existing studies [34] are too small to permit generalizations. There are, however, large numbers of patients with solid organ transplants who have been treated with MMF. Studying these patients has led to the following observations.
Pneumocystis jirovecii — Although it is somewhat counterintuitive, there is some reason to believe that MMF exerts a protective effect against P. jirovecii. In animal models, MMF demonstrates an antimicrobial effect against this organism [35]. Moreover, in four randomized, controlled trials of MMF in renal allograft transplant recipients, none of the 1068 patients who received MMF (compared with 10 of the 563 patients who did not) developed P. jirovecii infections [36].
Viral infections — In one study of heart transplant recipients, a higher incidence of herpes zoster was associated with MMF [37]. Of greater concern, however, is the risk of cytomegalovirus (CMV) infection. A higher incidence of tissue-invasive CMV infections has been documented in clinical trials of renal allograft recipients who received MMF as part of their immunosuppression regimens [38,39]. This same increase in incidence of tissue-invasive CMV infections has not been observed in trials of patients treated with MMF who have received liver, heart, or lung transplants [40-42].
Patients with rheumatic illness treated with MMF are presumably at risk for developing the same opportunistic infections seen in patients with solid organ transplants. These patient populations, however, may not be directly comparable. Patients with SLE, for example, are inherently more susceptible to infection than the general population. This may be due to a number of factors, including defects in chemotaxis, impaired phagocytosis, decreased immune complex clearance, abnormal complement levels, and mutations in mannose-binding lectin and Fc receptors [43]. Moreover, previous exposure to cytotoxic agents (such as cyclophosphamide) may have a prolonged effect on the immune system [44]. Even after the white blood cells in the peripheral circulation return to normal levels, there may be a delay in recovery of functional CD4 T lymphocytes [45]. These factors may make patients with rheumatic illnesses susceptible to a spectrum of opportunistic infections that is different from that of solid organ transplant patients treated with MMF.
Progressive multifocal leukoencephalopathy — There are case reports of progressive multifocal leukoencephalopathy (PML) occurring in patients who have received treatment with MMF. In a retrospective cohort study of over 32,000 renal transplant recipients in the United States, the incidence of PML was 14.4 cases per 100,000 person-years versus zero cases among the non-MMF users, but the difference was not statistically significant [46].
Neoplasia — Patients who receive immunosuppressive agents are at increased risk of developing malignant neoplasms, including lymphomas. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Lymphoproliferative disorders' and "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Prognosis'.)
Among the patients who develop lymphoid malignancies, many are taking a combination of immunosuppressive agents, and therefore the risk attributable to a single agent is uncertain. However, one reported case of central nervous system lymphoma that occurred during mycophenolate monotherapy for myasthenia gravis suggests that MMF use alone may confer an increased risk of lymphoid neoplasia [47]. MMF prescribing information includes a specific warning about lymphoma and other neoplasms as a result of immunosuppression. For patients with a prior history of lymphoma, MMF should be avoided if other therapeutic options exist. For patients with a history of solid tumor malignancies, the specific risks associated with comparable immunosuppressive regimens are less clear.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)
SUMMARY
●Mycophenolate (also known as mycophenolic acid [MPA]) is available in two different formulations: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). These formulations have different absorption characteristics and should not be used interchangeably. EC-MPS has the potential to reduce the incidence of adverse gastrointestinal (GI) effects, principally diarrhea, by delaying release of MPA into the small intestine instead of the stomach. Both formulations are rapidly hydrolyzed to the active metabolite MPA. To convert from MMF (CellCept) 1000 mg every 12 hours, switch to EC-MPS (Myfortic) 720 mg every 12 hours. (See 'Pharmacokinetics' above and 'Formulations' above.)
●MPA acts by reversibly inhibiting inosine monophosphate (IMP) dehydrogenase, leading to decreased B- and T-cell proliferation and to decreased antibody production, which is due to the dependence of activated lymphocytes upon de novo synthesis of purine nucleotides. MMF may lead to immunosuppression through other mechanisms as well. (See 'Mechanism of action' above.)
●Contraindications to the use of mycophenolate include pregnancy, lactation, and active systemic or potentially life-threatening infections. (See 'Contraindications' above.)
●Prior to treatment with mycophenolate, we routinely address the following (see 'Pretreatment considerations' above):
•Interaction of mycophenolate with other drugs (see 'Drug interactions' above)
•Appropriate immunizations prior to treatment (see 'Immunization requirements' above)
•Baseline laboratory testing including complete blood count (CBC) with differential, serum creatinine levels, urinalysis, liver function tests, hepatitis B and C virus serologies, and screening for latent tuberculosis (see 'Laboratory and clinical testing' above)
•Assess the need for Pneumocystis jirovecii (P. jirovecii) pneumonia (formerly called Pneumocystis carinii pneumonia or PCP) prophylaxis (see 'Prophylaxis for Pneumocystis jirovecii' above)
●The target dose of MMF for the treatment of most rheumatic diseases is generally between 1.5 and 3 grams daily, in divided doses. The maximum dose of MMF in patients with chronic renal failure (ie, a glomerular filtration rate less than 25 mL/minute) should not exceed 2 grams daily. A CBC should be performed one to two weeks after the start of therapy. If there is no evidence of bone marrow suppression at that time, it is our practice to check CBCs every six to eight weeks. (See 'Drug dose' above and 'Monitoring' above.)
●With appropriate patient selection and monitoring, the side effect profile of MMF is generally at least as good as those of most immunomodulatory agents used in rheumatic disease. GI symptoms and dose-related bone marrow suppression are the most commonly observed adverse effects, but these usually resolve with dose adjustments. The major categories of side effects include the following (see 'Adverse effects' above):
•GI symptoms (see 'Gastrointestinal' above)
•Bone marrow suppression (see 'Bone marrow suppression' above)
•Infection (see 'Infection' above)
•Neoplasia (see 'Neoplasia' above)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Stone, MD, who contributed to an earlier version of this topic review.
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