Mycophenolate mofetil - Drug Monograph

Introduction

Mycophenolate mofetil is an immunosuppressive prodrug of mycophenolic acid, widely used in transplantation medicine to prevent organ rejection. First approved by the FDA in 1995, it has become a cornerstone therapy in solid organ transplantation protocols, particularly for kidney, heart, and liver transplants. The drug represents a significant advancement in immunosuppressive therapy due to its selective mechanism of action and improved safety profile compared to older immunosuppressive agents.

Mechanism of Action

Mycophenolate mofetil undergoes rapid hydrolysis to its active metabolite, mycophenolic acid (MPA), following oral or intravenous administration. MPA functions as a selective, noncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo pathway of purine synthesis. This inhibition preferentially affects lymphocytes, which rely heavily on this pathway for proliferation. By depleting guanosine nucleotides necessary for DNA synthesis, MPA effectively suppresses T- and B-lymphocyte proliferation, antibody production, and cytotoxic T-cell generation, thereby preventing allograft rejection.

Indications

• Primary indication: Prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac, or hepatic transplants (used in combination with cyclosporine and corticosteroids)
• Off-label uses: Treatment of autoimmune disorders including lupus nephritis, pemphigus vulgaris, myasthenia gravis, and inflammatory bowel disease (based on clinical evidence and guidelines)

Dosage and Administration

• Oral: 1 g twice daily (maximum 1.5 g twice daily)
• IV: 1 g twice daily (switch to oral as soon as tolerated)

• Oral: 1.5 g twice daily
• IV: 1.5 g twice daily

• Oral: 1.5 g twice daily (may use 1 g twice daily in combination with thymoglobulin)
• IV: 1 g twice daily

• Renal impairment: No dosage adjustment needed for GFR >25 mL/min; use caution with GFR <25 mL/min
• Hepatic impairment: No specific dosage recommendations; monitor for toxicity
• Pediatric patients: 600 mg/m² twice daily (maximum 2 g daily)
• Geriatric patients: Use standard dosing with increased monitoring

Pharmacokinetics

Contraindications

• Hypersensitivity to mycophenolate mofetil, mycophenolic acid, or any component of the formulation
• Use in pregnancy (Category D) due to increased risk of miscarriage and congenital malformations
• Concomitant use with azathioprine due to additive bone marrow suppression

Warnings and Precautions

• Increased risk of congenital malformations and spontaneous abortions
• Increased susceptibility to infections and possible development of lymphoma

• Bone marrow suppression: Monitor blood counts weekly for first month, then monthly
• Progressive multifocal leukoencephalopathy (PML): Monitor for neurological symptoms
• Gastrointestinal hemorrhage and perforation: Use with caution in patients with GI disorders
• Pure red cell aplasia: Has been reported with therapy

Drug Interactions

• Antacids containing magnesium/aluminum: Decrease MPA absorption (separate administration by至少2 hours)
• Cholestyramine: Reduces MPA exposure by 40%
• Acyclovir/ganciclovir: Increased concentrations of both drugs
• Oral contraceptives: Reduced efficacy due to enterohepatic recirculation interference
• Probenecid: Increases MPA concentrations
• Rifampin: Decreases MPA exposure

Adverse Effects

• Leukopenia, anemia, thrombocytopenia
• Diarrhea, nausea, vomiting, constipation
• Urinary tract infections, CMV infections
• Hypertension, peripheral edema

• Sepsis, candidiasis, herpes infections
• GI hemorrhage, pancreatitis
• Tremor, headache, insomnia
• Rash, acne

• Progressive multifocal leukoencephalopathy
• Pure red cell aplasia
• Lymphoproliferative disorders
• Severe neutropenia

Monitoring Parameters

• Complete blood count: Weekly for first month, then twice monthly for 2-3 months, then monthly
• Renal function: Serum creatinine, BUN at regular intervals
• Liver function tests: Periodically
• Therapeutic drug monitoring: MPA AUC or trough levels in specific clinical situations
• Pregnancy testing: Before initiation and during therapy in women of childbearing potential
• Signs of infection: Continuous monitoring
• Neurological assessment: For symptoms suggesting PML

Patient Education

• Contraception: Use two reliable methods before, during, and for 6 weeks after therapy
• Infection risk: Avoid crowds and sick individuals; report fever, sore throat, or other infection signs
• Administration: Take on empty stomach unless GI upset occurs
• Missed dose: Take as soon as remembered unless close to next dose
• Blood monitoring: Emphasize importance of regular laboratory tests
• Vaccinations: Avoid live vaccines during therapy
• Pregnancy planning: Discuss reproductive risks and planning before initiation
• GI symptoms: Report persistent diarrhea, abdominal pain, or blood in stool
• Sun protection: Use sunscreen and protective clothing due to photosensitivity risk

References

1. Allison AC, Eugui EM. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev. 1993;136:5-28. 2. Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet. 1998;34(6):429-455. 3. FDA Prescribing Information: CellCept (mycophenolate mofetil). 2021. 4. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. Kidney Int. 2020;97(4S):S1-S99. 5. van Gelder T, Le Meur Y, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit. 2006;28(2):145-154. 6. Zuckermann A, Keogh A, Crespo-Leiro MG, et al. Randomized controlled trial of mycophenolate mofetil versus azathioprine in heart transplant recipients. J Heart Lung Transplant. 2018;37(5):580-589.