What is Mycophenolate Mofetil (MMF)?

What is Mycophenolate Mofetil (MMF)?

Mycophenolate mofetil (MMF) is an immunosuppressive prodrug that is converted to its active form, mycophenolic acid (MPA), which selectively inhibits inosine monophosphate dehydrogenase (IMPDH), thereby blocking DNA synthesis in T and B lymphocytes. 1

Mechanism of Action

MMF works through a highly specific immunosuppressive pathway:

• The active metabolite, mycophenolic acid, reversibly inhibits IMPDH, an enzyme critical for the de novo synthesis of guanosine nucleotides 2, 3
• This inhibition preferentially affects T and B lymphocytes because these cells are critically dependent on the de novo purine synthesis pathway, unlike other cells that can utilize salvage pathways 3, 4
• The result is decreased B and T cell proliferation, T cell apoptosis, and suppression of dendritic cells and IL-1 3
• This selective mechanism leads to suppression of cell-mediated immune responses and antibody formation without affecting all dividing cells 2

FDA-Approved Indications

MMF is FDA-approved for prophylaxis of organ rejection in patients who have received kidney, heart, or liver transplants, used in combination with cyclosporine and corticosteroids 1

Clinical Applications Beyond Transplantation

MMF has demonstrated efficacy in multiple autoimmune and immune-mediated conditions:

Hematologic Conditions

• Immune thrombocytopenia (ITP): Response rates of approximately 50% at 1 month, with durable responses of 56.7% to 61.9% at doses of 500-2000 mg/day in adults 2
• Pediatric dosing for ITP: 1300 mg/m² per day (maximum 2000 mg) 2

Graft-Versus-Host Disease

• Steroid-refractory acute GVHD: Overall response rates of 31-48%, with complete response rates of 26-42% 2
• Higher response rates observed in patients with lower grade GVHD at treatment initiation 2
• Typical dosing: 1-2 g daily, administered orally or intravenously 2

Dermatologic Conditions

• Psoriasis: Mean PASI reduction of 47% at 12 weeks with doses of 2-3 g daily 2
• Alternative studies showed 40-70% PASI reduction in 7 of 11 patients 2

Liver Transplantation

• Used as an antimetabolite in combination with calcineurin inhibitors to reduce CNI-related nephrotoxicity 2
• Has progressively replaced azathioprine as the preferred antimetabolite, though evidence for superiority over azathioprine in preventing acute cellular rejection is limited 2

Dosing Considerations

Standard Dosing Ranges

• Transplantation: Typically 1-1.5 g twice daily (2-3 g total daily dose) 2, 1
• Autoimmune conditions: 500-2000 mg daily, with gradual titration 2
• Interstitial lung disease: Start 500 mg twice daily, increase by 500 mg weekly to target of 1000 mg twice daily; may increase to 1500 mg twice daily if tolerated 4

Adverse Effects Profile

Common Side Effects

• Gastrointestinal toxicity is the most common adverse effect: diarrhea (6.8%), nausea, vomiting, and abdominal cramps occur in up to 35% of patients 2, 1
• These GI symptoms typically diminish with ongoing use 2

Hematologic Effects

• Neutropenia, anemia, and thrombocytopenia can occur but are relatively uncommon 2
• Regular monitoring of complete blood counts is required 4, 1

Infectious Complications

• Increased risk of viral infections, including shingles, herpes, CMV, BK virus, hepatitis B and C 1
• Risk of Progressive Multifocal Leukoencephalopathy (PML), a potentially fatal brain infection 1
• Fungal infections can occur with serious tissue and blood involvement 1

Serious Long-Term Risks

• Increased risk of lymphoma and other cancers, especially skin cancer 1
• Pure red cell aplasia has been reported 2
• Small increased risk of malignancy with prolonged use 2

Teratogenicity

• MMF is a potent teratogen and is absolutely contraindicated in pregnancy and lactation 2, 1
• Females of reproductive potential must use effective contraception and have negative pregnancy tests before initiation 1
• If pregnancy occurs during treatment, enrollment in the Mycophenolate Pregnancy Registry is recommended 1

Monitoring Requirements

Essential monitoring includes:

• Complete blood count and liver function tests at baseline and regularly during treatment 4, 1
• Pregnancy testing for females of reproductive potential 1
• Screening for G6PD deficiency is not required for MMF (this applies to dapsone) but general infection surveillance is needed 1
• Therapeutic drug monitoring of MMF levels (glucuronide) may be performed in some cases 4

Formulations

• Mycophenolate mofetil (MMF): The standard prodrug formulation 2, 1
• Enteric-coated mycophenolate sodium (EC-MPS): Developed to reduce gastrointestinal side effects by delaying release until the small intestine 2

Important Contraindications and Precautions

• Absolute contraindication: Allergy to mycophenolate mofetil or its components 1
• Do not use in patients with Lesch-Nyhan or Kelley-Seegmiller syndrome or other rare inherited HGPRT deficiency 1
• Live vaccines should not be administered during MMF treatment; other vaccines may have reduced efficacy 1
• Avoid breastfeeding as it is unknown if MMF passes into breast milk 1

Drug Interactions

Key interactions requiring dose adjustment or timing modifications:

• Sevelamer: Should be taken 2 hours after MMF 1
• Antacids containing magnesium and aluminum: Should not be taken simultaneously with MMF 1
• Proton pump inhibitors may affect absorption 1
• Antiviral agents (acyclovir, valacyclovir, ganciclovir, valganciclovir) may have altered levels 1
• Rifampin can reduce MMF efficacy 1
• Oral contraceptives: MMF may reduce effectiveness; additional barrier methods recommended 1