What is mycophenolate?

What is Mycophenolate?

Mycophenolate is a prescription immunosuppressive medication used primarily to prevent organ rejection in kidney, heart, and liver transplant recipients, and it works by selectively inhibiting T and B lymphocyte proliferation through blockade of a critical enzyme in the purine synthesis pathway. 1

Mechanism of Action

Mycophenolate functions as a prodrug that is converted to its active form, mycophenolic acid (MPA), which selectively and reversibly inhibits inosine monophosphate dehydrogenase (IMPDH), a pivotal enzyme in the de novo pathway of guanosine nucleotide synthesis 2, 3. This mechanism preferentially affects T and B lymphocytes because these cells are critically dependent on this pathway for proliferation, unlike other cell types that can use salvage pathways 3, 4.

Beyond simple lymphocyte inhibition, MPA produces several additional immunosuppressive effects 3:

• Decreases B and T cell proliferation
• Induces T cell apoptosis
• Suppresses dendritic cell function and IL-1 production
• Reduces production of adhesion molecules necessary for inflammatory cell trafficking
• Diminishes inducible nitric oxide synthase (iNOS) and oxidative stress

Available Formulations

Mycophenolate exists in two clinically equivalent formulations 3:

Mycophenolate mofetil (MMF): The original formulation, completely metabolized to MPA after oral administration, with rapid and complete absorption 2, 5.

Enteric-coated mycophenolate sodium (EC-MPS): Developed to delay MPA release until the small intestine, theoretically reducing upper gastrointestinal side effects 2. The dose equivalency is 720 mg EC-MPS twice daily = 1000 mg MMF twice daily 3.

However, the gastrointestinal tolerability advantage of EC-MPS over MMF remains controversial and has not been definitively established 3.

Clinical Applications

Primary Indication: Transplant Rejection Prevention

Mycophenolate is FDA-approved for preventing rejection in kidney, heart, and liver transplant recipients, used in combination with cyclosporine (or tacrolimus) and corticosteroids 1, 2. In liver transplantation, tacrolimus is the calcineurin inhibitor of choice in nearly 90% of patients, and mycophenolate has become the most commonly used antimetabolite, replacing azathioprine 2.

The evidence supporting mycophenolate over azathioprine comes from large randomized trials showing significantly lower rates of treatment failure (34.8-38.2% with MMF versus 50% with azathioprine at 6 months) and biopsy-proven rejection (15.9-19.7% with MMF versus 35.5% with azathioprine) 6.

Secondary Indications

Mycophenolate is used off-label for multiple autoimmune conditions 3:

• Systemic autoimmune rheumatic disease-associated interstitial lung disease (conditionally recommended as first-line)
• Autoimmune hepatitis (second-line therapy after steroid and azathioprine failure)
• Steroid-refractory acute graft-versus-host disease
• Immune thrombocytopenia
• Lupus nephritis
• Psoriasis and atopic dermatitis

Major Adverse Effects and Black Box Warnings

Critical Safety Concerns

Pregnancy (FDA Black Box Warning): Mycophenolate causes severe teratogenic and embryocidal effects, including cranial, facial, and cardiac abnormalities 7, 1. Women of childbearing potential must use two forms of contraception and have negative pregnancy tests before starting therapy. Notably, mycophenolate may decrease the effectiveness of hormonal contraceptives 7. The medication must be discontinued at least six weeks before planned conception 3.

Increased Infection Risk: Mycophenolate significantly increases susceptibility to opportunistic infections 1, 8:

• Viral infections: CMV (can cause tissue and blood infections), BK virus (causes kidney transplant failure), hepatitis B/C reactivation, herpes zoster
• Progressive Multifocal Leukoencephalopathy (PML): A potentially fatal brain infection requiring immediate discontinuation if suspected 1
• Fungal infections: Yeasts and other fungi causing serious tissue and blood infections

Increased Malignancy Risk: Patients have higher risk of lymphoma and other cancers, especially skin cancer 1. Monitor for unexplained fever, weight loss, lymph node swelling, or new/changing skin lesions 1.

Common Adverse Effects

Gastrointestinal toxicity is the most frequent side effect, occurring in up to 35% of patients and including diarrhea, nausea, vomiting, and abdominal cramps 3, 6. This may necessitate dose reduction or formulation switching 7.

Hematologic toxicity affects 23-45% of transplant patients 9:

• Leukopenia, anemia, and thrombocytopenia are common
• Severe neutropenia (ANC < 0.5 × 10³/µL) develops in 2-3.6% and may require switching to alternative immunosuppression 9

Other significant effects include hypertension, peripheral edema, headache, tremor, hyperglycemia, and respiratory infections 7.

Monitoring Requirements

Pre-Treatment Testing

Before initiating mycophenolate 7:

• Complete blood count (CBC) with differential
• Comprehensive metabolic panel including liver and renal function
• Hepatitis B, hepatitis C, and tuberculosis screening (if using with highly immunosuppressive regimens)
• Full body skin examination by dermatologist

Ongoing Monitoring Schedule

Intensive first-year monitoring 7, 9:

• Weeks 1-4: Weekly CBC counts
• Months 2-3: Twice monthly CBC counts
• Months 4-12: Monthly CBC counts
• After year 1: Every 1-3 months indefinitely

Additional laboratory monitoring every 1-3 months 7:

• Renal and hepatic profiles
• Mycophenolic acid blood levels are not routinely recommended but may be checked if GI intolerance develops or rejection is suspected despite standard dosing 7

Clinical Monitoring

Patients must check temperature frequently and immediately report fever, infection symptoms, neurologic changes, respiratory symptoms, or new skin lesions 7, 1.

Important Drug Interactions and Contraindications

Avoid live vaccines during mycophenolate therapy 7, 1.

Do not combine with azathioprine due to increased purine metabolism inhibition 7.

Drugs that reduce absorption (take mycophenolate separately) 1:

• Antacids containing magnesium/aluminum
• Iron supplements
• Bile acid sequestrants (cholestyramine, colesevelam, colestipol)
• Sevelamer (take 2 hours after mycophenolate)

Drugs with increased plasma concentrations: Acyclovir, valacyclovir, ganciclovir, and valganciclovir levels increase with mycophenolate, especially in renal impairment 7.

Renal impairment consideration: The glucuronide metabolite (MPAG) accumulates approximately five times normal levels in end-stage renal disease, increasing susceptibility to adverse effects 7.

Dosing Considerations

In Asian patients, target lower total daily doses: 2 g of MMF (or equivalent EC-MPS 1440 mg) versus 3 g daily in non-Asian populations 3. The optimal dose for transplant patients appears to lie between 2-3 g/day, balancing efficacy against gastrointestinal effects and infection risk 6.