4. Patient Presentation
Current Medications:
- Cyclobenzaprine (Flexeril): Muscle spasms in back
- IV Solu-Medrol (Methylprednisolone): Optic neuritis
- Glatiramer acetate (Copaxone): MS
- Meclizine (Antivert): Dizziness
- Topiramate (Topamax): Epilepsy
OTCs:
- Ibuprofen (Advil)
- Multivitamin
- Omega-3-FA
- Cholecalciferol (Vitamin D3)
5. Patient Presentation
Pertinent Labs:
- JCV anti-body: negative
- MRI: Extensive and enhancing demyelinating plaque
formation of multiple sclerosis
Symptoms:
– Fatigue, weakness
– Dimming of vision (not improved after administration of IV
Solu-Medrol)
– Left-sided numbness, paresthesias
– Increased urinary frequency
– Dizziness with potential of fall
6. Multiple Sclerosis (MS)
• Immune-mediated disease in which the body’s immune
system mistakenly attacks myelin in the central nervous
system
• Can affect the brain, spinal cord, and optic nerves in the
eyes
• No definite cause has been identified
7.
8. Clinical Presentation
• Symptoms vary in severity
and location from patient to
patient
h"p://cdn4.sci-news.com/images/2013/10/image_1438-mul<ple-
sclerosis.jpg
9. Diagnosis
• Relies on clinical judgment
– Exclusion of alternative
causes
• Tests:
1. MRI
- 2010 Mcdonald criteria
2. Evoked Potentials
3. Cerebrospinal Fluid
Examination
http://multiple-sclerosis-research.blogspot.com/2013/06/a-new-imaging-tool.html
10. Classifications of Multiple Sclerosis
• Patients with Aggressive RRMS have BOTH:
1. > 2 disabling relapses in previous year
2. Active MRI
DR. KUPE’S NOTE ON drkupe MULTIPLE SCLEROSIS Irfan Ziad MD UCD
12. CMRO Consensus Guidelines for the Diagnosis and Treatment of Multiple Sclerosis.
CMRO (2013): Treatment Algorithm
• For patients with RRMS:
– Initiate either IFNBs or Glatiramer acetate (Copaxone) depending on
preference of side effect profile and mode of administration (Level A)
13. CMRO Consensus Guidelines for the Diagnosis and Treatment of Multiple Sclerosis.
CMRO (2013): Treatment Algorithm
14. History of Present Illness
Month 1
• Dx of MS
• Began
Copaxone
Month 3
• INC
numbness,
tingling of
hands
• Intermittent
blurring of
vision
• Intermittent
fatigue
• Dizziness
Month 8
• Worsening
paresthesia
• OD confirmed
no optic nerve
disease
• Fatigue
• Dizziness
Month 10
• Developed
optic neuritis;
Painful loss of
vision (R) eye
despite
administration
of steroids
• Developed light
sensitivity
• Dizziness
• INC fatigue
Month 12
• Dimming of
vision
• Continued (L)
sided
paresthesia
• INC urinary
frequency
• Dizziness
Pertinent Labs:
- JCV anti-body: negative
- MRI: Extensive and enhancing demyelinating plaque formation of
multiple sclerosis
15. Treatment for Aggressive RRMS
• For patients with aggressive RRMS:
(> 2 disabling relapses in previous year AND active MRI)
• Consider Natalizumab (Tysabri) if negative for JCV anti-body
• Consider Fingolimod (Gilenya) if positive for JCV anti-body
Consensus Guidelines for the Diagnosis and Treatment of Multiple Sclerosis. CMRO. 2013
JC Virus:
- Does not result in any side effects for healthy individuals
- However, in select MS patients, the virus can activate and attack white matter
in brain triggering progressive multifocal leukoencephalopathy (PML)
16. Treatment for Aggressive RRMS
• For patients with aggressive RRMS:
(> 2 disabling relapses in previous year and active MRI)
• Consider Natalizumab (Tysabri) if negative for JCV anti-body
• Consider Fingolimod (Gilenya) if positive for JCV anti-body
Consensus Guidelines for the Diagnosis and Treatment of Multiple Sclerosis. CMRO. 2013
Pertinent Labs:
- JCV anti-body: negative
- MRI: Extensive and enhancing demyelinating plaque formation of multiple
sclerosis
17. Aggressive RRMS Medication
Comparison
• Insert chart comparing interferons with
Copaxone and efficacy: include dose, side
effect profile (use * for europe availability
only)
Fingolimod (Gilenya) Natalizumab (Tysabri)
Outcomes:
- Reduced relapse rate by 55%A
- Reduced short-term progression by 30%A
- Reduced relapse rate by 68%-76%B,C,D
- Reduced short-term progression by
42%C
MOA:
Binds to sphingosine 1-phosphate receptors 1,
3, 4, and 5 to form Fingolimod-phosphate. This
blocks lymphocytes' ability to emerge from
lymph nodes which reduces central
inflammation
Monoclonal antibody that block alpha-4
subunits of integrin molecules preventing
adhesion and transmigration of leukocytes
Dosage: 0.5mg PO daily
300 mg IV infusion given over 1 hr every 4
weeks
SE:
Increased ALT/AST (14%), Infections (13%),
Diarrhea (12%), Hypertension (6%),
Bradycardia, Blurred vision, Lymphopenia
(4%), Leukopenia (3%)
Headache (38%), Fatigue (27%),
Arthralgia (19%), Urinary tract infection
(20%)
Misc: - JCV (+)
- Monitor Bp and HR within 6 hrs of first
dose; Obtain ECG afterward; precautions
may vary based on patient response
- JCV (-)
- PML è REMS: MS TOUCH program
- Evaluate pt 3 months, after infusion
then 6 months therafter
A = Del Santo F et al. (2012), B = Tysabri (natalizumab) package insert. 2015., C = Polman CH et al. (2006), D = Pucci E et al. (2011)
18. Patient Plan
• Initiate Natalizumab (Tysabri)
– Had aggressive disease state
– Higher rates of relapse reduction and short-term
progression
– Better side effect profile
– JCV antibody (-)
• DC Glatiramer acetate (Copaxone)
19. Summary
1. MS is a disease where the immune system mistakenly attacks the CNS
2. Clinical symptoms of multiple sclerosis vary in severity and location from
patient to patient
3. Agents for MS have either of the following functions: (1) acute relapse, (2)
disease modifying, and (3) symptom management
4. Beta interferons or Glatiramer acetate are first-line treatments for RRMS;
selection of drug depends on patient preference and side effect profile
5. Progression of disease state and JCV antibody results will determine
whether to select Fingolimod or Natalizumab
20. References
1. Calabresi, Peter A. "Diagnosis and management of multiple sclerosis." American family physician 70.10 (2004):
1935-1944.
2. Gilenya (fingolimod) package insert. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation; 2012
May.
3. Goldenberg, Marvin M. "Multiple sclerosis review." Pharmacy and Therapeutics 37.3 (2012): 175.
4. Goodin, D. S., et al. "Assessment: The use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an
evidence-based review) Report of the Therapeutics and Technology Assessment Subcommittee of the
American Academy of Neurology." Neurology 71.10 (2008): 766-773.
5. John H. Noseworthy, M.D., Claudia Lucchinetti, M.D., Moses Rodriguez, M.D., and Brian G. Weinshenker, M.D.
Multiple Sclerosis. N Engl J Med 2000; 343:938-952September 28, 2000DOI: 10.1056/NEJM200009283431307
6. Tysabri (natalizumab) package insert. Cambridge, MA: Biogen Idec Inc.; 2015 May.
7. World Health Organization. "Atlas: multiple sclerosis resources in the world 2008." (2008).
8. Yamout, B., et al. "Consensus guidelines for the diagnosis and treatment of multiple sclerosis." Current Medical
Research & Opinion 29.6 (2013): 611-621.
21. Monitoring: Fingolimod
1. First Dose Monitoring
1. Administer the first dose in a setting with resources for symptomatic bradycardia.
2. First phase:
1. (during 6 hours)
2. After the initial dose, observe for 6 hours for signs/sx bradycardia. Perform hourly
pulse and blood pressure assessment.
3. 2nd phase:
1. (after 6 hours)
2. Obtain an ECG in all patients
3. Institute additional observation IF HR is < 45 BPM, if the heart rate is at the lowest
value after fingolimod receipt, or if the ECG shows new onset second degree or higher
AV block.
1. Begin continuous ECG monitoring if symptomatic bradycardia occurs. Continue
until findings resolved. If pharmacologic intervention is needed for symptomatic
bradycardia, institute continuous ECG monitoring in a medical facility, and
repeat the first dose monitoring strategy after the second fingolimod dose.
Overnight monitoring with continuous ECG in a medical facility is advised for
some patients (see precautions)
2. If interrupted for 1+ day during first 2 weeks, repeat the first dose monitoring.
3. If interrupted for 7+ days, during the third and fourth week of drug receipt, repeat the first dose
4. If DC’d for > 14 days after 1st month tx, repeat the first dose monitoring
23. Fingolimod vs Tysabri Study
Results
Fingolmod (Gilenya) Natalizumab (Tysabri)
First oral agent for approval of
FDA Approved for relapsing forms of MS in 2010
FREEDOMS (2010) RCT
1272 pts, 1:1:1 fingolimod 0.5, 1.5mg, and placebo at 2
years:
relapse rate of 0.18 vs 0.40 with placebo
disability progression of 17% vs 24.1% with placebo
TRANSFORMS (2010) RCT
1200 pts RRMS, fingolimod vs IFNB1a
relapse was 0.2 vs 0.33 in IFN
MRI favored fingolimod
Preliminary randomized trial: reduction in lesions over a 6
month period vs placebo
Del Santo F, Maratea D, Fadda V, et al. Treatments for
relapsing–remitting multiple sclerosis: summarising current
information by network meta-analy- sis. Eur J Clin
Pharmacol 2012;68:441-8
Reduced relapsing rate by 55% and short-term disability
progression by 30% compared to placebo
First monoclonal antibody approved as monotherapy for
RRMS in 2004
Meaning cannot be given with TNF-alpha inhibitors or
immunosuppressants such as 6-mercaptopurine,
azathioprine, cyclosporine, or methotrexate
FDA approval studies: MS1:
Has shown greater effect in reducing relapse by 76%
remained relapse free over 24 months (2 years) vs 41%
on placebo
Also for pts that had experienced 1 relapse while
receiving Avonex, 54% remained relapse free for over 24
months vs 46% placebo
Reduce Short-term disability progression by 42%
compared to placebo
AFFIRM: A randomized, placebo-controlled trial of
natalizumab for relapsing multiple sclerosis. (2006)
RCTs 942 pts, natalizumb vs placebo for 2 years
Inclusion: 0-5 EDSS, had MRI lesions, at least one
relapse in prior year
Nat associated with 68% reduction relapse rate at 1 year,
42% over 2 year, and 17% probability of progression vs
29% placebo (EDSS)
83% reduction in amount of new or enlarging T2 lesions
AE: fatigue and allergic reaction
SENTINEL
Sentinel = rough explosion = pts already on tx and it had
to stop early (exploded)
1171 pts, with RRMS, already on IFNB-1a tx, continued
to receive tx with tysabri (so not monotherapy)
Study stopped early bc 2 had PML
54% reduction in relapse at year 1, maintained at 2 years
24. Fingolimod vs Tysabri Study
Results
Fingolmod (Gilenya) Natalizumab (Tysabri)
Caution in patients that are renally or
hepatically impaired (child pugh > 10)
Associated with risk of varicella-zoster virus
infections; potentially fatal, tumor
development
CI:
Cardiovascular: recent (6 mo) MI, unstable
angina, stroke, transient ischemic attack,
decompensated heart failure requiring
hospitalization, or ClassIII/IV HF, QT
prolongation of > 500 msec
Heart block: Mobitz type II 2nd/3rd degree
AV block or sick sinus syndrome, unless pt
has pacemaker
tx with class II or III anti-arhythmic drugs
warnings:
macular edema: perform examination of
fundus 3-4 months after beginning tx; pts
with DM or uveitis are at increased risk
obtain PFTs, liver injury
Also for pts that had experienced
1 relapse CI:
Patients that have or have had
PML (range 1-11/1000 for
prevalence as of 2012), patients
that have experienced
hypersensitivity rxn (<1%)
Monitoring:
Clinpharm- after first infusion,
evaluate in 3 months, then 3
months later, then 6 months
thereafter
Special Populations:
Both are category C. May cause
fetal harm based on animal
studies
25. RRMS First-Line Medication
Comparison
• Insert chart comparing interferons with
Copaxone and efficacy: include dose, side
effect profile (use * for europe availability
only)
Drug
(Brand)
Dose Route Freq. Adverse Effects Cost (yearly)*
IFNB-1a
(Avonex)
30 mcg IM Weekly - Flu-like (61%)
- Anemia (8%)
$65,000
IFNB-1a
(Rebif)
22 or 44
mcg
SC 3x/week - Flu-like (28%)
- Injection site rxns (66%)
- Leukopenia (22%)
- Increased ALT/AST (17-27%)
$62,000
IFNB-1b
(Betaserone)
0.25 mg SC Every
other day
- Flu-like (60-76%)
- Injection site rxns (50-85%)
- Asthenia (49%)
- Menstrual disorder (17%)
- Leukopenia (10-16%)
- Increased ALT/AST (4-19%)
$69,000
Glatiramer
acetate
(Copaxone)
20 mg SC Daily - Injection site rxns (90%)
- Systemic reaction (15%)
$70,000
IFNB = Interferon beta
* Estimated from Goodrx.com May, 2015
