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 MStherapies 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

CNSCNS

• The cause is unknown, but immune

mediated physiology is widely accepted

Potential Triggers - Multiple Sclerosis

Environmental

factors

Abnormal immunologic response

Genetic

predisposition

Infectious agent

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 • 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, • 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

1950’s Interferons 1st

1986 Consortium of MS Centers founded

(CMSC)

Injectable DMT’s:1993 IFN-1b Betaseron1995 IFN-1a Avonex1996 Glatiramer2002 IFN-1a Rebif

Oral DMT’s:2010 Dalfampridine2010 Fingolimod2012 Teriflunomide2013 Dimethyl fumarate

1900 2000

1868 MS Named

1916 James Dawson describes pathology MS

1970’s ACTH replaced by IV steriods

1950’s Interferons 1st

identified

Other DMT’s:2014 Alemtuzumab

Future ?

Clinically Isolated Syndrome (CIS)

Drug Reduction in conversion to clinically definite MS at 3

CIS is a first episode of neurologic symptoms that lasts at least 24 hrs & is caused by inflammation or

demyelination in the CNS

clinically definite MS at 3 or 5 yr follow-up

Interferon beta-1b

Interferon beta 1a IM

Glatiramer acetate

37%

35%

45%

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 agentsinjectable 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’s1st 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 edemamacular 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 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 -injectablesDrug Dose Route Frequencyβ 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

(Copaxone) or 40 mg SQ 3 x week

Dosing DMTs -InjectablesDrug Dose Route Frequency

Mitoxantrone 12 mg/m2 IV Every 3 months

Natalizumab (Tysabri) 300 mg IV Every 4 weeks

Alemtuzumab 12 mg/day over 5 days IV Repeat in 1 year

Dosing -Oral AgentsDosing -Oral Agents

Drug Dose Route FrequencyFingolimod 0.5 mg PO daily

Teriflunomide 7 or 14 mg PO daily

Dimethyl fumarate 120 x 7 days then 240 mg PO twice daily

Dalfampridine 10 mg PO twice daily

Self assessment question

• Which of the following are oral disease

modifying therapies for MS ?

a. Interferons, copaxone & alemtuzumaba. 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 diseaseaggressive 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 • 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,• 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 MSphysical 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 re-

start monitoring as new therapy

Fingolimod (Gilenya)

• Use caution in patients taking beta blockers or anti-arrhythmics

• Live attenuated vaccines should be avoided during

the first 2 mo’s of therapy

• Antibody testing for Varicella Zoster virus perform at • 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 MSproliferating 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 stressthe 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• 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, 3rdfailure within 6 mo’s, hx of Mobitz type II, 3rd

degree AV block, sick sinus syndrome,

baseline QTc > 500 ms, classs Ia or II anti-

arrhythmics, negative VZV titers, pregnancy

Teriflunomide: positive PPD, LFT’s > 2x ULN

MS Medications Storage

Avonex*

powder

IFN-beta1a

Avonex*

prefilled

Refrigerate 36 – 46 F or at room temp up to 30 days. After mixing use with in 6 hrs if kept in fridge

Refrigerate 36 – 46 F or at room temp up to 7 daysprefilled

Syringe

Betaseron

IFN-beta1b

Extavia

IFN-beta1b

to 7 days

Room temp. Use immediately after mixing, or within 3 hrs if kept in fridge

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

Glatiramer*

Copaxone

Rebif*

IFN-beta1a

Fingolimod

Refrigerate 36 – 46 F or at room temp up to 30 days

Refrigerate 36 – 46 F or at room temp up to 30 days

Store in original blister pack at room temp

MS Medications Storage

Fingolimod

Gilenya

DMF

Tecfidera

Alemtuzumab

Lemtrada

Store in original blister pack at room temp

Store at room temp. Protect from light, store in original container

Store at room temp or refrigerate . Use 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)

Interferon beta-1a- Avonex- Rebif

65,104

65,44270,638- Rebif

Interferon beta -1a pegylated -Plegridy

Interferon beta-1b- Betaseron- Extavia

70,638

65,442

69,39757,694

MS DMT Annual Drug Cost** Approximate WAC or Manufacturer published wholesaler price **

Drug Annual Cost ($)

Mitoxantrone

Natalizumab

3167

64,480

Alemtuzumab

Oral agents- Fingolimod- Teriflunomide- Dimethy fumarate

59,250

70,75266,01765,520

Self Assessment questionsWhich 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, �Traditional DMTs are injectable: β interferons,

copaxone, mitoxantrone & natalizumab

�Newer DMTs are oral therapies: Fingolimod,

Teriflunomide and dimethyl fumarate

�Ongoing research: More oral medications

Kiranpal S. Sangha, Pharm.D.

Clinical Pharmacy Specialist –CNS

The University of Cincinnati Medical Center

Questions

Adjunct Asst. Professor Clinical Pharmacy,

James L. Winkle UC College of Pharmacy

Phone: 513-584-3564

Email: kiranpal.sangha@uchealth.com