Mycophenolate Mofetil...Pharmacology •Mycophenolate mofetil (MMF) is prodrug of mycophenolic acid (MPA) •94% oral bioavailability •Inactivated by glucoronyl transferase in liver

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


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?


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


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


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


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)


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


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


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


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



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


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


Key Points


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


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



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



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



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.


Documents

Mycophenolate Mofetil...Pharmacology •Mycophenolate mofetil (MMF) is prodrug of mycophenolic acid (MPA) •94% oral bioavailability •Inactivated by glucoronyl transferase in liver