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Pharmacologic Therapies for
Multiple Sclerosis: From
injectable to oral agents
KIRANPAL SINGH SANGHA, PHARM.D.
CLINICAL PHARMACY SPECIALIST –CNS
THE UNIVERSITY OF CINCINNATI
MEDICAL CENTER
Objectives
• List three oral therapies for Multiple
Sclerosis (MS)
• Describe dosing of common injectable
therapies for MS
• List a common adverse effect for the
interferon products
• Describe storage of common agents for MS
I have no conflicts of interest related to this presentation
What is Multiple Sclerosis ?
• Most common disabling neurological
disease of young adults
• Characterized by areas of inflammation,
demyelination, axonal loss & gliosis in the
CNS
• The cause is unknown, but immune
mediated physiology is widely accepted
Potential Triggers - Multiple Sclerosis
Genetic
predisposition
Infectious agent
Abnormal immunologic response
Environmental
factors
MS
Multiple Sclerosis
• Age of onset: 15 to 45 years
• Gender: 70% women
• Prevalence: 350,000 in the USA, about 2.5
million people worldwide
• Geography: incidence increases with
distance from equator
• Quality of life disease
• Immunotherapies do not treat symptoms
• Many MS patients feel their symptoms are
neglected by their physicians
Common Symptoms
Spasticity
Bladder symp.
Incontinence
Fatigue
Visual symp.
Optic neuritis, diplopia
Bowel symp.
Incontinence, constipation
Cognitive symp.
Depression & mood symp.
Sexual dysfunction
Pain
Why do we treat MS?
• Disease modifying therapies (DMT) have
been shown to reduce rate of relapse &
there is evidence of reduction of long term
disability
• Studies with interferon-beta 1a IM,
interferon-beta 1b, interferon beta 1a SQ
and glatiramer acetate have shown that
treating early (CIS) has been shown to
delay progression to clinically definite MS
• MS is the most common cause of non
traumatic neurologic disability in adults
Time line for Multiple Sclerosis
1986 Consortium of
MS Centers founded
(CMSC)
Injectable DMT’s:
1993 IFN-1b Betaseron
1995 IFN-1a Avonex
1996 Glatiramer
2002 IFN-1a Rebif
1950’s Interferons 1st
identified
1900
1868 MS
Named
Future ?
2000
1916 James
Dawson describes
pathology MS
Oral DMT’s:
2010 Dalfampridine
2010 Fingolimod
2012 Teriflunomide
2013 Dimethyl fumarate
1970’s ACTH
replaced by
IV steriods
Other DMT’s:
2014 Alemtuzumab
Clinically Isolated Syndrome (CIS)
CIS is a first episode of neurologic symptoms that
lasts at least 24 hrs & is caused by inflammation or
demyelination in the CNS
Interferon beta-1b
Reduction in conversion to
clinically definite MS at 3
or 5 yr follow-up
37%
Interferon beta 1a IM
35%
Glatiramer acetate
45%
Drug
MS Treatment -Acute Relapses
IV Methylprednisolone 1 gm/day x 3-5 days
Recent trials show equal efficacy of IV & PO
dosage forms. Some Clinicians are using
PO prednisone for relapses
Clinical Pearl - PO Prednisone 1000 mg/day x
3-5 days if IV therapy is not an option
If steroids fail plasmapheresis is an option
MS -Choosing initial DMT
• No consensus on initial therapy
• CMSC 2014 consensus statement says to initiate treatment
with an FDA approved DMT
• Availability of oral agents presents alternatives to
injectable agents
• Some suggest efficacy of the meds decreases if adherence
is < 80%
• Risks of certain adverse effects increase with comorbidities
• The only drug that should not be used 1st line is
alemtuzumab.
Treatment –DMT’s
1st generation -injectable:
Beta interferon-1a (Avonex), beta interferon-1b
(Betaseron), beta interferon-1a (Rebif), Glatiramer
acetate (Copaxone)
2nd generation –injectable to oral agents:
Mitoxantrone (Novantrone), Natalizumab (Tysabri),
Alemtuzumab (Lemtrada)
Oral agents – fingolimod, teriflunomide, dimethyl
fumarate. Dalfampridine
Brand Names have been used in presentation to distinguish products
Pre-drug testing
• All drugs except glatiramer need baseline
CBC with diff. & LFTs
• Fingolimod requires VZV IgG titers,
baseline EKG & ophthalmologic exam for
macular edema
• Teriflunomide – PPD and negative
pregnancy test
• Natalizumab –JCV Ab status
• Fingolimod, dimethyl fumarate – JCV Ab
status
Follow-up testing
• Interferons, natalizumab, dimethy fumarate CBC with diff, LFTs and clinic visits every 3
mo’s for 1 year
• Fingolimod – CBC with diff, LFTs & clinic visit 1
mo after starting then every 3 mo’s for the first
yr. If JCV Ab negative, yearly testing
• Teriflunomide – LFTs monthly for 6 mo’s, CBC
with diff every 6 mo’s.
• Natalizumab – If JCV Ab negative, every 6
mo’s.
If JCV Ab positive every 3 mo’s
Dosing DMTs -injectables
Drug
Dose
Route
Frequency
β INFN-1a (Avonex)
30 mcg
IM
Weekly
Peg INFN-beta1a
63 mcg x1
SQ
(Plegridy)
94 mcg in 14 days then 125 mcg q 14 days
β INFN-1b (Betaseron) 0.25 mg
SQ
Every other day
Extavia
β INFN-1a (Rebif)
44 mcg
SQ
Three times per
week
Glatiramer acetate
20 mg
SQ
Daily
or 40 mg
SQ
3 x week
(Copaxone)
Dosing DMTs -Injectables
Drug
Dose
12 mg/m2
Mitoxantrone
Natalizumab (Tysabri) 300 mg
Alemtuzumab
Route
Frequency
IV
Every 3 months
IV
Every 4 weeks
12 mg/day over 5 days
IV
Repeat in 1 year
Dosing -Oral Agents
Drug
Dose
Route
Frequency
Fingolimod
0.5 mg
PO
daily
Teriflunomide
7 or 14 mg
PO
daily
Dimethyl fumarate
Dalfampridine
120 x 7 days then 240 mg
10 mg
PO
PO
twice daily
twice daily
Self assessment question
• Which of the following are oral disease
modifying therapies for MS ?
a. Interferons, copaxone & alemtuzumab
b. Copaxone, fingolimod & mitoxantrone
c. Fingolimod, teriflunomide & dimethyl
fumarate
d. Alemtuzumab, natalizumab & copaxone
Injection Site reaction from
Glatiramer Acetate
DMTs continued
• Natalizumab (Tysabri)
Indicated: Monotherapy for relapsing forms of MS to
slow disability & reduce frequency of relapses
Should generally be used when other DMTs are
ineffective or intolerable or in patients with
aggressive disease
Dose: 300 mg IV q 4 weeks. TOUCH prescribing
program
Adverse Effects: Anxiety, fatigue, peripheral edema,
infusion related symmptoms, Hypersensitivity rxn,
Immunosuppression / Infections &
Progressive multifocal leukoencephalopathy
(PML)
Alemtuzumab (Lemtrada)
• Alemtuzumab is a CD52-directed cytolytic
antibody indicated for B-cell CLL & MS
• Restricted distribution program
• Dosing: 12 mg/day IV over 5 days and
repeat in year for 3 days
• Premedicate with diphenhydramine &
acetaminophen. Administer Bactrim &
acyclovir for PCP & herpes prophylaxis.
Dalfampridine ER (Ampyra)
US FDA approved 1/2010
• Dalfampridine is a K channel blocker
indicated to improve walking in pts with MS.
• Typical Dose: 10mg oral twice daily. Take
tablets whole, do not crush or chew.
• PK: Relative Fo 96%, low ppb, Tmax 3-4hrs,
Elimination T1/2 = 5-6 hrs, eliminated renally
(>90 %)
• AEs: seizures, insomnia, dizziness, HA,
nausea, contraindicated if Cr Cl < 50 ml/min
• Efficacy: A phase III study showed improved
walking (25 ft) in 43% pts vs 9% placebo
Fingolimod (Gilenya)
US FDA approved 9/2010
• Fingolimod is a sphingosine 1-phosphate receptor
modulator indicated to reduce the frequency of
clinical exacerbations and to delay accumulation of
physical disability with relapsing forms of MS
• Dose: 0.5 mg orally daily. Available: 0.5 mg caps
- Pts need to be observed for 6 hrs after the first
dose in an office or clinic for S/S bradycardia /
heart block. If med stopped > 2 weeks then restart monitoring as new therapy
Fingolimod (Gilenya)
• Use caution in patients taking beta blockers or antiarrhythmics
• Live attenuated vaccines should be avoided during
the first 2 mo’s of therapy
• Antibody testing for Varicella Zoster virus perform at
baseline. If VZV non-immune then vaccinate
• Ophthalmologic exam at baseline and every 3-4
mo’s for macular edema
• Animal studies suggest teratogenicity: use effective
contraception
Teriflunomide (AubagioR )
US FDA approved 9/2012
• Teriflunomide has selective reversible
inhibition of dihydroorotate dehydrogenase
that blocks pyrimidine synthesis in rapidly
proliferating cells. For relapsing forms of MS
• It is the active metabolite of leflunomide
• Available: 7 and 14 mg tablets
• Adult dose: 7 or 14 mg orally once daily
• AE: HA., Incr LFT, alopecia, diarrhea,
nausea, paresthesia
Dimethyl Fumarate (Tecfidera)
US FDA approved 3/2013
• Dimethyl fumarate (DMF) has been shown
to activate the nuclear factor like 2 (Nrf2)
pathway. The Nrf2 pathway is involved in
the cellular response to oxidative stress
• Available: 120 & 240 mg delayed release
caps. Swallow whole, do not crush/chew
• Adult Dose: Start 120 mg twice a day and
may incr to 240 mg bid after 7 days
Dimethyl Fumarate
•
•
•
•
Protect capsules from light.
AE: flushing, abdominal pain, diarrhea & N
Pregnancy: unknown effects
Monitor CBC at baseline and at least
annually. Withholding treatment is warranted
with serious infections
Absolute contraindications
Interferons: LFT’s at baseline > 2 x ULN
Fingolimod: LFT’s at baseline > 2 x ULN, MI,
stroke, TIA, unstable angina, decomp. heart
failure within 6 mo’s, hx of Mobitz type II, 3rd
degree AV block, sick sinus syndrome,
baseline QTc > 500 ms, classs Ia or II antiarrhythmics, negative VZV titers, pregnancy
Teriflunomide: positive PPD, LFT’s > 2x ULN
MS Medications Storage
Avonex*
powder
IFN-beta1a
Refrigerate 36 – 46 F or at room temp up
to 30 days. After mixing use with in 6 hrs if
kept in fridge
Avonex*
prefilled
Syringe
Refrigerate 36 – 46 F or at room temp up
to 7 days
Betaseron
IFN-beta1b
Room temp. Use immediately after mixing,
or within 3 hrs if kept in fridge
Extavia
IFN-beta1b
Room temp up to 77 F. Use immediately
after mixing or within 3 hrs if kept in fridge
* Do not freeze, protect from heat and light
MS Medications Storage
Glatiramer*
Copaxone
Refrigerate 36 – 46 F or at room temp up
to 30 days
Rebif*
IFN-beta1a
Refrigerate 36 – 46 F or at room temp up
to 30 days
Fingolimod
Gilenya
Store in original blister pack at room temp
DMF
Tecfidera
Store at room temp. Protect from light,
store in original container
Alemtuzumab Store at room temp or refrigerate . Use
Lemtrada
within 8 hrs of dilution
* Do not freeze, protect from heat and light
MS DMT Annual Drug Cost
** Approximate WAC or Manufacturer published wholesaler price **
Drug
Annual Cost ($)
Glatiramer (Copaxone)
65,104
Interferon beta-1a
- Avonex
- Rebif
65,442
70,638
Interferon beta -1a
pegylated -Plegridy
65,442
Interferon beta-1b
- Betaseron
- Extavia
69,397
57,694
MS DMT Annual Drug Cost
** Approximate WAC or Manufacturer published wholesaler price **
Drug
Annual Cost ($)
Mitoxantrone
3167
Natalizumab
64,480
Alemtuzumab
59,250
Oral agents
- Fingolimod
- Teriflunomide
- Dimethy fumarate
70,752
66,017
65,520
Self Assessment questions
Which of the following are common adverse effects
among the interferon products utilized for MS ?
a. Flushing
b. Acute kidney injury
c. Severe bradycardia
d. Flu like symptoms
Which of the following products can be stored at
room temperature for over 30 days ?
a. Interferon beta-1a (Avonex)
b. Glatiramaer (Copaxone)
c. Interferon Beta 1b (Betaseron)
d. Interferon-Beta 1a (Rebif)
Multiple Sclerosis
• Take home concepts
MS symptoms are from lesions in the CNS
Acute relapses: corticosteriods
Traditional DMTs are injectable: β interferons,
copaxone, mitoxantrone & natalizumab
Newer DMTs are oral therapies: Fingolimod,
Teriflunomide and dimethyl fumarate
Ongoing research: More oral medications
Questions
Kiranpal S. Sangha, Pharm.D.
Clinical Pharmacy Specialist –CNS
The University of Cincinnati Medical Center
Adjunct Asst. Professor Clinical Pharmacy,
James L. Winkle UC College of Pharmacy
Phone: 513-584-3564
Email: [email protected]