Lasmiditan (Reyvow™) New Drug Update

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Lasmiditan (Reyvow™) New Drug Update November 2019 Nonproprietary Name lasmiditan Brand Name Reyvow Manufacturer Eli Lilly and Company Form Tablets Strength 50 mg, 100 mg FDA Approval October 11, 2019 Market Availability Anticipated within 90 days of approval, following Drug Enforcement Agency (DEA) review FDA Approval Classification Standard Review FDB Classification- Specific TBD Therapeutic Class (HIC3) INDICATION1

Lasmiditan (Reyvow) is a serotonin 5-HT1F receptor agonist indicated for the acute treatment of migraine with or without aura in adults. Limitation of Use: Lasmiditan is not indicated for preventive treatment of migraine. PHARMACOKINETICS

After oral administration of lasmiditan, the median time to maximum serum concentration (Tmax) is 1.8 hours. Food, age, gender, race, ethnicity, body weight, or renal function do not have a clinically significant effect on the pharmacokinetics of lasmiditan. The agent is 55% to 60% plasma protein bound. Lasmiditan is primarily metabolized via hepatic and extrahepatic metabolism, primarily by non- cytochrome P450 enzymes (e.g., ketone reduction) and has no pharmacologically active metabolites. Its mean terminal half-life is 5.7 hours. CONTRAINDICATIONS/WARNINGS Lasmiditan does not have any contraindications. Lasmiditan has been associated with significant impairment in the ability to drive or operate machinery following a single dose. Patients should be advised not take lasmiditan unless they are able to avoid driving or operating machinery for at least 8 hours after each lasmiditan dose. Prescribers should be aware that the patient’s ability to determine their own mental alertness may also be affected and should discuss this with the patient.

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Central nervous system (CNS) depression may occur with use of lasmiditan, including sedation and dizziness. Use with alcohol or other CNS depressants may potentiate this affect. In clinical trials, use of lasmiditan was associated with symptoms consistent with serotonin syndrome, which may occur with or without coadministration of other serotonergic drugs. If symptoms associated with serotonin syndrome occur, lasmiditan should be discontinued. Lasmiditan labeling contains a warning about the overuse of acute migraine agents, which may lead to medication overuse headache. Medication overuse headache may present as migraine-like daily headaches or as a significant increase in frequency of attacks. Withdrawal of the offending agent(s) and treatment of symptoms may be necessary. DRUG INTERACTIONS Due to the propensity to cause CNS-related adverse effects, including sedation, lasmiditan should be used cautiously in combination with alcohol or other CNS depressants. Use of lasmiditan with medications that increase serotonin may increase the risk of serotonin syndrome; therefore, caution is advised with use of lasmiditan in patients taking other serotonergic agents. Lasmiditan has been associated with a heart rate decrease. Use of heart rate lowering drugs with lasmiditan may result in further heart rate lowering. Concomitant use of lasmiditan with p-glycoprotein (p-gp) or Breast Cancer Resistant Protein (BCRP) substrates should be avoided. COMMON ADVERSE EFFECTS The most common adverse reactions reported in clinical trials (incidence ≥ 5% and greater than placebo) with lasmiditan (reported as incidence with 50 mg, 100 mg, and 200 mg versus placebo, respectively) were dizziness (9%, 15%, and 17% versus 3%), fatigue (4%, 5%, and 6% versus 1%), paresthesia (3%, 7%, and 9% versus 2%), and sedation (6%, 6%, and 7% versus 2%). SPECIAL POPULATIONS Pregnancy Based on data from animal studies lasmiditan can cause embryofetal harm when administered to a pregnant woman. There are no adequate data on the risks associated with use in pregnant women. Pediatrics The safety and efficacy of lasmiditan have not been established in the pediatric population. Geriatrics In clinical trials, dizziness occurred more often in patients ≥ 65 years of age compared to younger adults (16% versus 14%, respectively). Patients ≥ 65 years of age experienced a larger increase in systolic blood pressure compared to younger patients. Clinical trials did not include an adequate number of patients ≥ 65 years of age to inform of differences in efficacy of lasmiditan compared to younger patients.

Hepatic Impairment Lasmiditan has not been studied in patients with severe hepatic impairment (Child-Pugh C); therefore, use in this patient population is not recommended. A dose adjustment is not required for patients with mild or moderate hepatic impairment (Child-Pugh A or B). Renal Impairment No dose adjustment is required based on renal function. DOSAGES The recommended dose is 50 mg, 100 mg, or 200 mg orally as needed, with or without food, for the treatment of migraine with no more than 1 dose taken in any 24 hour period. Patients should not take lasmiditan unless they are able to avoid driving or operating machinery for at least 8 hours after each lasmiditan dose. The safety of treating an average of more than 4 migraines per 30 days with lasmiditan has not been established. CLINICAL TRIALS2,3,4 A literature search was performed using “lasmiditan” and “migraine.” Two multicenter, randomized, double-blind, placebo-controlled clinical trials evaluated the efficacy and safety of lasmiditan for the acute treatment of migraine. The SAMURAI trial (A Study of Two Doses of LAsMiditan Compared to Placebo in the AcUte Treatment of MigRAIne) compared lasmiditan 100 mg and 200 mg to placebo, while the SPARTAN trial (A Study of Three Doses of Lasmiditan Compared to Placebo in the Acute TReaTment of MigrAiNe) compared lasmiditan 50 mg, 100 mg, and 200 mg to placebo. Both SAMURAI and SPARTAN enrolled adult patients ≥ 18 years of age with a diagnosis of migraine with or without aura as defined by the International Headache Society (IHS) diagnostic criteria. Patients were eligible for inclusion if they had a diagnosis of disabling migraine for ≥ 1 year, a Migraine Disability Assessment Score of ≥11, a migraine onset before 50 years of age and 3 to 8 migraine attacks per month (< 15 headache days per month). Patients were excluded from the trials if they met any of the following criteria: ≥ 15 headache days per month; initiation or change in previous migraine treatment within 3 months; or increased seizure risk. Patients with coronary artery disease, arrhythmias, or uncontrolled hypertension were excluded from the SAMURAI trial, but not the SPARTAN trial. Patients enrolled in the SAMURAI trial (n=2,231) were randomized 1:1:1 to receive lasmiditan 200 mg, lasmiditan 100 mg, or placebo for the treatment of their next migraine attack. Patients were instructed to take the study medication within 4 hours of the onset of headache and recorded their responses using an electronic diary. Of the enrolled patients, 1,856 patients received at least the first dose of study drug with 1,805 completing the study and 51 patients discontinuing before study completion. The primary endpoint for the SAMURAI trial was the percent of patients headache pain-free 2 hours after the first dose of study medication (200 mg lasmiditan versus placebo). Secondary endpoints included percent of patients headache pain-free 2 hours after the first dose of study medication (100 mg lasmiditan versus placebo) and the percent of the patients most bothersome symptom (MBS)-free 2 hours after the first dose of study medication (200 mg versus placebo and 100 mg versus placebo). More patients treated with lasmiditan 200 mg were headache pain-free 2 hours after the first dose compared to placebo (32.2% versus 15.3%, respectively; odds ratio [OR], 2.6; 95% confidence interval [CI], 2 to 3.6; p<0.001). Likewise, more patients treated with lasmiditan 100 mg were headache pain-free 2 hours after the first dose

compared to placebo (28.2% versus 15.3%, respectively; OR, 2.2; 95% CI, 1.6 to 3; p<0.001). Additionally, more patients receiving lasmiditan 200 mg compared to placebo were free of their MBS 2 hours after the first dose (40.7% versus 29.5%, respectively; OR, 1.6; 95% CI, 1.3 to 2.1; p<0.001) and lasmiditan 100 mg (40.9%; OR, 1.7; 95% CI, 1.3 to 2.2; p<0.001). Patients enrolled in the SPARTAN trial(n=3,005) were randomized 1:1:1:1 to receive lasmiditan 200 mg, lasmiditan 100 mg, lasmiditan 50 mg, or placebo for the treatment of their next migraine attack. Again, patients recorded their responses using an electronic diary. Of the enrolled patients, 2,583 patients received at least the first dose of the study drug with 2,310 patients providing any post-dose headache assessment. The primary endpoints for the SPARTAN trial were the percentage of patients’ headache pain-free and MBS-free at 2 hours postdose for each treatment arm. A greater percentage of patients treated with lasmiditan were headache pain-free 2 hours after the first dose compared to 21.3% with placebo (lasmiditan 200 mg: 38.8% [OR versus placebo, 2.3; 95% CI, 1.8 to 3.1; p=0.001]; 100 mg: 31.4% [OR versus placebo, 1.7; 95% CI, 1.3 to 2.2; p<0.001]; 50 mg: 28.6%, OR, 1.5; 95% CI, 1.1 to 1.9; p=0.003). Additionally, greater percentage of lasmiditan-treated patients experienced freedom from MBS at 2 hours postdose compared to 33.5% of those treated with placebo (lasmiditan 200 mg: 48.7%, OR, 1.9; 95% CI, 1.4 to 2.4; p<0.001; 100 mg: 44.2%, OR, 1.6; 95% CI, 1.2 to 2.0; p<0.001; 50 mg: 40.8%, OR,1.4; 95% CI, 1.1 to 1.8; p=0.009). The open-label, LonG-term Safety Study of LAsmiDItan in the Acute Treatment Of MigRaine (GLADIATOR) is an ongoing, prospective, randomized, open-label, phase 3 study to evaluate the long- term safety and efficacy of lasmiditan 100 mg and 200 mg for the treatment of migraine attacks for up to 1 year in patients who completed either SAMURAI or SPARTAN. An interim analysis of the GLADIATOR trial evaluated data for 1,978 patients who received ≥ 1 lasmiditan dose and treated 19,058 migraine attacks. Freedom from headache pain at 2 hours postdose was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. Based on the data assessed thus far, efficacy remained generally consistent over the study period. Treatment-emergent adverse events (TEAEs) generally decreased over time and were similar to those seen in previous trials, including dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). No cardiovascular TEAE related to vasoconstriction have been observed up to the interim evaluation point during the GLADIATOR trial. OTHER DRUGS USED FOR CONDITION5,6 Other agents used for the acute treatment of migraine include non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen (Tylenol®), caffeinated analgesic combinations (e.g., acetaminophen/aspirin/caffeine [Excedrin® extra strength]), triptans, butorphanol nasal spray, and ergotamines (e.g., ergotamine [Ergomar®], ergotamine with caffeine [Cafergot®, Migergot®], and dihydroergotamine [Migranal®]). PLACE IN THERAPY7,8,9 In 2015, the American Headache Society (AHS) published an assessment of the evidence for the acute treatment of migraine in adults, which reviewed articles published from 1998 to 2013. The AHS concluded that all available triptans and dihydroergotamine (nasal, inhaler) are effective migraine specific treatments. Acetaminophen, NSAIDs, butorphanol nasal spray, sumatriptan/naproxen, and acetaminophen/aspirin/caffeine were also rated as effective nonspecific treatments for migraine.

In their 2019 position statement on integrating new migraine treatments into clinical practice, the AHS recommends NSAIDs, non-opioid analgesics, acetaminophen, or caffeinated analgesic combinations for mild‐to‐moderate migraines. AHS recommends triptans or dihydroergotamine for moderate or severe migraines or mild‐to‐moderate migraines that are unresponsive to first-line therapy of NSAIDs or caffeinated analgesic combinations.

Triptans are selective 5-HT1B/D agonists whose activity against migraines is dependent on vasoconstriction of the cerebral vessels. This mechanism also causes vasoconstriction in other vessels, including cardiac vasoconstriction, and results in triptans being contraindicated in patients with cardiovascular disease, cerebrovascular disease, uncontrolled hypertension, and hemiplegic migraine. Lasmiditan is a selective 5-HT1F agonist whose mechanism is dependent on neuronal pathways, although not fully understood, and has not been associated with vasoconstriction. Data from clinical trials suggest that lasmiditan (Reyvow) may be a safe and effective option for the acute treatment of migraines for patients who are refractory to other migraine treatments or have cardiovascular risk factors precluding the use of other antimigraine agents (e.g., triptans). Due to significant impairment in the ability to drive or operate machinery with lasmiditan, patients should not take lasmiditan unless they are able to avoid driving or operating machinery for at least 8 hours after each lasmiditan dose. The manufacturer of lasmiditan awaits DEA scheduling. SUGGESTED UTILIZATION MANAGEMENT Anticipated Therapeutic Class Review Anti-migraine Agents, Other (TCR) Placement Clinical Edit Initial Approval Criteria ▪ Patient must be ≥ 18 years of age; AND ▪ Patient must have a diagnosis of migraine, with or without aura; AND ▪ Patient must not have headache frequency ≥ 15 headache days per month; AND ▪ Patient must not have hypersensitivity to any component of the product; AND ▪ Patient must not have severe hepatic impairment (Child-Pugh C); AND ▪ Patient must have tried and failed to at least one of the following: NSAID, non-opioid analgesic, acetaminophen OR caffeinated analgesic combination; AND ▪ Patient must have tried and failed, or have contraindication to, ≥ 2 preferred triptans; AND ▪ Prescriber attests patient has been educated about need to refrain from driving or operating machinery for ≥ 8 hours after dose. Renewal Criteria ▪ Patient must continue to meet the above criteria; AND ▪ Patient has not had any treatment-limiting adverse effects (e.g., central nervous system depression, sedation, serotonin syndrome, medication overuse headache); AND ▪ Patient must demonstrate resolution in headache pain or reduction in headache severity, as assessed by prescriber.

Quantity Limit 4 doses per 30 days Duration of Approval Initial: 1 year Renewal: 1 year Drug to Disease Hard Edit None

REFERENCES

1 Reyvow [package insert]. Indianapolis, IN; Eli Lily; October 2019. 2 Kuca B, Silberstein SD, Wietecha L, et al. Lasmiditan is an effective acute treatment for migraine: A phase 3 randomized study. Neurology. 2018;91(24):e2222–e2232. DOI: 10.1212/WNL.0000000000006641. 3 Goadsby PJ, Wietecha LA, Dennehy EB, et al. Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine. Brain. 2019;142(7):1894–1904. DOI:10.1093/brain/awz134. 4 Brandes JL, Klise S, Krege JH, et al. Interim results of a prospective, randomized, open-label, phase 3 study of the long-term safety and efficacy of lasmiditan for acute treatment of migraine (the GLADIATOR study). Cephalalgia. 2019;39(11):1343–1357. DOI: 10.1177/0333102419864132. 5 The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019; 59: 1-18. DOI: 10.1111/head.13456. Available at: https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.13456. Accessed November 12, 2019. 6 MarmuraMJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the American Headache Society evidence assessment of migraine pharmacotherapies. Headache. 2015; 55(1): 3-20. DOI: 10.1111/head.12499. Available at: https://headachejournal.onlinelibrary.wiley.com/doi/abs/10.1111/head.12499. Accessed November 12, 2019. 7 MarmuraMJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the American Headache Society evidence assessment of migraine pharmacotherapies. Headache. 2015; 55(1): 3-20. DOI: 10.1111/head.12499. Available at: https://headachejournal.onlinelibrary.wiley.com/doi/abs/10.1111/head.12499. Accessed November 12, 2019. 8 The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache.2019; 59: 1-18. DOI:10.1111/head.13456 Available at: https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.13456. Accessed November 12, 2019. 9 Oswald JC, Schuster NM. Lasmiditan for the treatment of acute migraine: a review and potential role in clinical practice. J Pain Res. 2018; 11: 2221–2227. DOI:10.2147/JPR.S152216