What is Cellcept (mycophenolate mofetil)?

What is CellCept (Mycophenolate Mofetil)?

CellCept (mycophenolate mofetil) is an FDA-approved immunosuppressant medication used primarily to prevent organ rejection in patients who have received kidney, heart, or liver transplants, and it works by selectively inhibiting lymphocyte proliferation through blockade of purine synthesis. 1

Mechanism of Action

• Mycophenolate mofetil is a prodrug that is rapidly converted to its active form, mycophenolic acid (MPA), after oral administration 1
• MPA is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo pathway of guanosine nucleotide synthesis 1, 2
• T- and B-lymphocytes are critically dependent on the de novo purine synthesis pathway for proliferation, unlike other cell types that can utilize salvage pathways, which explains MPA's selective cytostatic effects on lymphocytes 1, 2
• MPA is five-fold more potent against the type II isoform of IMPDH (expressed in activated lymphocytes) compared to the type I isoform (expressed in most cell types), further enhancing its lymphocyte-selective immunosuppression 2

FDA-Approved Indications

• Prevention of organ rejection in adult patients who have received kidney, heart, or liver transplants 1
• Used in combination with cyclosporine (or tacrolimus) and corticosteroids as part of triple immunosuppressive therapy 1, 3
• Safe and effective in children who received kidney transplants, though safety and efficacy in pediatric heart or liver transplant recipients is not established 1

Dosing and Administration

• Standard adult dosing is 1 g twice daily (2 g/day total) for renal transplant recipients, though doses up to 1.5 g twice daily (3 g/day total) have been used 4, 5
• Pediatric dosing for kidney transplant is 1300 mg/m² per day with a maximum of 2000 mg daily 4
• Food decreases peak concentration (Cmax) by 40% but does not affect overall absorption (AUC), so it can be taken with or without food 1
• The drug is rapidly and essentially completely absorbed after oral administration, with 94% bioavailability 1

Clinical Efficacy

• In large randomized controlled trials, mycophenolate mofetil significantly reduced the incidence of acute rejection compared to azathioprine during the first 6 months after renal transplantation 3, 6, 5
• Treatment failure (defined as biopsy-proven rejection, graft loss, death, or drug discontinuation) occurred in 34.8-38.2% of patients on MMF versus 50% on azathioprine at 6 months 5
• Biopsy-proven rejection rates were 15.9-19.7% with MMF compared to 35.5% with azathioprine 5
• In cardiac transplantation, MMF improved both patient and graft survival rates, while in renal transplantation it reduced graft loss due to rejection but did not show significant improvement in overall patient or graft survival in initial trials 3
• Response in immune thrombocytopenia (ITP) is relatively slow, with approximately 15% response at 1 week but roughly 50% response by 1 month, with durable response rates of 56.7-61.9% 4

Adverse Effects and Safety Profile

Common adverse effects include:

• Gastrointestinal disturbances (diarrhea in 6.8% of patients, more common than with azathioprine), nausea, vomiting, and abdominal pain 4, 1
• Hematologic toxicity including neutropenia, anemia, and thrombocytopenia 4, 1
• Increased susceptibility to opportunistic infections (viral, fungal, and bacterial) 1, 3

Serious adverse effects include:

• Progressive multifocal leukoencephalopathy (PML), a potentially fatal brain infection caused by JC virus in immunocompromised patients 1
• Cytomegalovirus (CMV) and BK virus infections, which can cause tissue damage and transplant failure 1
• Pure red cell aplasia 4
• Increased risk of lymphoma and other malignancies, especially skin cancer, with prolonged use 4, 1

Critical Contraindications and Warnings

• Mycophenolate mofetil is absolutely contraindicated in pregnancy due to severe teratogenic effects, with a 49% miscarriage rate, 2% stillbirth rate, and 23% structural anomaly rate when used during pregnancy 7
• Documented congenital malformations include hypoplastic nails, shortened fifth fingers, microtia, cleft lip/palate, absence of auditory canals, and cardiac defects including Tetralogy of Fallot 7
• Women of childbearing potential must use two reliable forms of contraception simultaneously, starting 4 weeks before therapy, during therapy, and for 6 weeks after discontinuation 1
• Contraindicated in patients with hypersensitivity to mycophenolate mofetil or mycophenolic acid 1
• Should not be used in patients with Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, or other rare inherited deficiencies of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) 1
• Breastfeeding is not recommended during treatment as it is unknown whether the drug passes into breast milk 1

Monitoring Requirements

• Complete blood count (CBC) and platelet counts should be monitored every 2 weeks for the first 2 months, then monthly until 6 months, and bimonthly thereafter 4
• Liver function tests and renal function should be monitored regularly 4
• Patients should be monitored for signs of infection, including fever, prolonged tiredness, and lymph node swelling 1
• Therapeutic drug monitoring of mycophenolic acid levels (targeting AUC of 20-60 µg·h/mL) may be performed in some centers 7

Drug Interactions

• Antacids containing magnesium and aluminum should not be taken simultaneously with mycophenolate mofetil as they decrease absorption 1
• Sevelamer should be taken 2 hours after mycophenolate mofetil 1
• Proton pump inhibitors may decrease mycophenolic acid exposure 1
• Oral contraceptives may be less effective; additional barrier contraception is required 1
• Acyclovir, valacyclovir, ganciclovir, and valganciclovir may compete for renal tubular secretion, increasing concentrations of both drugs 1
• Rifampin significantly decreases mycophenolic acid exposure and should be avoided 1

Off-Label Uses

• Treatment of autoimmune disorders including systemic lupus erythematosus and immune thrombocytopenia (ITP) 4
• Treatment of steroid-refractory acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation, with overall response rates of 31-48% 4
• Treatment of psoriasis and psoriatic arthritis, though evidence is limited to uncontrolled studies showing 40-70% reduction in disease severity 4
• Treatment of interstitial lung disease, typically starting at 500 mg twice daily and titrating to 1000-1500 mg twice daily 8

Important Clinical Pearls

• Live vaccines should not be administered to patients taking mycophenolate mofetil, and other vaccines may be less effective during treatment 1
• The 3 g/day dose provides greater efficacy than 2 g/day but is associated with more gastrointestinal toxicity and invasive CMV infections 5
• Patients should be counseled to report any new skin lesions, unexplained fever, weight loss, or changes in neurological function immediately 1
• Unlike calcineurin inhibitors, mycophenolate mofetil is not typically associated with direct thyroid toxicity 9
• The drug has been in clinical use since 1995 for transplantation, though mycophenolic acid was originally discovered in 1893 for its antibacterial properties 4