January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. Mycophenolate Mofetil Cynthia L. Chen, MD The Permanente Medical Group, Northern California Diablo Service Area February 17, 2018
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only.
Mycophenolate Mofetil
Cynthia L. Chen, MD
The Permanente Medical Group, Northern California
Diablo Service Area
February 17, 2018
I have no relevant conflicts of interest to disclose.
I will be discussing off-label use of medications.
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Outline
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Indications
Pharmacology
Formulations/Dosing
Adverse Reactions
Pregnancy
Monitoring
Clinical Questions
• What is the mechanism of action?
• What is the most common side effect?
• What are the black box warnings?
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Mycophenolate mofetil
Indications
• Off-label for ALL dermatologic diagnoses
• Psoriasis
• Autoimmune blistering diseases• BP, CP, EBA, PNP, PF, PV, linear IgA
• Chronic eczematous dermatitis
• Connective tissue disease• DM, LE, diffuse systemic sclerosis, Churg-Strauss,
hypocomplementemic UV, MPA, Wegener’s, nodular vasculitis
• Graft versus host disease
• Also: cutaneous Crohn’s disease, erythema multiforme, erythema nodosum, LP/LPP, sarcoid, PG, NLD
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Pharmacology
• Mycophenolate mofetil (MMF) is prodrug of mycophenolicacid (MPA)
• 94% oral bioavailability
• Inactivated by glucoronyl transferase in liver• 82% of the inactive metabolite MPAG is bound to plasma albumin• Remainder converted into active drug via enterohepatic
recirculation• MPAG converted back to MPA by β-glucuronidase, found in highest
quantities in skin and GI tract
• Majority excreted as inactive metabolite in the urine – thus, higher drug levels in patients with renal failure
• Remainder excreted in stool
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Mechanism of Action
• Cytostatic effect on T and B lymphocytes
• Non-competitively inhibits inosine monophosphate dehydrogenase (IMPDH) which is needed for de novo purine synthesis, specifically guanosine nucleotides
• T and B lymphocytes are dependent on this pathway for proliferation, other cells use a salvage pathway that T and B cells lack – selectivity
• Suppresses antibody formation
• Decreases lymphocyte and monocyte adhesion to endothelial cells
• Inhibits fibroblast function
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Formulations
• MPA: more GI upset
• MMF: better bioavailability, efficacy, tolerability
• Enteric-coated delayed-release mycophenolate sodium (EC-MPS): better GI side effect profile
• 1gm mycophenolate mofetil (Cellcept) equivalent to 720mg mycophenolate sodium (Myfortic)
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Adult dosing
• MMF: 250mg capsules, 500mg tablets, 200mg/mL oral suspension• Start at 500mg twice daily and increase to effective dose of 1-
2g/day
• Max dose 3g/day
• No higher than 1g twice daily for patients with glomerular filtration rate <25mL/min
• EC-MPS: 180mg and 360mg tablets
• Generics of both available
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Adverse Reactions
• Gastrointestinal: most common• Nausea, diarrhea, anorexia, cramping, vomiting, anal tenderness
• Dose dependent
• Solutions: Switch to EC-MPS
Divide dosing over 3 daily doses instead of 2
Reduce dose
Take with food (cannot be done with EC-MPS), caution PP!s
• Genitourinary• Urgency, frequency, dysuria, sterile pyuria
• Hematologic• Anemia, leukopenia, thrombocytopenia
• Dose dependent, mild, reversible
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Adverse Reactions
• Infection (black box warning): bacterial, fungal, protozoal, new or reactivated viral, or opportunistic infections, JC virus
• Malignancies (black box warning): lymphoma and nonmelanoma skin cancer• Related to intensity/duration of therapy
• Mostly relevant in transplant population
• Cases of primary CNS lymphoma and EBV-associated lymphoproliferative disease reported in patients taking MMF for autoimmune conditions
• Live attenuated vaccines should be avoided
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Pregnancy
• Category D
• Black box warning: first trimester pregnancy loss and congenital malformations of external ear, cleft palate
• Any female of childbearing potential must be on birth control 4 weeks before, during, and 6 weeks after therapy
• Theoretical decrease in efficacy of oral contraceptives; hormonal + barrier
• Solo birth control options: IUD, tubal sterilization, partner vasectomy
• Not recommended during lactation, metabolites found in breastmilk of rats
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Common interactions
• Drugs that reduce MMF levels:• Rifampin, quinolones, metronidazole - decreased enterohepatic circulation
• Cholestyramine – decreased enterohepatic circulation
• Antacids - chelation
• Drugs that raise MMF levels:• Salicylates – protein binding displacement
• Acyclovir– competitive renal tubular secretion (MMF may also raise its levels)
• Drug levels reduced by MMF:• Nevirapine
• Levonorgestrel?
• Increase risk of bone marrow suppression:• Azathioprine
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Monitoring
• Baseline: CBC with diff, Cr, AST/ALT, pregnancy test
• Case reports of reactivation of TB and HBV/HCV, screen on case by case basis
• Monitoring labs: CBC with diff, Cr, ALT every 2 weeks for first month, then monthly for 3 months, then every 3 months and one month after every dose increase
• Most laboratory abnormalities involve CBC
• Clinical: signs and symptoms of infection; neurological symptoms (hemiparesis, confusion, cognitive deficiencies, ataxia) suggestive of PML; skin exams
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Key Points
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Used in variety of autoimmune and inflammatory skin conditions
Inhibits de novo purine synthesis, T and B cell proliferation
GI side effects: switch to EC-MPS, divide or reduce dose, take with food
Black box warnings: infection, malignancies, teratogenicity
Birth control necessary until 6 weeks after medication is stopped
Most lab abnormalities involve CBC
Clinical Questions
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Clinical Questions
• What is the mechanism of action of mycophenolate?
A. Binds FK506, then inhibits calcineurin, affecting calcium-dependent processes
B. Monoclonal anti-IL4 receptor antibody
C. Inhibits inosine monophosphate dehydrogenase, interfering with de novo purine synthesis
D. Inhibits dihydrofolate reductase, interfering with purine and pyrimidine synthesis
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Mycophenolate mofetil
Clinical Questions
• Which of the following is the most common side effect of mycophenolate?
A. Gastrointestinal side effects
B. CBC abnormalities
C. Back pain
D. Gingival hyperplasia
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Mycophenolate mofetil
Clinical Questions
• All of the following are black box warnings for mycophenolate except:
A. Risk of first trimester pregnancy loss and birth defects
B. Risk of serious infection
C. Risk of malignancy, including lymphoma and skin cancer
D. Risk of hypertension
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Mycophenolate mofetil
References
• Assmann T and T. Ruzicka. New immunosuppressive drugs in dermatology (mycophenolate mofetil, tacrolimus): unapproved uses, dosages, or indications. Clinics in Dermatology 2002; 20: 505-14.
• Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management. Drug Saf 2001; 24(9):645-63.
• O’Neill BP et al. EBV-associated lymphoproliferative disorder of CNS associated with the use of mycophenolate mofetil. Neuro Oncol 2007; 9(3): 364–369.
• Orvis AK et al. Mycophenolate mofetil in dermatology. JAAD 2009; 60 (2): 183-99.
• Schadt CR and JP Zwerner. Mycophenolate mofetil and mycophenolic acid. In Comprehensive Dermatologic Drug Therapy, Third Edition. 2013: 15, 190-8.
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