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.
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 2
Outline
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 3
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?
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 4
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 5
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 6
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 7
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)
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 8
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 9
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 10
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 11
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 12
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 13
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 14
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 15
Key Points
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 16
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 17
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 18
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 19
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
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 20
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.
January 23, 2018 | © 2011 Kaiser Foundation Health Plan, Inc. For internal use only. 21