2019 MPhA Annual Networking Learning Event & MTM

2019 MPhA Annual Networking Learning Event & MTM Symposium 10.03.19 Migraine Update Natalie Roy, PharmD Fairview Medication Therapy Management Pharmacist MHealth Neurology Clinic Disclosure Natalie Roy reports no actual or potential conflicts of interest associated with this presentation Learning Objectives Upon successful completion of this activity, pharmacists should be able to:

Differentiate episodic and chronic migraine by listing criteria for diagnosis of each type, including concomitant symptoms and frequency of headaches. Determine appropriateness of therapy for migraine prevention and develop a treatment plan for patient cases. Explain the mechanism and place in therapy for the Calcitonin gene-related peptide (CGRP) inhibitors. Define medication overuse in the context of migraine management. List evidence-based abortive therapies based on the 2018 American Headache Society Guidelines. Learning Objectives Upon successful completion of this activity, pharmacy technicians should be able to: Identify the three possible symptoms associated with migraines.

List at least five medications that can be used to prevent migraines. Describe the consequences of medication overuse headaches. Prevalence of Migraine 3rd most prevalent illness in the world 6 leading cause of disability th 20.7% of females 9.7% of males $26

billion/year Highest prevalence age 18-44 Burch R et al. Headache. 2018 www.migraineresearchfoundation.org Diagnosis of Migraine At least 5 attacks Each attack lasts 4-72 hours when untreated or unsuccessfully treated Headache includes 2 of the following: Unilateral location Pulsating quality Moderate or severe pain intensity Aggravation by or causing avoidance of routine physical activity (ie: walking or climbing stairs)

During headache, 1 of the following occurs: Nausea and/or vomiting Photophobia and phonophobia Position statement. Headache. 2019. Migraine Type Episodic Migraine* Migraine-like or tensiontype-like headache on <15 days/month (MHD) MHD = monthly headache days MMD = monthly migraine days

Chronic Migraine* Migraine-like or tensiontype-like headache on 15 days/month for > 3 months (MHD) Migraine with or without aura on 8 days/month (MMD) *+/- Aura Position statement. Headache. 2019. Pathophysiology Migraine is a complex condition thought to involve: Vasculature Central and peripheral neuronal pathways involved in pain signaling

Inflammation Activation of trigeminovascular system Role of Calcitonin Gene-Related Peptide (CGRP) Abortive Treatments Should be offered to ALL patients with migraine Treat at first sign of pain to improve probability of achieving freedom from pain and reduce disability Poorly controlled attacks are at risk of acute medication overuse, medication overuse headache, and progression to chronic migraine Avoid overuse Abortive Treatments

Mild-moderate attacks Moderate-severe attacks NSAIDs (including aspirin) Triptans Acetaminophen Dihydroergotamine (DHE) Caffeinated analgesic combinations (ie: Excedrin) Position statement. Headache. 2019.

Management of Nausea/Vomiting Use alternate formulations of abortive therapies ODT: rizatriptan, zolmitriptan Nasal spray: sumatriptan, zolmitriptan SubQ: sumatriptan Anti-emetics can also help abort refractory migraines Abortive Treatment Pearls Try higher dose first and decrease if side effects ie: 100 mg of sumatriptan vs 50 mg

Attempt multiple trials of an abortive before determining lack of efficacy Create a stratified migraine action plan Plan for mild headache (ie: will take ibuprofen) Plan for moderate-severe headache (ie: will take sumatriptan) Plan for nausea/rescue treatment (ie: will take prochlorperazine) Opioids? May improve pain, but not productivity May increase risk of conversion to chronic migraine

Can interfere with triptan efficacy Response decreases over time leading to escalating doses Use of opioids may up-regulate CGRP receptors, resulting in increased migraines Tepper SJ. Headache. 2012 Medication Overuse Headaches American Headache Society (AHS): 10 days/month for ergot derivatives, triptans, opioids, combination analgesics, and drugs from other classes that are not individually overused 15 days/month for non-opioid analgesics, acetaminophen, and NSAIDs

Avoiding Medication Overuse NSAIDs, acetaminophen, non-opioid combo (ie: Excedrin) < 14 days/month total Triptans < 9 days/month total Opioids < 1 day/week total or AVOID altogether Preventive Treatments Lifestyle modification (nutrition, exercise, hydration, sleep) Avoid triggers

Pharmacologic medication considered if: Contraindication to acute treatments Failure of acute treatments Overuse of acute treatments Preventive Treatments Position statement. Headache. 2019. Oral Preventive Treatments Position statement. Headache. 2019. Oral Preventive Treatment Use Selection based on evidence of efficacy, tolerability,

comorbidities, consideration of women of child-bearing age, provider/patient preference Start low and titrate slowly until target response develops, maximum/target dose is reached, or tolerability issues Adequate trial: at least 8 weeks at a target dose (cumulative benefits may occur over 6-12 months) Combining preventive medications from different drug classes can be useful Successful Migraine Prevention 50% reduction in frequency of MMD or MHD Patient-reported decrease in attack duration and/or severity Improved response to acute treatment Reduction in migraine-related disability,

reduction in psychological distress, and improvement in functioning CGRP in Migraine Calcitonin generelated peptide (CGRP): 37-amino acid neuropeptide that functions as a messenger in nerve cells and as a vasodilator Edvisson L et al. Nat Rev Neurol. 2018 CGRP Inhibitors

Monoclonal antibodies to the CGRP receptor Inhibit function of CGRP at receptor, leaving other calcitonin-family receptors functionally intact Erenumab (Aimovig) Monoclonal antibodies to the CGRP ligand Inhibit function of CGRP at all calcitonin-family receptors Galcanezumab (Emgality), Fremanezumab (Ajovy), Eptinezumab (??) Monoclonal antibodies are eliminated via the reticuloendothelial system (no hepatotoxicity) Approved for prevention of chronic and episodic migraine CGRP Inhibitors Erenumab

(Aimovig) Galcanezumab Fremanezumab (Emgality) (Ajovy) Eptinezumab (??) Episodic Migraine, decrease in monthly migraine days (MMD) 6 MONTH STUDY

6 MONTH STUDY 3 MONTH STUDY TBD Decrease in MMD by 3.2/3.7 (70 mg/140 mg) vs 1.8 placebo Decrease in MMD by 4.7/4.3 (120 mg study 1/2) vs 2.8/2.3 placebo (study 1/2)

Decrease in MMD by 3.7/3.4 (225 mg monthly/675 mg quarterly) vs 2.2 placebo Episodic migraine, 50% response 43.3%/50% vs 26.6% 62%/59% vs 39%/36% 47.7%/44.4% vs 27.9% TBD

Chronic Migraine, decrease in MMD or MHD of moderate severity (MHD-MS) 3 MONTH STUDY 3 MONTH STUDY 3 MONTH STUDY TBD Decrease in MMD by

6.6/6.6 vs 4.2 Decrease in MMD by 4.8 vs 2.7 Decrease in MHD-MS 4.6/4.3 vs 2.5 and MMD 5/4.9 vs 3.2 Chronic Migraine, 50% response 39.9%/41.2% vs 23.5% 28% vs 15%

40.8%/37.6% vs 18.1% TBD Data from prescribing information (package inserts) CGRP Inhibitors Erenumab (Aimovig) Galcanezumab Fremanezumab (Emgality) (Ajovy)

Eptinezumab (??) Dosing 70 mg or 140 mg monthly SubQ injection 240 mg loading dose then 120 mg monthly SubQ injection 225 mg monthly

or 675 mg quarterly SubQ injection TBD dose IV Adverse reactions Injection site reactions; constipation Injection site reactions

Injection site reactions TBD Cost (WAC) $575/month $575/month $575/month TBD

Longer-term Data 3-year safety data for erenumab in episodic migraine population: most common side effects included upper respiratory tract infections, sinusitis, back pain, but none were significantly different rates from placebo 4.5-year safety data for erenumab showing no new safety concerns Open-label study for episodic migraine showing sustained efficacy through 4.5 years No long-term RCT data CGRP Inhibitors Summary Cautious Optimism Abby Metzler, U of MN Headache Neurologist

First class of preventive medications designed based on migraine pathophysiology Monthly or quarterly dosing options Super-responders but unable to identify who these patients are yet Generally well tolerated WAC $575/month similar in cost to Botox treatments May need to fail multiple other preventive agents first for insurance to approve Preventive Treatment Pearls Avoid most preventive medications in pregnant or lactating women, especially valproic acid and topiramate Migraine may improve over time; re-evaluate therapeutic response at 3-6 months and if possible

taper or discontinue therapy if patient no longer meets criteria for preventive treatment Adherence to preventive treatments is often poor Other Approved Therapies OnabotulinumtoxinA (Botox) FDA approved for chronic migraine External Trigeminal Nerve Stimulation device (Cefaly) FDA approved for prevention or acute treatment

www.americanmigrainefoundation.org Other Emerging Therapies Gepants CGRP receptor antagonists for acute treatment May provide improved tolerability over triptans with similar efficacy Lasmiditan 5-HT1F receptor agonist for acute treatment May reduce side effects related to vasoconstriction compared to triptans, which are 5-HT1B/D receptor agonists Post-test Question 1 Which of the following CGRP inhibitors

targets the CGRP receptor? A) B) C) D) Erenumab Galcanezumab Fremanezumab Eptinezumab Post-test Question 2 Which is the MOST appropriate scenario for migraine preventive therapy? A) 2 headache days per month with moderate response to

ibuprofen and minimal functional impairment B) 3 headache days per month with poor response to sumatriptan and severe functional impairment C) 4 headache days per month with good response to sumatriptan but minimal response to acetaminophen D) 5 headache days per month with good response to rizatriptan and minimal functional impairment Post-test Question 3 Which is the LEAST appropriate treatment plan? A) Topiramate for a 24 year old male with no co-morbid conditions who has not taken any preventive medications and currently takes ibuprofen 6-8 days/month B) Amitriptyline for a 26 year old female with depression who is taking an oral contraceptive

C) Erenumab for a 34 year old female who has tried/failed topiramate, propranolol, and amitriptyline D) Galcanezumb for a 30 year old male with hypertension who has not tried any preventive medications Post-test Question 4 Which is NOT a preferred abortive medication for episodic migraine? A) B) C) D) E) Imitrex SubQ

Aleve Fiorinal Excedrin Maxalt-MLT Post-test Question 5 Which is the best education point for a patient with chronic migraine on Ajovy and sumatriptan? A) Limit oral sumatriptan use to < 15 days/month to avoid medication overuse B) Take Ajovy as a monthly 225 mg SubQ injection to prevent migraines C) If experiencing nausea during a migraine, you can take SubQ sumatriptan D) Limit sleep during a migraine attack

MHealth Headache Care Team Sarah Benish, MD Neurologist Abby Metzler, MD Neurologist (UCNS certified headache specialist) Farha Ikramuddin, MN MPH Physiatrist

Parisa Salehi, MD Physiatrist Stephanie Standal, MD Physiatrist Ludmila Johnson, MSN, RN, CNP Neurological Nurse Practitioner William Robiner, PhD, ABPP, LP Psychologist Steve Palmer, MA, LMFT Behavioral Health Clinician Natalie Roy, PharmD MTM Pharmacist References

Burch R, Rizzoli P, Loder E. The Prevalence and Impact of Migraine and Severe Headache in the United States: Figures and Trends From Government Health Studies. Headache. 2018;58(4):496-505. Migraine Facts. Migraine Research Foundation. Available at: https ://migraineresearchfoundation.org/about-migraine/migraine-facts/. Accessed September 2019. The American Headache Society Position Statement On Integrating New Migraine Treatments Into Clinical Practice. Headache. 2019;59(1):1-18. Tepper SJ. Opioids should not be used in migraine. Headache. 2012;52 Suppl 1:30-4. Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol. 2018;14(6):338-350. Amgen and Novartis. Aimovig (erenumba-aooe) [package insert]. US Food and Drug Administration website. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761077s000lbl.pdf. Revised May 2018.

Accessed September 2019. Eli Lily. Emgality (galcanezumab-gnlm) [package insert]. US Food and Drug Administration website. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761063s000lbl.pdf. Revised Septemeber 2018. Accessed September 2019. Teva. Ajovy (fremanezumab-vfrm) [package insert]. US Food and Drug Administration website. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761089s000lbl.pdf. Revised September 2018. Accessed September 2019. Questions? Natalie Roy, PharmD [email protected]

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