Mycophenolate Mofetil

Transcription

1 Mycophenolate Mofetil Cynthia L. Chen, MD The Permanente Medical Group, Northern California Diablo Service Area February 17, 2018 January 23, Kaiser Foundation Health Plan, Inc. For internal use only.

2 I have no relevant conflicts of interest to disclose. I will be discussing off-label use of medications. January 23, Kaiser Foundation Health Plan, Inc. For internal use only. 2

3 Outline Indications Pharmacology Formulations/Dosing Adverse Reactions Pregnancy Monitoring January 23, Kaiser Foundation Health Plan, Inc. For internal use only. 3

4 Clinical Questions Mycophenolate mofetil What is the mechanism of action? What is the most common side effect? What are the black box warnings? January 23, Kaiser Foundation Health Plan, Inc. For internal use only. 4

5 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, Kaiser Foundation Health Plan, Inc. For internal use only. 5

6 Pharmacology Mycophenolate mofetil (MMF) is prodrug of mycophenolic acid (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, Kaiser Foundation Health Plan, Inc. For internal use only. 6

7 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, Kaiser Foundation Health Plan, Inc. For internal use only. 7

8 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, Kaiser Foundation Health Plan, Inc. For internal use only. 8

9 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, Kaiser Foundation Health Plan, Inc. For internal use only. 9

10 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, Kaiser Foundation Health Plan, Inc. For internal use only. 10

11 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, Kaiser Foundation Health Plan, Inc. For internal use only. 11

12 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, Kaiser Foundation Health Plan, Inc. For internal use only. 12

13 January 23, Kaiser Foundation Health Plan, Inc. For internal use only. 13

14 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, Kaiser Foundation Health Plan, Inc. For internal use only. 14

15 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, Kaiser Foundation Health Plan, Inc. For internal use only. 15

16 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 January 23, Kaiser Foundation Health Plan, Inc. For internal use only. 16

17 Clinical Questions January 23, Kaiser Foundation Health Plan, Inc. For internal use only. 17

18 Clinical Questions Mycophenolate mofetil 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, Kaiser Foundation Health Plan, Inc. For internal use only. 18

19 Clinical Questions Mycophenolate mofetil 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, Kaiser Foundation Health Plan, Inc. For internal use only. 19

20 Clinical Questions Mycophenolate mofetil 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, Kaiser Foundation Health Plan, Inc. For internal use only. 20

21 References Assmann T and T. Ruzicka. New immunosuppressive drugs in dermatology (mycophenolate mofetil, tacrolimus): unapproved uses, dosages, or indications. Clinics in Dermatology 2002; 20: Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management. Drug Saf 2001; 24(9): O Neill BP et al. EBV-associated lymphoproliferative disorder of CNS associated with the use of mycophenolate mofetil. Neuro Oncol 2007; 9(3): Orvis AK et al. Mycophenolate mofetil in dermatology. JAAD 2009; 60 (2): Schadt CR and JP Zwerner. Mycophenolate mofetil and mycophenolic acid. In Comprehensive Dermatologic Drug Therapy, Third Edition. 2013: 15, January 23, Kaiser Foundation Health Plan, Inc. For internal use only. 21