multiple sclerosis

MULTIPLE SCLEROSIS (MS)

PRESENTED BY: Sandeepkumar Balabbigari

CYCLE 7: Qualitas Pharmacy Services

February 2nd, 2016

OBJECTIVES

•Review the etiology and epidemiology of the multiple sclerosis (MS)

•Identify the different types of MS and their associated symptoms

•Understand the pharmacology of the different MS treatments

DISEASE STATE OVERVIEW

BACKGROUND

•Most common inflammatory demyelinating disease of the CNS

•Characterized by inflammation, demyelination, and axon degeneration leading to chronic neurodegeneration

•Myelin sheath is damaged resulting in a breakdown of communication between the CNS and periphery

EPIDEMIOLOGY

•More than 400,000 people in the United States and more than 2 million people globally are affected

•Mean age of onset ranges from 28 to 31 years

• Incidence varies geographically and genetically

•Smoking, Epstein-Barr Virus seropositivity, and other immunologic conditions are other risk factors

•Total lifetime cost: >$4million

ETIOLOGY

•Exact cause remains unknown

•Widely accepted theory: autoimmune disorder

•Autoimmunity is thought to be due to molecular mimicry

•Some evidence indicates MS is an immune-mediated disorder

• Inflammation with blood-brain-barrier disruption

•MS lesions and cerebrospinal fluid (CSF) may show inflammatory T cells, B cells, and macrophages

DIAGNOSIS

•Clinical diagnosis based on exclusion and history of symptoms

•Magnetic resonance imaging (MRI) •Examine active areas of inflammation and scar tissue

•Cerebrospinal fluid (CSF) • Identify certain antibodies and inflammatory cells

•McDonald Criteria •Evaluate patients symptoms to determine if they are suggestive of MS

SIGNS AND SYMPTOMS

•Highly variable between patients

•Most common initial symptom: optic neuritis

•As MS progresses, common signs and symptoms include: •Extreme fatigue

•Heat intolerance

•Depression

•Memory impairment

•Muscle spasticity

•Chronic pain

TYPES OF MS • Relapsing-remitting MS (RRMS)

• Most common (affects 80-85% patients)

• Symptoms flare for 1-3 months, then condition is stable in between attacks

• Secondary Progressive MS (SPMS)

• Initially presents like RRMS, but there is a progressive worsening of symptoms

• Primary Progressive MS (PPMS)

• Steady, gradual neurological decline

• Symptoms are constantly flared with no period of stability

• Progressive Relapsing MS (PRMS)

• Progressive decline in neurological function but with some relapse

TREATMENTS

•Managing acute exacerbations

•Corticosteroids

•Disease-modifying therapy

•Interferons

•Monoclonal Antibodies

•Other immunosuppressants

ACUTE EXACERBATIONS

MANAGING ACUTE EXACERBATIONS

•Indications for treatment include functionally disabling symptoms with evidence of neurologic impairment

•Treatment: methylprednisolone 500-1000 mg IV daily for 3 - 10 days with or without an oral taper (usually prednisone)

•High dose is essential to ensure T-cell death and prevent destruction of myelin sheath

•Plasma exchange (PE) may benefit patients who do not respond to corticosteroid therapy

CORTICOSTEROIDS: MECHANISM OF ACTION

•Decreases formation, release, and activity of inflammatory mediators and ultimately inhibits migration to the area of injury

•Used for anti-inflammatory activity, immunosuppressive properties, and antiproliferative actions

•Also reverse the dilation and increased vessel permeability in areas of inflammation

CORTICOSTEROIDS: SIDE EFFECTS

Short Term Side Effects

•Abdominal discomfort

•Weight gain

•Rounded face, upper back, and belly

•Hyperglycemia, hypertension

•Behavioral changes

•Increased risk for infection

Long Term Side Effects

•Worsening short term side effects

•Osteoporosis

•Adrenal insufficiency

•Glaucoma, cataracts

•Cardiovascular disease

•Slow wound healing

Side effects are managed by using the lowest dose for the shortest

time to achieve goals, treating preexisting conditions,

and monitoring

CORTICOSTEROIDS: INTERACTIONS

•Strong CYP3A4 Inducers: may decrease serum concentration of corticosteroids

•Strong CYP3A4 Inhibitors: may increase serum concentration of corticosteroids

•Immunosuppressants may enhance the risk for hematologic toxicities and risk of infections

DISEASE-MODIFYING THERAPIES

DISEASE-MODIFYING THERAPIES

•Goal is to slow the progression of the disease and reduce frequency and severity of relapses

•Not curative

•Treatment options •Self-administered injections

• IV infusions

•Oral agents

•All agents are indicated to treat relapsing forms of MS

SELF-ADMINISTERED INJECTIONS

•Interferon-β-1a

•Avonex® (IM)

Rebif® (SubQ)

•Peginterferon-β-1a

•Plegridy® (SubQ)

•Interferon-β-1b

Betaseron® (SubQ)

Extavia® (SubQ)

•Glatriamer

•Copaxone® (SubQ)

INTERFERONS

Mechanism of Action

•Unknown

•Immunomodulator

•Suppresses immune cell function and proliferation

Adverse Drug Reactions

•Flu-like symptoms

•Injection site and allergic reactions

•Depression and suicidal ideation

•Hematologic abnormalities

•Congestive heart failure

•Hepatic injury

INTERFERONS

•Monitoring & ADR Management

•Alleviate flu-like symptoms with analgesics and/or antipyretics

•Monitor baseline and changes in CBC, LFT, mental status

•Assess for signs and symptoms of cardiac disease progression

•Be aware of neutralizing antibodies

•No major drug interactions

GLATIRAMER (COPAXONE®)

Mechanism of Action

•Unknown

•Suppresses immune cell function and proliferation

•Interfere with antigen presenting cells (APCs)

Adverse Drug Reactions

•Immediate transient post-injection reaction

•Lipoatrophy and skin necrosis at injection site

•Increased risk for infection

GLATIRAMER

•Monitoring & ADR Management •Avoid lipoatrophy and necrosis by following proper injection technique and rotating injection sites

•Does not require as rigorous monitoring as interferon products

•Interactions •Other immunosuppressants may enhance the immunosuppressive effect

•Toxic effects of vaccines are enhanced

•Therapeutic effects of vaccines are diminished

IV INFUSIONS

•Alemtezumab

•Lemtrada® (IV solution)

•Natalizumab

•Tysabri® (IV solution)

•Mitoxantrone

•Novantrone® (IV solution)

IV INFUSIONS: MECHANISMS OF ACTION

•Alemtezumab (Lemtrada®)

• Binds to CD52 antigens on immune cells’ surfaces, which leads to the activation of cell death processes

•Natalizumab (Tysabri®)

• Binds to the α-4 subunit of integrin molecules to block adhesion and migration of immune cells

•Mitoxantrone (Novantrone®)

• Inserts into and divides DNA and RNA strands and prevents repair

IV INFUSIONS: ADVERSE DRUG REACTIONS

•Alemtezumab (Lemtrada®)

• >90% of patients in clinical trials experienced infusion reactions

• Increased risk of Herpes Simplex Virus infections

•Natalizumab (Tysabri®)

• Box Warning: increased risk of developing progressive multifocal leukoencephalopathy (PML)

• Hepatotoxicity and potential acute liver failure

IV INFUSIONS: ADVERSE DRUG REACTIONS

•Mitoxantrone (Novantrone®)

•Box Warning: myocardial toxicity and potentially-fatal heart failure (HF)

•Maximum lifetime dose: 140 mg/m2 and must discontinue if left ventricular ejection fraction (LVEF) is <50% or significantly reduced

•Temporary blue discoloration of sclera and urine

•Menstrual disorders

IV INFUSIONS: MONITORING & ADR MANAGEMENT

•Monitor CBC, signs of infection, dermatologic changes

•Alemtezumab (Lemtrada®)

• Premedicate with high-dose corticosteroids

• Administer herpes viral prophylaxis

•Natalizumab (Tysabri®)

• Monitor for symptoms of PML

• Monitor for signs of liver injury

•Mitoxantrone (Novantrone®)

• Evaluate for cardiac-related signs/symptoms

IV INFUSIONS: INTERACTIONS

•Other immunosuppressants may enhance the immunosuppressive effect

•Toxic effects of vaccines are enhanced

•Therapeutic effects of vaccines are diminished

ORAL AGENTS

•Dimethyl Fumarate

•Tecfidera® (capsule)

•Fingolimod

•Gilenya® (capsule)

•Teriflunomide

•Aubagio® (tablet)

ORAL AGENTS: MECHANISMS OF ACTION

•Dimethyl Fumarate (Tecfidera®) •Activates the nuclear factor-like 2 (Nrf2) pathway and increases interleukin-10, which have anti-inflammatory and cytoprotective properties

•Fingolimod (Gilenya®) •Sequesters lymphocytes within lymph nodes by modulating the sphingosine 1-receptor

•Teriflunomide (Aubagio®) • Inhibits de novo pyrimidine synthesis by inhibiting dihydroorotate dehydrogenase, thus having a ctoytostatic effect on lymphocytes

ORAL AGENTS: ADVERSE DRUG REACTIONS •Dimethyl Fumarate (Tecfidera®)

• Flushing

•GI events

• Increased risk of developing progressive multifocal leukoencephalopathy (PML)

•Fingolimod (Gilenya®)

• Contraindicated in patients with cardiac abnormalities

• Bradycardia

• Hepatic dysfunction

•Teriflunomide (Aubagio®)

• Contraindicated in patients with severe hepatic impairment and in pregnant women

• Box Warning: hepatic failure

ORAL AGENTS: MONITORING & ADR MANAGEMENT

•Monitor CBC and signs of infection

•Dimethyl Fumarate (Tecfidera®)

• Take with aspirin (up to 325 mg PO) and food 30 minutes prior to administration to decrease flushing and GI effects

• Withhold therapy if symptoms of PML appear

•Fingolimod (Gilenya®)

• First dose must be given in a healthcare setting due to the risk of bradycardia

• Monitor cardiac function

• Monitor liver function and enzymes

•Teriflunomide (Aubagio®)

• Monitor liver function and enzymes

SUMMARY

•MS is an inflammatory disease that causes axonal demyelination leading to chronic neurodegeneration

•Treatment of MS involves managing acute exacerbations and slowing disease progression with Disease-Modifying Therapy

•For most patients, the first-line treatment will be the self-administered injectable interferons or glatiramer

•IV infusions and oral agents are options for patients who cannot tolerate or whose condition does not respond well to the self-administered medications

REFERENCES

1. "Multiple Sclerosis by the Numbers: Facts, Statistics, and You." Healthline. Web. 19 Jan. 2016.

2. Ramagopalan SV, Sadovnick AD. Epidemiology of multiple sclerosis. Neurol Clin. 2011;292:207–217.

3. Goodin DS. The epidemiology of multiple sclerosis: insights to disease pathogenesis. Handb Clin Neurol.2014;122:231–266.

4. Libbey JE, McCoy LL, Fujinami RS. Molecular mimicry in multiple sclerosis. Int. Rev. Neurobiol.2007;79:127–147.

5. Roach E.S. Is multiple sclerosis an autoimmune disorder? Arch. Neurol. 2004;61:1615–1616.

6. Buchman AL. Side effects of corticosteroid therapy. J Clin Gastroenterol. 2001;33:289–294. doi: 10.1097/00004836-200110000-00006.

7. Costello, K., J. Halper, and R. Kalb. "The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence." (n.d.): n. pag. National MS Society. Multiple Sclerosis Coalition, Mar. 2015. Web. 19 Jan. 2016.

8. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: http://online.lexi.com. 19 Jan. 2016.

9. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. 19 Jan. 2016.

10. Burnetti, Luigi. " Musculoskeletal Disorders: Multiple Sclerosis & Amyotrophic Lateral Sclerosis." Rutgers University. Mar. 2015. Lecture.

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