Subject: CGRP Inhibitors

ARCHIVED (NOT ACTIVE RETIRED) Archived: 08/01/18 09-J2000-98 Original Effective Date: 06/15/18 Reviewed: 05/09/18 Revised: 08/01/18 Next Review: ARCHIVED (NOT ACTIVE RETIRED) Subject: CGRP Inhibitors THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION. Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions Related Guidelines Other References Updates DESCRIPTION: Migraine is a common disabling primary headache disorder affecting approximately 20% of women and 6 to 10% of men in the United States. The highest prevalence is in adults 18 to 44 years of age. A migraine episode (or attack) may be associated with specific triggers, such as stress, hormones, hunger, or sleep, and can present with moderate-to-severe pain, nausea, vomiting, photophobia, phonophobia and with an overall reduced ability to function. Between migraine attacks, pain and other symptoms may remain, and patients' neurological function may not return to normal (pre-headache); therefore, the duration of impairment may be longer than the migraine episode, which can lead to ongoing disability. According to the International Headache Society s 3 rd edition of the International Classification of Headache Disorders (ICHD-3), migraine has two major types: migraine without aura and migraine with aura. There are several subtypes and subforms of migraines that fall under these two types and patients may fulfill criteria for more than one type. Additionally, patients may be diagnosed with chronic migraine, a condition inclusive of all migraine types. Chronic migraine is defined as headache occurring on 15 or more days per month for more than three months, which, on at least eight days per month, has

the features of migraine headache. Approximately 10% of individuals with migraine have chronic migraine. Treatment for migraines includes both non-pharmacologic and pharmacologic therapies and can be generally categorized as acute or preventative in nature. Acute medications are administered once migraine symptoms have started and include analgesics (acetaminophen, aspirin, ibuprofen), triptans, and ergots. The use of acute therapy more frequently than 10 days per month is associated with the development of medication overuse headaches and chronic daily headaches. Preventative medications are generally used in individuals who have four or more days with headaches per month and include antidepressants, antiepileptics, beta-blockers, and botulinum toxins. These medications usually do not eliminate all migraines, but can help to reduce the frequency and severity of attacks. Calcitonin gene-related peptide (CGRP) is a vasodilator and neurotransmitter released during migraine attacks. The CGRP pathway can be targeted using small molecule antagonists resulting in a reduction in migraine frequency. Three CGRP inhibitors are currently being developed: erenumab is a fully human monoclonal antibody that binds to the CGRP receptor and fremanezumab and galcanezumab are two humanized monoclonal antibodies that target the CGRP ligand. The safety and efficacy of erenumab were evaluated in adults with chronic migraine in a randomized, double-blind, placebo-controlled phase 2 study. Chronic migraine was defined as 15 or more headache days per month, of which eight or more were migraine days. Patients were excluded if they were older than 50 years at migraine onset and if they had a history of cluster headache or hemiplegic migraine, or chronic migraine with continuous pain. Patients were also excluded from the study if they had no therapeutic response (reduction in frequency, duration, or severity of headache) with prophylaxis of more than three treatment categories after an adequate trial (at least 6 weeks of treatment at generally accepted doses). Migraine preventive drugs were prohibited during the study and 2 months before the start of the baseline phase. Botulinum toxin injections in the head or neck region were prohibited during the study and for at least 4 months before the start of the baseline phase. Patients were randomly assigned (3:2:2) to subcutaneous placebo (n=286), erenumab 70 mg (n=191), or erenumab 140 mg (n=190), given every 4 weeks for 12 weeks. The primary endpoint was the change in monthly migraine days from baseline to the last 4 weeks of double-blind treatment (weeks 9-12). At baseline, the monthly migraine days were 18.2 (SD 4.7), 17.9 (SD 4.4), and 17.8 (SD 4.7) for the placebo, erenumab 70 mg, and erenumab 140 mg groups respectively. Monthly headache days were 21.1 (SD 3.9), 20.5 (SD 3.8), and 20.7 (SD 3.8) for the placebo, erenumab 70 mg, and erenumab 140 mg groups, respectively. Monthly acute migraine-specific drug use days were 9.6 (SD 7.6) for placebo, 8.8 (SD 7.2) for erenumab 70 mg, and 9.7 (SD 7.0) for erenumab 140 mg. Erenumab 70 mg and 140 mg reduced monthly migraine days versus placebo (both doses -6 6 days vs placebo -4 2 days; difference -2 5, 95% CI -3 5 to -1 4, p<0 0001). Adverse events were reported in 110 (39%) of 282 patients, 83 (44%) of 190 patients, and 88 (47%) of 188 patients in the placebo, 70 mg, and 140 mg groups, respectively. The most frequent adverse events were injection-site pain, upper respiratory tract infection, and nausea. Serious adverse events were reported by seven (2%), six (3%),

and two (1%) patients, respectively; none were reported in more than one patient in any group or led to discontinuation. 11 patients in the 70 mg group and three in the 140 mg group had anti -erenumab binding antibodies; none had anti-erenumab neutralizing antibodies. No clinically significant abnormalities in vital signs, laboratory results, or electrocardiogram findings were identified. The safety and efficacy of fremanezumab were evaluated in adults with chronic migraine in a randomized, double-blind, placebo-controlled phase 3 study. Chronic migraine was defined as 15 or more headache days per month, of which eight or more were migraine days. Patients were excluded if they were older than 50 years at migraine onset. Patients were also excluded from the study if they had no therapeutic response (reduction in frequency, duration, or severity of headache) with prophylaxis of more than two treatment categories after an adequate trial (at least 6 weeks of treatment at generally accepted doses). Up to 30% of patients using a stable dose of one migraine-preventive medication for at least 2 months before the beginning of the preintervention period were enrolled and allowed to continue these medications. Botulinum toxin injections in the head or neck region were prohibited during the study and for at least 4 months before the start of the baseline phase. Patients were randomly assigned (1:1:1) to subcutaneous placebo (n=375), fremanezumab 675 mg quarterly (at baseline and placebo at weeks 4 and 8; n=376), or fremanezumab 675 mg monthly (at baseline and weeks 4 and week 8; n=379). The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted 4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose. At baseline, the mean number of headache days per month was 13.3, 13.2, and 12.8 in the placebo, fremanezumab quarterly, and fremanezumab monthly groups, respectively. The least-squares mean (±SE) reduction in the average number of headache days per month was 2.5±0.3 with placebo, 4.3±0.3 with fremanezumab quarterly, 4.6±0.3 with fremanezumab monthly (P<0.001 for both comparisons with placebo). The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 18% in the placebo group, 38% in the fremanezumab quarterly group, 41% in the fremanezumab monthly group (P<0.001 for both comparisons with placebo). Abnormalities of hepatic function occurred in 5 patients in each fremanezumab group (1%) and 3 patients in the placebo group (<1%). Guidelines from the American Academy of Neurology and the American Headache Society have not yet been updated to include CGRP inhibitors a summary of their recommendations for prevention of migraine are below. Level A The following medications are established as effective and should be offered for migraine prevention: Antiepileptic drugs (AEDs): divalproex sodium, sodium valproate, topiramate

β-blockers: metoprolol, propranolol, timolol Triptans: frovatriptan for short-term MAMs prevention Level B The following medications are probably effective and should be considered for migraine prevention: Antidepressants: amitriptyline, venlafaxine β-blockers: atenolol, nadolol Triptans: naratriptan, zolmitriptan for short-term MAMs prevention Level C The following medications are possibly effective and may be considered for migraine prevention: ACE inhibitors: lisinopril Angiotensin receptor blockers: candesartan α-agonists: clonidine, guanfacine AEDs: carbamazepine β-blockers: nebivolol, pindolol Level U Evidence is conflicting or inadequate to support or refute the use of the following medications for migraine prevention: AEDs: gabapentin Antidepressants o o Selective serotonin reuptake inhibitor/selective serotonin-norepinephrine reuptake inhibitors: fluoxetine, fluvoxamine Tricyclics: protriptyline Antithrombotics: acenocoumarol, Coumadin, picotamide β-blockers: bisoprolol Calcium-channel blockers: nicardipine, nifedipine, nimodipine, verapamil Acetazolamide Cyclandelate Level A negative The following medication is established as ineffective and should not be offered for migraine prevention:

Lamotrigine Level B negative The following medication is probably ineffective and should not be considered for migraine prevention: Clomipramine Level C negative The following medications are possibly ineffective and may not be considered for migraine prevention: Acebutolol Clonazepam Nabumetone Oxcarbazepine Telmisartan POSITION STATEMENT: Comparative Effectiveness The FDA has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility is not considered medically necessary. Initiation of CGRP inhibitor therapy (erenumab, fremanezumab) meets the definition of medical necessity when ALL of the following criteria are met: 1. Member is diagnosed with chronic migraine and meets BOTH of the following: a. 15 or more migraine-like or tension-like headache days per month for a minimum of three months documentation from the medical record must be provided b. 8 or more migraine headache days per month for a minimum of three months documentation from the medical record must be provided 2. Member meets one of the following: a. Member has had an inadequate response to at least two months of treatment with three or more of the following medications selected from at least two migraine prophylaxis classes documentation from the medical record must be provided: i. Antidepressants: amitriptyline, venlafaxine ii. Antiepileptic drugs (AEDs): divalproex sodium, sodium valproate, topiramate

iii. Beta-Blockers: atenolol, metoprolol, nadolol, propranolol, timolol b. Member has a contraindication to all of the following documentation from the medical record must be provided: i. Antidepressants: amitriptyline, venlafaxine ii. Antiepileptic drugs (AEDs): divalproex sodium, sodium valproate, topiramate iii. Beta-Blockers: atenolol, metoprolol, nadolol, propranolol, timolol 3. Member has not received botulinum toxin injections for migraine prophylaxis in the past four months 4. Member will not initiate botulinum toxin injections for migraine prophylaxis while using CGRP inhibitor therapy 5. Member will not use in combination with another CGRP inhibitor 6. Member is prescribed CGRP inhibitor therapy by (or in consultation with) a headache specialist certified by the United Council for Neurologic Subspecialties (UCNS) Approval duration: 3 months Continuation of CGRP inhibitor therapy (erenumab, fremanezumab) meets the definition of medical necessity when ALL of the following criteria are met: 1. Authorization/reauthorization has been previously approved by Florida Blue in the past two years for treatment of chronic migraine, OR the member has previously met all indication-specific criteria. 2. Member meets ONE of the following: a. Member demonstrates a clinically meaningful response to treatment as indicated by the any of the following: i. Decreased migraine headache days from baseline documentation from the medical record must be provided ii. Decreased migraine frequency from baseline documentation from the medical record must be provided iii. Decreased use of acute abortive migraine medications from baseline documentation from the medical record must be provided b. Member currently demonstrates a beneficial response to treatment AND has been receiving treatment for a minimum of 15 months 3. Member has not received botulinum toxin injections for migraine prophylaxis in the past four months 4. Member will not initiate botulinum toxin injections for migraine prophylaxis while using CGRP inhibitor therapy 5. Member is not using in combination with another CGRP inhibitor

6. Member is prescribed CGRP inhibitor therapy by (or in consultation with) a headache specialist certified by the United Council for Neurologic Subspecialties (UCNS) Approval duration: 12 months DOSAGE/ADMINISTRATION: THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE. FDA-approved Pending FDA approval Dose Adjustments Pending FDA approval Drug Availability Pending FDA approval PRECAUTIONS: Boxed Warning Pending FDA approval Contraindications Pending FDA approval Precautions/Warnings Pending FDA approval BILLING/CODING INFORMATION: The following codes may be used to describe: HCPCS Coding J3590 Unclassified biologics

ICD-10 Diagnosis Codes That Support Medical Necessity G43.701 43.709 Chronic migraine without aura, not intractable G43.711 43.719 Chronic migraine without aura, intractable REIMBURSEMENT INFORMATION: Refer to section entitled POSITION STATEMENT. PROGRAM EXCEPTIONS: Federal Employee Program (FEP): Follow FEP guidelines. State Account Organization (SAO): Follow SAO guidelines. Medicare Part D: BCBSF has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline. Medicare Advantage: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline review date. DEFINITIONS: Acute medication: Pharmacologic agent used to treat a migraine attack, sometimes referred to as abortive medication. Chronic migraine: Headache occurring on 15 or more days/ month for more than three months, which, on at least eight days/month, has the features of migraine headache. Episodic migraine: Patients diagnosed with migraine who do not meet the criteria for chronic migraine. Note that this term is not a clinical diagnosis. Headache Impact Test (HIT-6): A six-item questionnaire developed to measure the burden and level of disability in migraine patients. The questionnaire asks patients about their head pain, social, work and cognitive functioning, vitality, and psychological distress. An overall severity level is generated, with scores ranging from 36 to 78 and higher scores indicate more severe impact. The HIT-6 can be found online (http://campaign.optum.com/optum-outcomes/what-we-do/diseasespecific-health-surveys/hit- 6.html) Hemicrania continua: Persistent, strictly unilateral headache, associated with ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead and facial sweating, miosis, ptosis and/or eyelid oedema, and/or with restlessness or agitation. The headache is absolutely sensitive to indomethacin. Medication overuse headache: Headache occurring on 15 or more days/ month in a patient with a preexisting primary headache and developing as a consequence of regular overuse of acute or symptomatic

headache medication (on 10 or more or 15 or more days/month, depending on the medication) for more than three months. It usually, but not invariably, resolves after the overuse is stopped. Migraine Disability Assessment (MIDAS): A five-item questionnaire developed to help patients measure the number of days that migraines impacted their lives. The questionnaire asks patients about the number of days during last three months that they were inhibited by their headaches in different forms. Migraine with aura: Recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory or other central nervous system symptoms that usually develop gradually and are usually followed by headache and associated migraine symptoms. Migraine without aura:- Recurrent headache disorder manifesting in attacks lasting 4 72 hours. Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity and association with nausea and/or photophobia and phonophobia. Migraine-Specific Quality of Life Questionnaire (MSQ): A 14-item questionnaire that measures the health-related quality of life in migraine patients. The questionnaire asks patients about three essential aspects (domains) over the past month: role function-restrictive (RFR), role functionpreventive (RFP), and emotional function (EF). New daily persistent headache: Persistent headache, daily from its onset, which is clearly remembered. The pain lacks characteristic features, and may be migraine-like or tension-type-like, or have elements of both. Preventive therapy: Any routinely-given therapy used with the goal of reducing the frequency, intensity, or duration of attacks. Probable migraine: Patients with probable migraine fulfill all but one criteria for migraine without aura or migraine with aura. RELATED GUIDELINES: Botulinum Toxins, 09-J0000-29 OTHER: International Classification of Headache Disorders (ICHD-3) selected classification and diagnostic criteria Migraine without aura Description: Recurrent headache disorder manifesting in attacks lasting 4 72 hours. Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity,

aggravation by routine physical activity and association with nausea and/or photophobia and phonophobia. Diagnostic criteria: A. At least five attacks 1 fulfilling criteria B D B. Headache attacks lasting 4 72 hours (when untreated or unsuccessfully treated) 2,3 C. Headache has at least two of the following four characteristics: 1. unilateral location 2. pulsating quality 3. moderate or severe pain intensity 4. aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs) D. During headache at least one of the following: 1. nausea and/or vomiting 2. photophobia and phonophobia E. Not better accounted for by another ICHD-3 diagnosis. Notes: 1. One or a few migraine attacks may be difficult to distinguish from symptomatic migrainelike attacks. Furthermore, the nature of a single or a few attacks may be difficult to understand. Therefore, at least five attacks are required. Individuals who otherwise meet criteria for Migraine without aura but have had fewer than five attacks should be coded Probable migraine without aura. 2. When the patient falls asleep during a migraine attack and wakes up without it, duration of the attack is reckoned until the time of awakening. 3. In children and adolescents (aged under 18 years), attacks may last 2 72 hours (the evidence for untreated durations of less than two hours in children has not been substantiated). Migraine with aura Description: Recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory or other central nervous system symptoms that usually develop gradually and are usually followed by headache and associated migraine symptoms.

Diagnostic criteria: A. At least two attacks fulfilling criteria B and C B. One or more of the following fully reversible aura symptoms: 1. visual 2. sensory 3. speech and/or language 4. motor 5. brainstem 6. retinal C. At least three of the following six characteristics: 1. at least one aura symptom spreads gradually over 5 minutes 2. two or more aura symptoms occur in succession 3. each individual aura symptom lasts 5 60 minutes 1 4. at least one aura symptom is unilateral 2 5. at least one aura symptom is positive 3 6. the aura is accompanied, or followed within 60 minutes, by headache D. Not better accounted for by another ICHD-3 diagnosis. Notes: 1. When, for example, three symptoms occur during an aura, the acceptable maximal duration is 360 minutes. Motor symptoms may last up to 72 hours. 2. Aphasia is always regarded as a unilateral symptom; dysarthria may or may not be. 3. Scintillations and pins and needles are positive symptoms of aura. Chronic Migraine Description: Headache occurring on 15 or more days/ month for more than three months, which, on at least eight days/month, has the features of migraine headache. Diagnostic criteria: A. Headache (migraine-like or tension-type-like 1 ) on 15 days/month for >3 months, and fulfilling criteria B and C

B. Occurring in a patient who has had at least five attacks fulfilling criteria B D for Migraine without aura and/or criteria B and C for Migraine with aura C. On 8 days/month for >3 months, fulfilling any of the following 2 : 1. criteria C and D for Migraine without aura 2. criteria B and C for Migraine with aura 3. believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative D. Not better accounted for by another ICHD-3 diagnosis. 3 5 Notes: 1. The reason for singling out Chronic migraine from types of episodic migraine is that it is impossible to distinguish the individual episodes of headache in patients with such frequent or continuous headaches. In fact, the characteristics of the headache may change not only from day to day but even within the same day. Such patients are extremely difficult to keep medication-free in order to observe the natural history of the headache. In this situation, attacks with and those without aura are both counted, as are both migraine-like and tension-type-like headaches (but not secondary headaches). 2. Characterization of frequently recurring headache generally requires a headache diary to record information on pain and associated symptoms day by day for at least one month. 3. Because tension-type-like headache is within the diagnostic criteria for Chronic migraine, this diagnosis excludes the diagnosis of Tension-type headache or its types. 4. New daily persistent headache may have features suggestive of Chronic migraine. The latter disorder evolves over time from Migraine without aura and/ or Migraine with aura; therefore, when these criteria A C are fulfilled by headache that, unambiguously, is daily and unremitting from <24 hours after its first onset, code as New daily persistent headache. When the manner of onset is not remembered or is otherwise uncertain, code as Chronic migraine. 5. The most common cause of symptoms suggestive of chronic migraine is medication overuse, as defined under Medication-overuse headache. Around 50% of patients apparently with Chronic migraine revert to an episodic migraine type after drug withdrawal; such patients are in a sense wrongly diagnosed as Chronic migraine. Equally, many patients apparently overusing medication do not improve after drug withdrawal; the diagnosis of Medicationoveruse headache may be inappropriate for these (assuming that chronicity induced by drug overuse is always reversible). For these reasons, and because of the general rule to apply all relevant diagnoses, patients meeting criteria for Chronic migraine and for Medicationoveruse headache should be coded for both. After drug withdrawal, migraine will either revert to an episodic type or remain chronic, and should be re-diagnosed accordingly; in the latter case, the diagnosis of Medication-overuse headache may be rescinded. New daily persistent headache (NDPH)

Description: Persistent headache, daily from its onset, which is clearly remembered. The pain lacks characteristic features, and may be migraine-like or tension-type-like, or have elements of both. Diagnostic criteria: A. Persistent headache fulfilling criteria B and C B. Distinct and clearly remembered onset, with pain becoming continuous and unremitting within 24 hours C. Present for >3 months D. Not better accounted for by another ICHD-3 diagnosis. 1 4 Notes: 1. New daily persistent headache is unique in that headache is daily from onset, and very soon unremitting, typically occurring in individuals without a prior headache history. Patients with this disorder invariably recall and can accurately describe such an onset; if they cannot do so, another diagnosis should be made. Nevertheless, patients with prior headache (Migraine or Tension-type headache) are not excluded from this diagnosis, but they should not describe increasing headache frequency prior to its onset. Similarly, patients with prior headache should not describe exacerbation associated with or followed by medication overuse. 2. New daily persistent headache may have features suggestive of either Migraine or Tensiontype headache. Even though criteria for Chronic migraine and/or Chronic tension-type headache may also be fulfilled, the default diagnosis is New daily persistent headache whenever the criteria for this disorder are met. In contrast, when the criteria for both New daily persistent headache and Hemicrania continua are met, then the latter is the default diagnosis. 3. Abortive drug use may exceed the limits defined as causative of Medication-overuse headache. In such cases, the diagnosis of New daily persistent headache cannot be made unless the onset of daily headache clearly predates the medication overuse. When this is so, both diagnoses, New daily persistent headache and Medication-overuse headache, should be given. 4. In all cases, other secondary headaches such as Acute headache attributed to traumatic injury to the head, Headache attributed to increased cerebrospinal fluid pressure and Headache attributed to low cerebrospinal fluid pressure should be ruled out by appropriate investigations. Hemicrania continua

Description: Persistent, strictly unilateral headache, associated with ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead and facial sweating, miosis, ptosis and/or eyelid oedema, and/or with restlessness or agitation. The headache is absolutely sensitive to indomethacin. Diagnostic criteria: 1. Unilateral headache fulfilling criteria B D 2. Present for >3 months, with exacerbations of moderate or greater intensity 3. Either or both of the following: 1. at least one of the following symptoms or signs, ipsilateral to the headache: a) conjunctival injection and/or lacrimation b) nasal congestion and/or rhinorrhoea c) eyelid oedema d) forehead and facial sweating e) miosis and/or ptosis 2. a sense of restlessness or agitation, or aggravation of the pain by movement 4. Responds absolutely to therapeutic doses of indomethacin 1 5. Not better accounted for by another ICHD-3 diagnosis. Note: 1. In an adult, oral indomethacin should be used initially in a dose of at least 150 mg daily and increased if necessary up to 225 mg daily. The dose by injection is 100 200 mg. Smaller maintenance doses are often employed. Medication-overuse headache Description: Headache occurring on 15 or more days/ month in a patient with a pre-existing primary headache and developing as a consequence of regular overuse of acute or symptomatic headache medication (on 10 or more or 15 or more days/month, depending on the medication) for more than three months. It usually, but not invariably, resolves after the overuse is stopped. Diagnostic criteria:

A. Headache occurring on 15 days/month in a patient with a pre-existing headache disorder B. Regular overuse for >3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache 1 3 C. Not better accounted for by another ICHD-3 diagnosis. Notes: 1. Patients should be coded for one or more subtypes of Medication-overuse headache according to the specific medication(s) overused and the criteria for each below. For example, a patient who fulfils the criteria for Triptan-overuse headache and the criteria for one of the subforms of Non-opioid analgesic-overuse headache should receive both these codes. The exception occurs when patients overuse combination-analgesic medications, who are coded Combination analgesic-overuse headache and not according to each constituent of the combination-analgesic medication. 2. Patients who use multiple drugs for acute or symptomatic treatment of headache may do so in a manner that constitutes overuse even though no individual drug or class of drug is overused; such patients should be coded Medication-overuse headache attributed to multiple drug classes not individually overused. 3. Patients who are clearly overusing multiple drugs for acute or symptomatic treatment of headache but cannot give an adequate account of their names and/or quantities are coded Medication-overuse headache attributed to unspecified or unverified overuse of multiple drug classes until better information is available. In almost all cases, this necessitates diary follow-up. REFERENCES: 1. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2018 [cited 4/30/18]. Available from: http://www.clinicalpharmacology.com/. 2. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; 2000 Feb 29 - [cited 4/30/18]. Available from: http://clinicaltrials.gov/. 3. DRUGDEX System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 4/30/18]. Available from: http://www.thomsonhc.com/. 4. Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. The New England Journal of Medicine. 2017; 377:2123-32. 5. International Headache Society. The international classification of headache disorders. (3rd ed.) Cephalalgia. 2018; 38: 1 211. 6. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food a nd Drug Administration; 2018 [cited 4/30/18]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/. 7. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012; 78(17):1337-45.

8. Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomized, double-blind placebo-controlled phase 2 trial. Lancet Neurology. 2017; 16:425 34. COMMITTEE APPROVAL: This Medical Coverage Guideline (MCG) was approved by the Florida Blue Pharmacy Policy Committee on 05/09/18. GUIDELINE UPDATE INFORMATION: 06/15/18 New Medical Coverage Guideline. 08/01/18 Move to Prime Standard. Archive MCG.