Multiple Sclerosis Presentation

MULTIPLE SCLEROSIS Catherine Van, PharmD, BCPS Assistant Professor, Pharmacy Practice Learning Objectives (Part I) • Identify types of multiple sclerosis (MS), risk factors, and clinical presentations • Compare all disease modifying agents based on MOA, Black Box warning, and significant adverse effects Introduction/Epidemiology • Multiple sclerosis (MS) o Inflammatory disease of the central nervous system o Refers to two characteristics of the disease: multiple neurologic symptoms that accrue over time, and characteristic plaques or sclerosed areas seen in numerous areas of the brain and spinal cord • Diagnosed between the ages of 15 and 50 years with a peak incidence occurring in the fourth decade • Affected women more than men (2.8:1) • Occurs more frequently in Whites of Scandinavian ancestry compared to other ethnic groups Wallin MT, et al. Neurology. 2019;92(10):e1029-e1040; Multiple Sclerosis International Federation. Atlas of MS, 3rd edition; Dipiro 12e Chapter 74 Epidemiology Wallin MT, et al. Neurology. 2019;92(10):e1029-e1040; Multiple Sclerosis International Federation. Atlas of MS, 3rd edition; Dipiro 11e Chapter 72 Epidemiology Etiology • Exact cause of MS unknown • Thought to develop in genetically susceptible individuals exposed to random events and environmental factors that could trigger immunemediated CNS damage Dipiro 12e Chapter 74 Risk Factors • Gender • Specific ethnicity • Genes: genetic variation accounts for approximately 30% of the overall disease risk • Environmental factors: o Cigarette smoking o Viruses - Epstein–Barr virus (EBV) ▪ Strong and consistent association between history or serological evidence (mainly anti‐EBNA IgG) of past EBV infection and increased risk of developing MS o Vitamin D deficiency/low sun exposure ▪ MS prevalence increases with greater distance from the equator Dipiro 11e Chapter 72; Waubant E, Lucas R, Mowry E, et al. Ann Clin Transl Neurol. 2019 Sep; 6(9): 1905–1922. Risk Factors • Environmental factors (cont.): o Childhood/adolescence obesity ▪ Double the risk of developing pediatric and adult MS compared with normal‐weight individuals (from observational studies) ▪ Association largely confirmed in females o Geographic gradient ▪ Migration from a low- to high-risk area when < 15 years old → acquires the same chance of developing MS as those who live in a high-risk area all their lives ▪ Migration from a high- to low-risk area, the individual retains high risk status if the move is made after the age of 15 years but acquires the lower risk if the move is made prior to this age Dipiro 11e Chapter 72; Waubant E, Lucas R, Mowry E, et al. Ann Clin Transl Neurol. 2019 Sep; 6(9): 1905–1922. Pathophysiology Immune cells enter CNS → Demyelination → Axons susceptible to damage → Irreversible axonal damage (seen as lesions or “black holes” on T1–weighted MRI) → disability Dipiro 11e Chapter 72; Dipiro 12e Chapter 74 Clinical Presentation • Primary Symptoms/Signs o Visual complaints/optic neuritis o Gait problems and falls o Paresthesias o Pain o Spasticity o Weakness o Ataxia o Speech difficulty o Psychological changes o Cognitive changes o Fatigue o Bowel/bladder dysfunction o Sexual dysfunction o Tremor Dipiro 12e Chapter 74 Secondary Symptoms • • • • Respiratory infections Recurrent UTIs Urinary calculi Decubiti and osteomyelitis • Osteoporosis • Poor nutrition • Depression Dipiro 12e Chapter 74 Tertiary Symptoms affects quality of life • Financial problems • Personal/social problems • Vocational problems • Emotional problems MS Classification • Relapsing-Remitting MS • Secondary-Progressive MS • Primary Progressive MS Dipiro 12e Chapter 74 Relapsing-Remitting MS • Most common disease course • Characterized by clearly defined attacks/relapses of new or increasing neurologic symptoms • Followed by periods of partial or complete recovery (remissions) • During remissions, all symptoms may disappear, or some symptoms may continue and become permanent • No apparent progression of disease during periods of remission https://www.nationalmssociety.org/What-is-MS/Types-of-MS diagnosedIn earlier ages Secondary-Progressive MS • Follows an initial relapsing-remitting course • Some people diagnosed with RRMS will eventually transition to a secondary progressive course • There is a progressive worsening of neurologic function (accumulation of disability) over time accumulate neurological damage https://www.nationalmssociety.org/What-is-MS/Types-of-MS Primary Progressive MS • Characterized by worsening neurologic function (accumulation of disability) from the onset of symptoms, without early relapses or remissions • Often diagnosed at a later age • Worse prognosis than those who present initially with RRMS https://www.nationalmssociety.org/What-is-MS/Types-of-MS Diagnosis • No definitive diagnostic test • Clinically definite MS requires documentation of two or more episodes of symptoms and 2 or more signs that reflect pathology in anatomically noncontiguous white matter tracts of the CNS o Symptoms must last for > 24 hours o Occur as distinct episodes that are separated by a month or more o At least one of the 2 required signs must be present on neurologic examination Diagnostic Criteria D The revised McDonald Criteria • Damage in at least 2 separate areas of CNS oBrain, Spinal Cord, Optic Nerves AND • Damage occurred 1 month apart • AND Rule out all other possible diagnoses • These tools may be used to look for a 2nd area of damage in a person with only 1 attack https://www.nationalmssociety.org/For-Professionals/Clinical-Care/Diagnosing-MS/Diagnosing-Criteria Diagnostic Tools Medical history- Birthplace, family history, places traveled Neurologic Exam- Evaluate mental, emotional, language functions Movement, coordination, balance, vision, and other four senses D Magnetic Resonance Imaging (MRI)- Gold standard Best at detecting MS plaques or scarring in different parts of CNS Can differentiate old lesions from those that are new or active Diagnosis not solely based on MRI (other diseases cause similar lesions) Some people (geriatrics) have spots without ANY diseases Cerebrospinal Fluid (CSF)- Clear, colorless fluid bathes brain and spinal cord Serves as shock absorber for CNS; Circulates nutrients and removes waste products from brain “Spinal Tap” findingsElevated levels of IgG antibodies and oligoclonal bands Findings indicate autoimmune response within CNS Visual Evoked Potential (VEP) • Test measures the electrical activity of the brain in response to stimulation of specific sensory nerve pathway • Detects the slowing of electrical conduction caused by demyelination o Even when the change is too subtle to be noticed by the person or to show up on neurologic examination Prognosis Indicator Favorable Prognosis Unfavorable Prognosis Age at onset < 40 years > 40 years Gender Female Male Initial symptoms Optic neuritis or sensory symptoms Motor or cerebella symptoms Attack frequency in early disease Low High Course of disease Relapsing/remitting Progressive Dipiro 12e Chapter 74 DISEASE-MODIFYING THERAPIES (DMTS) Oral: Injectable: Fingolimod (Gilenya) Interferon beta-1a Cladribine (Mavenclad) Avonex Siponimod (Mayzent) Rebif Teriflunomide (Aubagio) Interferon beta-1b Dimethyl fumarate Betaseron (Tecfidera) Extavia Dalfampridine (Ampyra) Peginterferon beta-1a Infusion: (Plegridy) drawn from market Natalizumab (Tysabri) Daclizumab (Zinbryta) Alemtuzumab (Lemtrada) Glatiramer acetate (Copaxone, Glatopa) Mitoxantrone (Novantrone) Ofatumumab (Kesimpta) Ocrelizumab (Ocrevus) with Interferons ➢ Differs from naturally occurring human protein by a single amino acid substitution and the lack of carbohydrate side chains ➢ Mechanism in the treatment of MS is unknown • Beta-1a: o Alters the expression and response to surface antigens o Enhance immune cell activities o Properties of interferon beta that modify biologic responses are mediated by cell surface receptor interactions • Beta-1b: o Enhancement of suppressor T cell activity o Reduction of proinflammatory cytokines o Down-regulation of antigen presentation o Reduced trafficking of lymphocytes into the central nervous system o Improves MRI lesions, decreases relapse rate, and disease severity in patients with secondary progressive MS A Brand Interferon Beta 1a Avonex® Labeled Indication Rebif ® Relapsing forms of MS (including clinically isolated syndrome, relapsingremitting disease, and active secondary progressive disease) Dose and Route 30 mcg IM qweekly Prefilled syringe; prefilled autoinjector Dose Eni Adjustment Renal: no adjustment Hepatic: no adjustment; caution if active liver disease or ALT>2.5 x ULN Warning • • • • • * Anaphylaxis Autoimmune disorder Injection site necrosis Hepatotoxicity Flu-like symptoms 22 or 44 mcg SQ 3x/week Prefilled syringe; autoinjector • • • • Thyroid dysfunction Bone marrow suppression: pancytopenia, leukopenia Neuropsychiatric disorders: psychosis, depression, suicidal ideation Disease states: cardiovascular, seizure, thyroid dysfunction Drug Interactions Theophylline, Zidovudine MonitoringD Thyroid function tests, CBC w/ diff, transaminase levels (LFT q6 months for Avonex), CMP, sx of autoimmune disorders, s/sx of psychiatric disorder (e.g. depression and/or suicidal ideation), s/sx of new onset/worsening cardiovascular disease ADR- Interferon Beta 1a • Headache • Injection site rxn: do not • Fatigue inject where skin is irritated, bruised, scarred or infected • Vision abnormalities • Flu-like symptoms: fever, myalgia • Skeletal pain • Depression • Leukopenia • Increase LFT • UTI • URTI **DO NOT SHAKE Store in refrigerator; allow to warm to RT prior to use; Pregnancy category C CI: Hypersensitivity to natural or recombinant interferon beta, albumin human or any other component of the formulation Brand A Interferon Beta 1b Betaseron® Labeled Indication Extavia® Relapsing forms of MS (including clinically isolated syndrome, relapsingremitting disease, and active secondary progressive disease in adults) Dose and Route 0.25 mg SQ qod Administration Must be used immediately after reconstitution If not used immediately, can refrigerate up to 3 hours Dose Adjustment Renal: no adjustment Hepatic: no adjustment Warning • • • • • Anaphylaxis Autoimmune disorder Injection site necrosis Hepatotoxicity Flu-like symptoms 0.25 mg SQ qod • • • • Thyroid dysfunction Bone marrow suppression: pancytopenia, leukopenia Neuropsychiatric disorders: psychosis, depression, suicidal ideation Disease states: cardiovascular, seizure, thyroid dysfunction Drug Interactions Theophylline, Zidovudine Monitoring CMP, CBC w/ diff., LFTs at 1, 3, and 6 months w/ initiation and prn thereafter Thyroid function q6month w/ history thyroid dysfunction or clinically necessary; flu-like symptoms, allergic or anaphylactic reactions, injection site reactions, worsening of cardiac symptoms (in heart failure patients); s/sx of depression ADR- Interferon Beta 1b • Peripheral edema • Depression • Weakness • Inflammation • Headache • Injection site reaction • Hypertonia • Menorrhagia • Lymphopenia • Impotence • Myalgia, asthenia • Dysmenorrhea • Neutropenia • Flu-like symptoms: • Incoordination transient **DO NOT SHAKE CI: Hypersensitivity to natural or recombinant interferon beta, albumin human or any other component of the formulation Pregnancy category C Peginterferon beta-1a (Plegridy) • Indication: Relapsing forms of MS • Dose: 63 mcg SQ on day 1; 94 mcg on day 15 → maintenance: 125 mcg SQ every 14 days beginning on day 29; (can also be given IM) • ADR: injection site reaction, arthralgia, HA, flulike symptoms oSerious: CHF, injection site necrosis, hepatitis, angioedema, suicidal thoughts • Monitoring: LFT, CBC w/ diff., cardiac disease, signs/symptoms of infection, bleeding, anemia, psychiatric disorders Glatiramer acetate (Copaxone) • MOA: immune modulator • Dose: 20 mg SC daily or 40 mg SC 3 times per week (administered at least 48 hours apart) • Indication: o Relapsing forms of MS • Dose adjustment: o Renal/hepatic: No dosage adjustment provided • Store in refrigerator Glatiramer acetate (Copaxone) • Pregnancy category B • Adverse Drug Reactions o Vasodilation, chest pain o Pain, anxiety &o Lipoatrophy (may not resolve) o Rash, flushing, urticaria o Injection site reactions: redness, swelling, itchiness o Weakness, back pain o Dyspnea o Infection, flu-like symptoms, diaphoresis • NOTE: Allergy warning o Contains mannitol: CI in mannitol allergy Ofatumumab (Kesimpta®) • MOA: Anti-CD20 monoclonal antibody • Indications: relapsing forms of MS • Dose: 20 mg SQ once weekly for 3 doses (weeks 0, 1, and 2) then 20 mg SQ once monthly starting at week 4 I• CI: active hepatitis B virus infection • ADR:AInfections (including URTI, UTI, etc.); injection site rxns; headache; back pain; decreased serum immunoglobulins Fyl• Monitoring: quantitative serum immunoglobulins (at baseline, throughout treatment as clinically necessary); Hep B virus screening (baseline and as clinically necessary); s/sx of PML; MRI (as clinically indicated) *• Store in original container at 2°C to 8°C (36°F to 46°F); do not shake; protect from light - Last Resort MitoXANtrone (Novantrone) • Class: Antineoplastic Agent, Anthracenedione • FDA indication: relapsing-remitting MS or secondary progressive MS (not indicated: primary progressive MS) • Dosing: 12 mg/m2 IV every 3 months o MAX. lifetime cumulative dose: 140 mg/m2 * S o D/C use with LVEF<50% or clinically significant reduction in LVEF & Fl• Dose Adjustment: o Renal: none o Hepatic: should not receive Fri• Monitoring: CBC w/ diff, LFTs, pregnancy test, injection site for extravasation, ECG, LVEF MitoXANtrone (Novantrone) *• BBW: o Do not use if neutrophil count <1500 cells/mm3 ▪ Monitor blood count and infection o Myocardial toxicity (LVEF <50%) and HF o Increased risk of secondary AML D• IV administration only o Severe local tissue damage if extravasation o Short IV infusion over 5-25 min; do not infuse over <3-5 minutes • Administered by MD supervision and eyes *• Blue-green coloration of secretions 24 post may persist his infusion MitoXANtrone (Novantrone) • ADR: &• Pregnancy Category D Natalizumab (Tysabri) • Labeled indication: relapsing forms of MS • Dose: 300mg IV infused over 1 hour every 4 wks Fri• Dose Adjustment o Renal: No dosage adj. provided o Hepatic: No dosage adj. provided; D/C use with jaundice or s/sx of hepatic injury • Storage: must refrigerate (warm solution to room temp. prior to administration) &• REMS drug: TOUCH Prescribing Program Natalizumab (Tysabri) • Contraindication * o Hypersensitivity o Current or history of Progressive Multifocal Leukoencephalopathy (PML) viral brain infection (can be fatal) • BBW: * o Increase risk of PML • Warning/precautions: o Hepatotoxicity o Herpes infection Do Infusion-related reactions Chypersensitivity) o Immune reconstitution inflammatory syndrome (IRIS) upon discontinuation o Infections (eg. Opportunistic infections) o Depression - Natalizumab (Tysabri) &• Pregnancy Category C Fi • ADRs o Headache, fatigue, depression o Rash o Abdominal discomfort o UTI o Arthralgia, extremity pain, back pain o Upper respiratory infection, lower respiratory infection • Monitoring Al o S/Sx of hepatotoxicity, infection, depression o S/Sx of hypersensitivity during infusion and 1 hour post infusion o S/Sx suggestive of PML (weakness in one side of the body, vision disturbance, changes in memory or thinking) during treatment and for 6 months after discontinuation * Generics but Brand for interferous ONLY Alemtuzumab (Lemtrada) • Indication: Relapsing remitting MS and active secondary progressive multiple sclerosis • Dose: 12 mg/d IV for 5 days then 12 mg/d IV for 3 days administered 12 months after first dose o Premedicate with methylprednisone (1000mg) prior to infusion for D first 3 days Ao Herpes viral prophylaxis on day 1 and continue at least 2 months 3 after completion of treatment or until CD4+ count is ≥200cells/mm a• CI: HIV infection; active infection D• BBW: fatal autoimmune conditions; infusion rxns; malignancies; stroke A• REMS * • Monitoring: CBC w/diff, SCr, urinalysis, infusion reactions (monitor 2hr period), risk of malignancies, skin exams Ocrelizumab (Ocrevus®) • MOA: Anti-CD20 monoclonal antibody & ONLY one • Indications: Multiple sclerosis, relapsing or primary [ • • • • for : progressive Dose: 300 mg IV on day 1, followed by 300 mg 2 weeks later; subsequent doses of 600 mg are administered once every 6 months (beginning 6 months after the first 300 mg dose); premedication needed prior to each infusion CI: history of life-threatening infusion reaction to ocrelizumab; active hepatitis B virus (HBV) infection ADR: infusion reaction, infection, malignancies Monitoring: Hepatitis B virus screening in all patients prior to therapy initiation; infusion reactions during infusion and for at least 1 hour following the end of the infusion Question Which side effects are seen with interferon therapy (Avonex, Betaseron, Extavia, Rebif, or Peginterferon)? Select all that apply. a. Flu-like symptoms b. Depression c. Chest tightness d. Skin injection-site reactions ORAL DRUGS Fingolimod (Gilenya) • Labeled indication: oRelapsing forms of MS and delay disability progression • Dose: 0.5 mg PO qdaily • Dose Adjustments oRenal: no adjustment necessary oHepatic: ▪ Mild-mod- no adj. provided ▪ Severe- monitor closely and use with caution Fingolimod (Gilenya) D• CI: o Baseline QTc interval1≥500 msec docaine flecalnide/amodarone o Concurrent use of a class Ia or III antiarrhythmic o 2∘ or 3∘ AV block, unless pt has pacemaker o Within 6 months prior to treatment initiation , ▪ ▪ ▪ ▪ ▪ MI Unstable angina Stroke TIA Decompensated heart failure (requiring hospitalization)/ NYHA class III/IV HF • Note D o Avoid live vaccines during treatment and 2 months after o PML Warning Fingolimod (Gilenya) Special Alert: • PML Warning (August 2013) • Labeling Revised with Stronger Cardiovascular Warnings and Recommendations (May 2012) • When initiating 1st treatment dose for all patients: o Monitor: ▪ Signs/symptoms of bradycardia for at least 6 hours ▪ Hourly pulse and BP measurement o ECG/EKG done prior to dosing and at the end of observation period, cardiovascular monitoring should continue until any symptoms resolve o High risk pts: Extended cardiovascular monitoring (>6hrs-overnight) ▪ Severe bradycardia (HR <45bpm) after 1st dose ▪ QT prolongation prior to fingolimod ▪ Other meds that can slow the HR or atrioventricular conduction ▪ Take other meds that prolong the QT interval • Fatality Reported Within 24 Hours of Initial Administration of Fingolimod (Gilenya®) [December 2011] & Fingolimod (Gilenya) S Ell • ADR: o Headache o Diarrhea o Increase AST, ALT o Back pain o Flu like symptoms • DDI: Category X: Antiarrhythmic Agents (class Ia and III) • Monitoring parameters o Decreases in HR bradycardia o Ophthalmologic exam: Macular edema o Infections o Respiratory function D• Pregnancy: elimination takes 2 months; should wait 2 months before becoming pregnant o Pregnancy Registry Teriflunomide (Aubagio®) • Labeled indication: relapsing forms of MS • Dose: 7 mg or 14 mg PO qdaily • Adjustment: o Renal: no adjustment o Hepatic (severe): contraindicated &• Contraindications o Severe hepatic impairment o Concomitant use with leflunomide (Arava) ▪ Teriflunomide is the active metabolite of leflunomide o Pregnant women o Women of childbearing age who will not use contraception reliably o Pregnancy Category X Teriflunomide (Aubagio®) • BBW: DA• Hepatotoxicity: o Same risk as leflunomide: hepatic failure → death o Do not initiate with: ▪ Pre-existing acute or chronic liver disease or ▪ ALT> 2x ULN ▪ Caution w/ concurrent hepatotoxic drugs o Discontinue with ALT>3x ULN and use drug elimination procedure (eg. cholestyramine, activated charcoal) • Pregnancy: Embryotoxic * o Birth defects Teriflunomide (Aubagio®) NOTE: Aubagio can stay in the blood for up to 2 years after stopping use Drug elimination procedure: • To achieve <0.02 mg/L of teriflunomide, administer either of the following • Cholestyramine: 8 g every 8 hours for 11 days 7 o If not tolerated, may decrease to 4 g every 8 hours for 11 days o The 11 days do not need to be consecutive unless plasma concentrations need to be lowered rapidly alternative Dose Fyi • Activated charcoal: 50 g every 12 hours for 11 days D Teriflunomide (Aubagio®) Fui • ADR: oSteven-Johnson syndrome, liver failure, neutropenia, respiratory infection, activation of TB, alopecia, hypophosphatemia, diarrhea/nausea, headache, arthralgia, hypertension, neuropathy • Monitoring: oCBC, LFT, blood pressure, pregnancy, TB Smay cause HTW) Crisk) Dimethyl fumarate (Tecfidera®) • Indication: relapsing forms of MS • Dose: 120 mg PO BID x 7 days, then 240 mg PO BID • Dose Adjustment: No renal/hepatic adj necessary butter maytake Peanut = *o Flushing (can give aspirin 30 min prior) o Abd pain/Diarrhea/Nausea o Pruritus o Increase LFT o Infection o Decrease WBC • Monitoring: CBC prior to and every 3 months thereafter and as clinically necessary, LFT (prior to treatment initiation and during treatment as clinically indicated) • ADR: or yoe a Dalfampridine (Ampyra)* INFO : • Approved in 2010 for ability to improve walking in MS • Improved walking speed by about 25% in all forms of MS • Potassium channel blocker (nonspecific) Class MOA indication • Improves conduction in focally demyelinated axons by delaying repolarization and prolonging the duration of action potentials • Enhanced neuronal conduction is thought to strengthen skeletal muscle fiber twitch activity→ improving peripheral motor neurologic function Dosing • 10 mg PO every 12 hours (maximum 20 mg/day) Administration • With or w/out food • Do NOT chew, crush, dissolve or divide tablet ContraindicationY• History of seizures (FDA Alert July 2012) • CrCl ≤50mL/min ADR F • UTI • Dizziness • Insomnia • HA Note • Pregnancy category C Fyi Cladribine (Mavenclad) • Indication: relapsing forms of MS (relapsing-remitting; active secondary progressive) • Dose: 3.5 mg/kg PO and divided into 2 yearly treatment courses with each treatment course divided into 2 treatment cycles separated by 23-27 days Fyi• Dose Adjustment (for PO): o CrCl <60 mL/minute: Use is not recommended o Moderate to severe impairment (Child-Pugh classes B and C): Use is not recommended • ADR: URTI, HA, lymphocytopenia, nausea, depression D• CI: current malignancy; pregnancy; men or women of reproductive potential who do not plan to use effective contraception during therapy and for 6 months after the last dose in each treatment course; HIV infection; active chronic infections (eg, hepatitis or tuberculosis); breastfeeding (during treatment or for 10 days after last dose) Siponimod (Mayzent) • Indication: relapsing forms of MS D • Dose: PO daily (based on CYP2C9 genotype) • MOA: sphingosine-1-phosphate (S1P) receptor modulator that blocks the lymphocytes' ability to emerge from lymph nodes • **CYP2C9 genotype must be determined prior to initiation D • Dose Adjustment: No renal/hepatic adj necessary • First dose monitoring for 6 hours recommended for D patients with sinus bradycardia (HR <55 bpm), first- or second-degree AV block, or a history of MI or heart failure • ADR: HA, hypertension, peripheral edema, bradycardia Siponimod (Mayzent) • CI: oCYP2C9*3/*3 genotype * oRecent (in the past 6 months) myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure oSecond-degree, third-degree atrioventricular block, or sick sinus syndrome, unless patient has a functioning pacemaker SUMMARY TABLES Drug Interferon beta-1a (Avonex) Prefilled syringe & autoinjector - albumin free Interferon beta-1a (Rebif) Prefilled syringe & autoinjector - contain albumin Dosing Contraindications/BBW 30 mcg IM once weekly CI: Hypersensitivity to natural or recombinant interferon beta, human albumin (albumin-containing formulations only), or any 22 or 44 mcg SQ 3 times weekly other component of the (doses should be separated by at formulation least 48 hours) Interferon beta-1b (Betaseron; Extavia) 0.25 mg SQ every other day CI: History of hypersensitivity to natural or recombinant interferon beta, albumin (human), or any component of the formulation Peginterferon beta1a (Plegridy) 63 mcg SQ on day 1; 94 mcg on day 15 → maintenance: 125 mcg SQ every 14 days beginning on day 29 (can also be given IM) CI: Hypersensitivity to natural or recombinant interferon beta or peginterferon, or any component of the formulation Drug Dosing Contraindications/BBW Glatiramer acetate (Copaxone, Glatopa) 20 mg SQ once daily or 40 mg SQ 3 times per week administered at least 48 hours apart CI: Hypersensitivity to glatiramer acetate, mannitol, or any component of the formulation Ofatumumab (Kesimpta) 20 mg SQ once weekly for 3 CI: Active hepatitis B doses (weeks 0, 1, and 2) virus infection then 20 mg SQ once monthly starting at week 4 Drug Dosing Contraindications/BBW Mitoxantrone (Novantrone) 12 mg/m2 IV every 3 months (maximum lifetime cumulative dose: 140 mg/m2; discontinue with LVEF <50% or clinically significant reduction in LVEF CI: Hypersensitivity to mitoxantrone or any component of the formulation BBW: • Bone marrow suppression: Do not use if neutrophil count <1500 cells/mm3 (monitor blood count and infection) • Myocardial toxicity (LVEF <50%) and HF • Increased risk of secondary acute myeloid leukemia • IV administration only; under the supervision of provider experienced in the use of cytotoxic chemotherapy agents Natalizumab (Tysabri) 300 mg IV infused over 1 hour every 4 weeks CI: Hypersensitivity to natalizumab or any component of the formulation; current or history of progressive multifocal leukoencephalopathy (PML) BBW: Increase risk of PML REMS drug Drug Dosing Contraindications/BBW Alemtuzumab (Lemtrada) 12 mg IV daily for 5 consecutive days, followed 12 months later by 12 mg IV daily for 3 consecutive days CI: Hypersensitivity, HIV infection; active infection BBW: • Bone marrow suppression (may be fatal) • Infusion reactions (may be fatal): Monitor patients for at least 2 hours after each infusion; premedication recommended • Serious, including fatal, bacterial, viral, fungal, and protozoan infections • Serious, fatal autoimmune conditions • Increased risk of malignancies • Serious and life-threatening stroke 300 mg IV on day 1, followed by 300 mg 2 weeks later; subsequent doses of 600 mg are administered once every 6 months (beginning 6 months after the first 300 mg dose); premedication needed prior to each infusion CI: History of life-threatening infusion reaction to ocrelizumab; active hepatitis B virus (HBV) infection REMS drug Ocrelizumab (Ocrevus) Drug Dosing Contraindications/BBW Fingolimod (Gilenya) 0.5 mg PO once daily CI: • Hypersensitivity • Baseline QTc interval ≥500 msec • Concurrent use of a class Ia or III antiarrhythmic • 2∘ or 3∘ AV block, unless pt has pacemaker • Within 6 months prior to treatment initiation ▪MI ▪Unstable angina ▪Stroke; TIA ▪Decompensated heart failure (requiring hospitalization)/ NYHA class III/IV HF Teriflunomide (Aubagio) 7 mg or 14 mg PO once daily CI: Hypersensitivity to teriflunomide, leflunomide, or any component of the formulation; severe hepatic impairment; coadministration with leflunomide; pregnant women; females of reproductive potential not using effective contraception BBW: hepatotoxicity, embryofetal toxicity Dimethyl fumarate (Tecfidera) 120 mg PO twice daily for 7 days then 240 mg PO twice daily CI: Hypersensitivity to dimethyl fumarate or any component of the formulation Drug Dosing Contraindications/BBW Dalfampridine (Ampyra) 10 mg PO every 12 hours (maximum daily dose: 20 mg) CI: Hypersensitivity; history of seizure; moderate or severe renal impairment (CrCl ≤50 mL/minute) Cladribine (Mavenclad) 3.5mg/kg PO and divided into 2 yearly treatment courses with each treatment course divided into 2 treatment cycles separated by 23-27 days CI (for oral use): Hypersensitivity; current malignancy; pregnancy; men or women of reproductive potential who do not plan to use effective contraception during therapy and for 6 months after the last dose in each treatment course; HIV infection; active chronic infections (eg, hepatitis or tuberculosis); breastfeeding (during treatment or for 10 days after last dose) BBW (for oral use): • Increased risk of malignancy • Teratogenicity Siponimod (Mayzent) PO once daily (based on CYP2C9 genotype) CI: • CYP2C9*3/*3 genotype • Recent (in the past 6 months) MI, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure • Second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker MULTIPLE SCLEROSIS PART II Catherine Van, PharmD, BCPS Assistant Professor, Pharmacy Practice Learning Objectives (Part II) • Discuss recommendations for disease modifying agents (DMTs) in pregnancy and lactation • Examine management strategies for MS • Formulate appropriate treatment plan for a patient diagnosed with MS Pregnancy and DMTs Drug Washout prior to planned pregnancy? Recommendations for use during pregnancy Recommendations for use during breastfeeding* Interferon beta (class) No washout needed May be considered for use during pregnancy Probably compatible with breastfeeding Glatiramer acetate (Copaxone, Glatopa) No washout needed Best evidence for safe use during pregnancy Probably compatible with breastfeeding *Women with MS should be advised that it is acceptable to choose not to breastfeed in order to go back on their DMT for prevention of postpartum relapse. If the patient does breastfeed (while off therapy), she should be advised that exclusive breastfeeding (less than 1 formula feeding per day) is more likely to suppress MS disease activity. This may not be equivalent to suppression achieved from DMT, however 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis Pregnancy and DMTs Drug Washout prior to planned pregnancy? Recommendations for use during pregnancy Recommendation for use during breastfeeding* Ofatumumab (Kesimpta) 6 months after Limited data in pregnant women last dose → Avoid Consider risks vs. benefits → Probably compatible Mitoxantrone (Novantrone) 6 months May cause fetal harm if administered during pregnancy → Avoid Excreted in breast milk. Avoid breastfeeding. Natalizumab (Tysabri) Avoid washout period before pregnancy to reduce pregnancy relapse risks May be considered for use Excreted in breast milk. during pregnancy in case of Avoid breastfeeding. highly active disease/high relapse risk. If continued during pregnancy, it is necessary to monitor fetus for mild-tomoderate thrombocytopenia and anemia after delivery. 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis Coyle PK. Management of women with multiple sclerosis through pregnancy and after childbirth. Ther Adv Neurol Dis. 2016;9(3):198-210.; Lexicomp Pregnancy and DMTs Drug Washout prior Recommendations Recommendations to planned for use during for use during pregnancy? pregnancy breastfeeding* Alemtuzumab 4-month delay/ Limited data in (Lemtrada) discontinuation pregnant women. recommended Avoid using during pregnancy. Excreted in breast milk. Avoid breastfeeding. Ocrelizumab (Ocrevus) Excreted in breast milk. Avoid breastfeeding. 4- to 6-month washout after last infusion recommended Limited data in pregnant women. Avoid using during pregnancy. 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis Pregnancy and DMTs Drug Washout prior to planned pregnancy? Recommendations for use during pregnancy Recommendations for use during breastfeeding* Fingolimod (Gilenya) 2-month washout recommended in labeling; Extended washout may increase risk of 1st trimester or postpartum relapse Not recommended for use in pregnancy. Abnormalities seen in animal models at low doses Excreted in breast milk. Avoid breastfeeding. Teriflunomide (Aubagio) Discontinue and accelerated elimination; Monitor serum levels (goal < 0.02 mcg/mL). Employ accelerated elimination protocol in case of accidental pregnancy. Teratogenic/ embryolethal not confirmed in humans to date. Do not use before or during pregnancy. Excreted in breast milk. Avoid breastfeeding. Dimethyl fumarate (Tecfidera) No washout needed Not recommended for use in pregnancy. Abnormalities seen in animal models at low doses May be excreted in breast milk. Avoid breastfeeding. 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis Pregnancy and DMTs Drug Washout prior to planned pregnancy? Recommendations for use during pregnancy Recommendations for use during breastfeeding* Dalfampridine (Ampyra) Not available Information related to the use of dalfampridine in pregnancy is limited → Avoid Avoid breastfeeding until additional information is available Cladribine (Mavenclad) 6 months after the last course Contraindicated Contraindicated during treatment and for 10 days after last dose Siponimod (Mayzent) Not available May cause fetal harm → Avoid Limited data → Avoid Use effective contraception during therapy and for 10 days after the last siponimod dose 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis; Lexicomp Canibano B, Deleu D, Mesraoua B, et al. J Drug Assess. 2020; 9(1): 20–36. 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis Treatment Goals • Improve patient’s overall quality of life • Minimize long-term disability • Decrease MS exacerbations or relapse and ultimately halting disease progression • Develop realistic expectations over their lifetime • Develop long-term management plan Dipiro 11e Chapter 72 Non-pharmacologic Therapy • Occupational therapy: improve ability to complete activities of daily living or learn new techniques or tools to accomplish these tasks • Physical therapy: improve muscle strength to help patients improve their gait and balance • Stretching exercises: help reduced muscle spasms or help patients learn how to use mobility aid such as canes, or walkers Dipiro 11e Chapter 72 Treatment Options • Treatment of acute attacks/exacerbations oShorten the duration and possibly decrease the severity of the attack • Disease-modifying therapies (DMTs) oAlter the course of the illness, and diminish progressive disability over time • Symptomatic treatment oMaintain the patient’s quality of life Dipiro 12e Chapter 74 MS Exacerbations • Caused by inflammation in the CNS → Damage to myelin → Slows or disrupts transmission of nerve impulses → New or worsening symptoms • No two exacerbations are alike o Vary from person to person o Vary from exacerbation to exacerbation D• True exacerbation: o MUST last at least 24 hours o MUST be at least 30 days from previous attack o Can last from few days to several weeks or even months • Rule out other causes prior to treatment National MS Society Website. Managing Relapses. Treatment of Exacerbations • Mild exacerbations o Do NOT produce functional decline → No treatment required • Moderate-severe exacerbations o Functional ability is affected → High-dose corticosteroids (methylprednisolone or prednisone) o MOA for corticosteroids in MS is unknown ▪ Speculated to improve recovery by decreasing edema in the area of demyelination o IV methylprednisolone shown to shorten duration of exacerbations o Steroids have NOT been shown to affect disease progression Dipiro 12e Chapter 74 Methylprednisolone (Solu-Medrol) Doses Duration 500-1,000 mg/day IV 3 days up to 10 days (rarely) based on clinical response • Functional recovery after an exacerbation is more rapid if corticosteroids are initiated within 2 weeks of symptom onset o Improvement usually begins after 3 to 5 days • If methylprednisolone not available, equivalent doses of oral prednisone or dexamethasone can be substituted o Dexamethasone use not well supported in the literature G) Short-term use ADRs: ___________________________ Insomnia Long-term use ADRs: ___________________________ weight gain , Dipiro 12e Chapter 74 Methylprednisolone (Solu-Medrol) Short-term use ADRs -Sleep disturbance -a-Ptsmetallic taste in mouth, and, rarely, Gl upset with DM → elevation of BG → reQuiring insulin Long-term use ADRs -Acne -fungal infections -Mood -Rarely,alteration Gl hemorrhage (especially in hospitalized patients or in those taking aspirin) Dipiro 12e Chapter 74 DMT Algorithms & Dimethyl fumarate, fingolimod, siponimod, teriflunomide, glatiramer acetate, interferon beta 1a and 1b, ofatumumab, natalizumab, ocrelizumab = has indication for CIS 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis D DMT Algorithms – Highly Active RRMS 1 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis DMT Algorithms – Highly Active RRMS 2 * D * 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis DMT Algorithms – RRMS 1 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis DMT Algorithms – RRMS 2 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis DMT Algorithms – PPMS gi * only approval for primary EDSS=Expanded Disability Status Scale; PPMS=Primary Progressive MS 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis DMT Algorithms – Switching DMT 1 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis DMT Algorithms – Switching DMT 2 2019 CMSC Practical Guidelines for the Selection of DiseaseModifying Therapies in Multiple Sclerosis DMT Algorithms – Switching DMT 3 • Generally, injectable therapies (interferons and glatiramer acetate) are considered to have lower to mid-level efficacy, but are effective in many patients with moderate disease activity • Orally administered agents (dimethyl fumarate, fingolimod, teriflunomide, etc.) range from mid- to higherlevel efficacy • IV monoclonal antibody therapies (natalizumab, ocrelizumab, and alemtuzumab) are in the highestefficacy category o Alemtuzumab considered the highest efficacy of the monoclonal categories but may not have a suitable risk profile for patients with mild-to moderate disease activity 2019 CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis Guideline Comparison Switching DMT AAN=American Academy of Neurology CMSC=Consortium of MS Centers 2019 CMSC Practical Guidelines for the Selection of DiseaseModifying Therapies in Multiple Sclerosis DMT Algorithms – Stopping DMT 2019 CMSC Practical Guidelines for the Selection of DiseaseModifying Therapies in Multiple Sclerosis Symptomatic Management Gait Difficulties and Spasticity • Spasticity commonly encountered and tends to affect the legs more markedly than the arms → falls • Baclofen (Lioresal): short-acting GABA analog; preferred agent for spasticity o Usually started at 10 mg PO TID then titrated upward to achieve the desired response o Most patients achieve a satisfactory response with dosages between 40 and 80 mg/day o Should not be discontinued abruptly to avoid the possibility of seizures o Avoid use if patient on dialysis, CrCl <30 mL/minute * Dipiro 12e Chapter 74; Lexicomp Symptomatic Management Gait Difficulties and Spasticity (Cont.) • Tizanidine (Zanaflex): short-acting, α-adrenergic agonist that acts in CNS increasing presynaptic inhibition of motor neurons o Appears to have efficacy comparable to baclofen o Dosage must be titrated slowly over 2 to 4 weeks, starting with 4 mg at bedtime, with adjustments based on clinical response ▪ Effective tolerated dosages have ranged from 2 to 36 mg/day o ADRs: sedation, dizziness, dry mouth, hypotension, hepatotoxicity o Can be added in small dosages to baclofen, sometimes creating better results and making smaller doses of each drug possible Dipiro 12e Chapter 74 Symptomatic Management Gait Difficulties and Spasticity (Cont.) • If unable to tolerate baclofen or tizanidine: diazepam, clonazepam, or dantrolene sodium may be considered as alternatives o Less effective than baclofen or tizanidine • Mild spasticity may respond to moderately high doses of gabapentin (Neurontin; 1,800-3,600 mg/day) • Pregabalin (Lyrica; 75-300 mg/day) may also be considered • Botulinum toxin type A (Botox; dose depending on the muscles injected) has been shown to be effective in alleviating spasticity o Use is best limited to smaller areas of focal muscle spasm • For additional gait disruptions, dalfampridine (Ampyra; 20 mg/day) has been shown to improve walking speed in patients with MS Dipiro 12e Chapter 74 Symptomatic Management Fatigue • One of the most common complaints in MS patients • Can be severely disabling • Presents in the mid-to-late afternoon and can increase with heat exposure, exertion, concurrent infection, spasticity, weakness, and depression • Ginkgo biloba possibly effective for reducing fatigue in MS Dipiro 12e Chapter 74 Symptomatic Management Fatigue (Cont.) • Medications used to treat fatigue o Amantadine: ▪ Class: Anti-Parkinson’s agent, Dopamine agonist, Antiviral agent ▪ Used often and may offer significant relief o Class: CNS stimulants ▪ Modafinil (Provigil), armodafinil (Nuvigil) ▪ Armodafinil reaches peak concentrations more quickly with potentially fewer side effects than modafinil ▪ Methylphenidate (Ritalin), dextroamphetamine (Dexedrine) ▪ In patients suffering from both depression and fatigue, consider a more activating antidepressant such as fluoxetine Dipiro 12e Chapter 74 Question Pt needs a higher potency med SW is a 72-year-old male currently on Interferon-βla (Rebif) 44 mcg SQ three times per week, warfarin, and amiodarone. Lab reveals patient is JCV negative. In the past 6 months, he has had three exacerbations and multiple new enhancing lesions on MRI. Following discontinuation of Rebif, what is the best next step in his course of therapy? a. Natalizumab high-potency b. Glatiramer acetate low-potency (last resort c. Mitoxantrone on amiodarone d. Fingolimod a voided due to pt (PPI) Question CC, a 52-year-old female, is having difficulty walking without stopping every 25 ft (~7.5 m) or so to take a break. Which drug is the most appropriate choice for CC at this time? a. Mitoxantrone b. Modafinil - c. Interferon-βla (Extavia) d. Dalfampridine approved indication for walking speed In MS References Wallin MT, et al. Neurology. 2019;92(10):e1029-e1040 2. Multiple Sclerosis International Federation. Atlas of MS, 3rd edition. https://www.atlasofms.org/map/unitedkingdom/epidemiology/number-of-people-with-ms 3. Bainbridge JL, Miravalle A, Wong P, Makelky MJ. Multiple Sclerosis. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw Hill; 2020. 4. Bainbridge JL, Miravalle A, Wong P, Makelky MJ, Rajkovic S. Multiple Sclerosis. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill; 2023. 5. Waubant E, Lucas R, Mowry E, et al. Environmental and genetic risk factors for MS: an integrated review. Ann Clin Transl Neurol. 2019 Sep; 6(9): 1905–1922. 6. National MS Society. https://www.nationalmssociety.org/What-is-MS/Types-of-MS 7. 2017 McDonald MS Diagnostic Criteria. https://www.nationalmssociety.org/For-Professionals/ClinicalCare/Diagnosing-MS/Diagnosing-Criteria 8. All Drugs information from Lexicomp/package inserts 9. CMSC DMT Guideline Writing Group. CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis. 2019. https://mscare.sharefile.com/share/view/s79d1bfdca884318b 10. Coyle PK. Management of women with multiple sclerosis through pregnancy and after childbirth. Ther Adv Neurol Dis. 2016;9(3):198-210. 11. Canibano B, Deleu D, Mesraoua B, et al. Pregnancy-related issues in women with multiple sclerosis: an evidence-based review with practical recommendations. J Drug Assess. 2020; 9(1): 20–36. doi: 10.1080/21556660.2020.1721507 12. National MS Society. Managing Relapses. https://www.nationalmssociety.org/Treating-MS/ManagingRelapses#:~:text=Treating%20exacerbations,The%20good%20news&text=The%20most%20common%20treatment%20regimen,term%20benefit%20on %20the%20disease. 1.