DailyMed Label: Reyvow

DailyMed Label: Reyvow

2022

DailyMed Prescription

Reyvow

lasmiditan

Eli Lilly and Company

NDC: 0002-4312

NDC: 0002-4312

NDC: 0002-4491

NDC: 0002-4491

REYVOW (lasmiditan) is a serotonin (5-HT) 1F receptor agonist for oral administration. The chemical name of lasmiditan hemisuccinate is 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide hemisuccinate. It has the empirical formula of C 19 H 18 F 3 N 3 O 2 •0.5[C 4 H 6 O 4 ] and a molecular weight of 436.41 (hemisuccinate). Lasmiditan hemisuccinate has the following structural formula: Lasmiditan hemisuccinate is a white, crystalline powder that is sparingly soluble in water, slightly soluble in ethanol, and soluble in methanol. A 1 mg/mL aqueous solution of lasmiditan hemisuccinate has a pH of 6.8 at ambient conditions. REYVOW 50 mg tablets contain 50 mg lasmiditan (equivalent to 57.824 mg lasmiditan hemisuccinate) and the inactive ingredients as follows: Excipients – croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate. Color mixture ingredients – black ferric oxide, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide. REYVOW 100 mg tablets contain 100 mg lasmiditan (equivalent to 115.65 mg lasmiditan hemisuccinate) and the inactive ingredients as follows: Excipients – croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate. Color mixture ingredients – black ferric oxide, polyethylene glycol, polyvinyl alcohol, red ferric oxide, talc, titanium dioxide. Structural Formula

REYVOW ® is indicated for the acute treatment of migraine with or without aura in adults. REYVOW ® is a serotonin (5-HT) 1F receptor agonist indicated for the acute treatment of migraine with or without aura in adults. ( 1 ) Limitations of Use REYVOW is not indicated for the preventive treatment of migraine. ( 1 ) Limitations of Use REYVOW is not indicated for the preventive treatment of migraine.

The recommended dose of REYVOW is 50 mg, 100 mg, or 200 mg taken orally, as needed. No more than one dose should be taken in 24 hours, and REYVOW should not be taken unless the patient can wait at least 8 hours between dosing and driving or operating machinery [see Warnings and Precautions ( 5.1 )] . A second dose of REYVOW has not been shown to be effective for the same migraine attack. The safety of treating an average of more than 4 migraine attacks in a 30-day period has not been established. REYVOW may be taken with or without food. Administer tablets whole; do not split, crush, or chew. The recommended dose is 50 mg, 100 mg, or 200 mg taken orally, as needed. ( 2 ) No more than one dose should be taken in 24 hours. ( 2 , 5.1 ) Administer tablets whole. ( 2 )

REYVOW (lasmiditan) tablets are available in two strengths: 50 mg tablet: light gray, oval, film coated, tablets with “L-50” debossed on one side and “4312” on the other 100 mg tablet: light purple, oval, film coated, tablets with “L-100” debossed on one side and “4491” on the other Tablets: 50 mg, 100 mg ( 3 )

None. None. ( 4 )

Driving Impairment: Advise patients not to drive or operate machinery until at least 8 hours after taking each dose of REYVOW. Patients who cannot follow this advice should not take REYVOW. Patients may not be able to assess their own driving competence and the degree of impairment caused by REYVOW. ( 5.1 ) Central Nervous System (CNS) Depression: REYVOW may cause CNS depression and should be used with caution if used in combination with alcohol or other CNS depressants. ( 5.2 , 7.1 ) Serotonin Syndrome: Reactions consistent with serotonin syndrome were reported in patients treated with REYVOW. Discontinue REYVOW if symptoms of serotonin syndrome occur. ( 5.3 ) Medication Overuse Headache: Detoxification may be necessary. ( 5.4 ) REYVOW may cause significant driving impairment. In a driving study, administration of single 50 mg, 100 mg, or 200 mg doses of REYVOW significantly impaired subjects' ability to drive [see Clinical Studies ( 14.2 )] . Additionally, more sleepiness was reported at 8 hours following a single dose of REYVOW compared to placebo. Advise patients not to engage in potentially hazardous activities requiring complete mental alertness, such as driving a motor vehicle or operating machinery, for at least 8 hours after each dose of REYVOW. Patients who cannot follow this advice should not take REYVOW. Prescribers and patients should be aware that patients may not be able to assess their own driving competence and the degree of impairment caused by REYVOW. REYVOW may cause central nervous system (CNS) depression, including dizziness and sedation [see Adverse Reactions ( 6.1 )] . Because of the potential for REYVOW to cause sedation, other cognitive and/or neuropsychiatric adverse reactions, and driving impairment, REYVOW should be used with caution if used in combination with alcohol or other CNS depressants [see Drug Interactions ( 7.1 )] . Patients should be warned against driving and other activities requiring complete mental alertness for at least 8 hours after REYVOW is taken [see Warnings and Precautions ( 5.1 )] . In clinical trials, reactions consistent with serotonin syndrome were reported in patients treated with REYVOW who were not taking any other drugs associated with serotonin syndrome. Serotonin syndrome may also occur with REYVOW during coadministration with serotonergic drugs [e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular signs (e.g., hyperreflexia, incoordination), and/or gastrointestinal signs and symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue REYVOW if serotonin syndrome is suspected. Overuse of acute migraine drugs (e.g., ergotamines, triptans, opioids, or a combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (i.e., medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients including withdrawal of the overused drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

The following clinically significant adverse reactions are described elsewhere in the labeling:

REYVOW may further lower heart rate when administered with heart rate lowering drugs. ( 7.3 ) Concomitant administration of REYVOW and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of REYVOW to cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions, REYVOW should be used with caution if used in combination with alcohol or other CNS depressants [see Warnings and Precautions ( 5.2 )] . Concomitant administration of REYVOW and drugs (e.g., SSRIs, SNRIs, TCAs, MAO inhibitors, trazodone, etc.), over-the counter medications (e.g., dextromethorphan), or herbal supplements (e.g., St. John's Wort) that increase serotonin may increase the risk of serotonin syndrome [see Warnings and Precautions ( 5.3 )] . Use REYVOW with caution in patients taking medications that increase serotonin. REYVOW has been associated with a lowering of heart rate [see Adverse Reactions ( 6.1 )] . In a drug interaction study, addition of a single 200 mg dose of REYVOW to propranolol decreased heart rate by an additional 5 beats per minute compared to propranolol alone, for a mean maximum of 19 beats per minute. Use REYVOW with caution in patients taking concomitant medications that lower heart rate if this magnitude of heart rate decrease may pose a concern. Coadministration of REYVOW with P-gp substrates where a small change in substrate plasma concentration may lead to serious toxicities (e.g., digoxin) is not recommended [see Clinical Pharmacology ( 12.3 )] .

Based on animal data, may cause fetal harm. ( 8.1 ) REYVOW has not been studied in patients with severe hepatic impairment (Child-Pugh C) and its use in these patients is not recommended. ( 8.6 ) Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to REYVOW during pregnancy. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-833-464-4724. To learn more please call or visit www.migrainepregnancyregistry.com. Risk Summary There are no adequate data on the developmental risk associated with the use of REYVOW in pregnant women. In animal studies, adverse effects on development (increased incidences of fetal abnormalities, increased embryofetal and offspring mortality, decreased fetal body weight) occurred at maternal exposures less than (rabbit) or greater than (rat) those observed clinically (see Data) . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated rates of major birth defects (2.2% to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraine may be at increased risk for preeclampsia and gestational hypertension during pregnancy. Data Animal Data Oral administration of lasmiditan (0, 100, 175, or 250 mg/kg/day) to pregnant rats throughout organogenesis resulted in increases in skeletal variations at the mid and high doses and reduced fetal body weight at the high dose. The high dose was associated with maternal toxicity. At the no-effect dose (100 mg/kg/day) for adverse effects on embryofetal development in rats, plasma exposure (AUC) was approximately 10 times that in humans at the MRHD. Oral administration of lasmiditan (0, 50, 75, or 115 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in malformations (skeletal and visceral), increases in skeletal variations and embryofetal mortality, and decreased fetal body weight at the highest dose tested, which was associated with maternal toxicity. Plasma exposure (AUC) at the no-effect dose (75 mg/kg/day) for adverse effects on embryofetal development in rabbits was less than that in humans at the MRHD. Oral administration of lasmiditan (0, 100, 150, or 225 mg/kg/day) to rats throughout pregnancy and lactation resulted in increases in stillbirth and neonatal mortality at the highest dose tested, which was associated with maternal toxicity and delayed parturition. Plasma exposure (AUC) at the no-effect dose (150 mg/kg/day) for adverse effects on pre- and postnatal development was approximately 16 times that in humans at the MRHD. Risk Summary There are no data on the presence of lasmiditan in human milk, the effects of lasmiditan on the breastfed infant, or the effects of lasmiditan on milk production. Excretion of lasmiditan and/or metabolites into milk, at levels approximately 3 times those in maternal plasma, was observed in lactating rats following oral administration of lasmiditan. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for REYVOW and any potential adverse effects on the breastfed infant from REYVOW or from the underlying maternal condition. Safety and effectiveness in pediatric patients have not been established. In controlled clinical trials, dizziness occurred more frequently in patients who were at least 65 years of age (19% for REYVOW, 2% for placebo) compared to patients who were less than 65 years of age (14% for REYVOW, 3% for placebo). A larger increase in systolic blood pressure also occurred in patients 65 years of age and older compared to patients who were less than 65 years of age [see Adverse Reactions ( 6.1 )] . Clinical studies of REYVOW did not include sufficient numbers of subjects aged 65 and over to determine whether there is a difference in efficacy in these patients compared to younger subjects. However, in clinical pharmacology studies, no clinically relevant effect on exposure to REYVOW was observed in elderly subjects [see Clinical Pharmacology ( 12.3 )] . In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. No dosage adjustment is needed for patients with mild or moderate hepatic impairment (Child-Pugh A or B). REYVOW has not been studied in patients with severe hepatic impairment (Child-Pugh C) and its use in these patients is not recommended.

REYVOW (lasmiditan) 50 mg tablets are light gray, oval, film coated, tablets with “L-50” debossed on one side and “4312” on the other. REYVOW (lasmiditan) 100 mg tablets are light purple, oval, film coated, tablets with “L-100” debossed on one side and “4491” on the other. Strengths 50 mg 100 mg Tablet color Light gray Light purple Imprint (debossed) L-50 4312 L-100 4491 Carton of 8 NDC 0002-4312-08 NDC 0002-4491-08 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Lasmiditan binds with high affinity to the 5-HT 1F receptor. Lasmiditan presumably exerts its therapeutic effects in the treatment of migraine through agonist effects at the 5-HT 1F receptor; however, the precise mechanism is unknown. Cardiac Electrophysiology At a dose two times the maximum recommended daily dose, REYVOW does not prolong the QTc interval to any clinically relevant extent. Absorption Following oral administration, lasmiditan is rapidly absorbed with a median t max of 1.8 hours. In patients with migraine, the absorption or pharmacokinetics of lasmiditan was not different during a migraine attack versus during the interictal period. Effect of Food Coadministration of lasmiditan with a high-fat meal increased the mean lasmiditan C max and AUC values by 22% and 19%, respectively, and delayed the median t max by 1 hour. This difference in exposure is not expected to be clinically significant [see Dosage and Administration ( 2 )] . Lasmiditan was administered without regard to food in clinical efficacy studies. Distribution The human plasma protein binding of lasmiditan is approximately 55% to 60% and independent of concentration between 15 and 500 ng/mL. Elimination Lasmiditan was eliminated with a geometric mean t ½ value of approximately 5.7 hours. No accumulation of lasmiditan was observed with daily dosing. Lasmiditan is primarily eliminated via metabolism, with ketone reduction representing the major pathway. Renal excretion is a minor route of lasmiditan clearance. Metabolism Lasmiditan undergoes hepatic and extrahepatic metabolism primarily by non-CYP enzymes. The following enzymes are not involved in metabolism of lasmiditan: MAO-A, MAO-B, flavin monooxygenase 3, CYP450 reductase, xanthine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase, and aldo-keto reductases. Lasmiditan is also metabolized to M7 (oxidation on piperidine ring) and M18 (combination of M7 and M8 pathways). These metabolites are considered pharmacologically inactive. Excretion Recovery of unchanged lasmiditan in urine was low and accounted for approximately 3% of the dose. Metabolite S-M8 represented approximately 66% of the dose in urine, with the majority of recovery within 48 hours postdose. Specific Populations Age, Sex, Race/Ethnicity, and Body Weight Based on a population pharmacokinetic (PK) analysis, age, sex, race/ethnicity, and body weight did not have a significant effect on the PK (C max and AUC) of lasmiditan. Therefore, no dose adjustments are warranted based on age, sex, race/ethnicity, or body weight. Geriatric Use In a clinical pharmacology study, administration of lasmiditan to subjects 65 years of age or older demonstrated 26% greater exposure in AUC(0-∞) and 21% higher C max , compared to subjects 45 years of age or less. This difference in exposure is not expected to be clinically significant [see Use in Specific Populations ( 8.5 )] . Renal Impairment In a clinical pharmacology study, administration of lasmiditan to subjects with severe renal impairment (eGFR <30 mL/min/1.73 m 2 ) demonstrated 18% greater exposure in AUC(0-∞) and 13% higher C max , compared to subjects with normal renal function. No dose adjustment is required based on renal function. Hepatic Impairment In a clinical pharmacology study, subjects with mild and moderate hepatic impairment (Child-Pugh Class A and B, respectively) demonstrated 11% and 35%, respectively, greater exposure [AUC(0-∞)] to lasmiditan, compared to subjects with normal hepatic function. The C max were higher by 19% and 33%, respectively, for subjects with mild and moderate hepatic impairment. This difference in exposure is not expected to be clinically significant. The use of lasmiditan has not been studied in subjects with severe hepatic impairment [see Use in Specific Populations ( 8.6 )] . Drug Interaction Studies Potential for Lasmiditan to Affect Other Drugs Drug Metabolizing Enzymes Lasmiditan is an in-vitro inhibitor of CYP2D6 but did not significantly inhibit the activity of other CYP450 enzymes. Modeling and simulation of the impact of lasmiditan on the exposure of dextromethorphan, a recognized sensitive CYP2D6 substrate, indicate that lasmiditan is unlikely to exert clinically significant inhibition of CYP2D6. Lasmiditan, M7, S-M8, and [S,R]-M18 are not reversible or time-dependent inhibitors of monoamine oxidase A (MAO-A). Daily dosing of lasmiditan did not alter the PK of midazolam, caffeine, or tolbutamide, which are substrates of CYP3A, CYP1A2, and CYP2C9, respectively. Coadministration of lasmiditan with sumatriptan, propranolol, or topiramate resulted in no clinically meaningful changes in exposure of these medicinal products. Drug Transporters In a drug interaction study in healthy volunteers, co-administration of 200 mg REYVOW with dabigatran (P-gp substrate) increased the systemic exposures, AUC and C max , of dabigatran by 25% and 22%, respectively [see Drug Interactions ( 7.4 )] . Co-administration of 200 mg REYVOW with rosuvastatin (BCRP substrate) did not affect exposures of rosuvastatin. Lasmiditan inhibits OCT1 in-vitro . However, in a drug-drug interaction study with lasmiditan and sumatriptan (OCT1 substrate), no change in sumatriptan PK was observed. Lasmiditan inhibits renal efflux transporters, MATE1 and MATE2-K, in-vitro . Potential for Other Drugs to Affect Lasmiditan Drug Metabolizing Enzymes Lasmiditan undergoes hepatic and extrahepatic metabolism primarily by non-CYP enzymes. Therefore, it is unlikely that CYP inhibitors or inducers will affect lasmiditan pharmacokinetics. Clinical studies of lasmiditan with sumatriptan, propranolol, or topiramate did not show any significant drug interaction potential. Drug Transporters Lasmiditan is a substrate for P-gp in-vitro .

Carcinogenesis No drug-related tumors were observed following oral administration of lasmiditan to TgRasH2 mice at doses of up to 150 (males) or 250 (females) mg/kg/day for 26 weeks or to rats at doses of up to 75 mg/kg/day for 2 years. Plasma exposures (AUC) at the highest dose tested in rats were approximately 15 times that in humans at the maximum recommended human dose (MRHD) of 200 mg/day. Mutagenesis Lasmiditan was negative in in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays. Impairment of Fertility Oral administration of lasmiditan to male (0, 100, 175, or 200 mg/kg/day) or female (0, 100, 150, or 200 mg/kg/day) rats prior to and during mating and continuing in females to Gestation Day 7 resulted in no adverse effects on fertility or reproductive performance. Plasma exposures (AUC) at the highest dose tested (200 mg/kg/day) were approximately 26 times that in humans at the MRHD.

The efficacy of REYVOW in the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials [Study 1 (NCT02439320) and Study 2 (NCT02605174)]. These studies enrolled patients with a history of migraine with and without aura according to the International Classification of Headache Disorders (ICHD-II) diagnostic criteria. Patients were predominantly female (84%), and White (78%), with a mean age of 42 years (range 18-81). Twenty-two percent of patients were taking preventive medication for migraine at baseline. Study 1 randomized patients to REYVOW 100 mg (n=744), or 200 mg (n=745) or placebo (n=742) and Study 2 randomized patients to REYVOW 50 mg (n=750), 100 mg (n=754), or 200 mg (n=750) or placebo (n=751). Patients were allowed to take a rescue medication 2 hours after taking study drug; however, opioids, barbiturates, triptans, and ergots were not allowed within 24 hours of study drug administration. The primary efficacy analyses were conducted in patients that treated a migraine with moderate to severe pain within 4 hours of the onset of the attack. The efficacy of REYVOW was established by an effect on pain freedom at 2 hours and Most Bothersome Symptom (MBS) freedom at 2 hours compared to placebo for Studies 1 and 2. Pain freedom was defined as a reduction of moderate or severe headache pain to no pain, and MBS freedom was defined as the absence of the self-identified MBS (photophobia, phonophobia, or nausea). Among patients who selected an MBS, the most commonly selected MBS was photophobia (54%), followed by nausea (24%), and phonophobia (22%). In both studies, the percentage of patients achieving pain freedom and MBS freedom 2 hours after treatment was significantly greater among patients receiving REYVOW at all doses compared to those receiving placebo (see Table 2 ). Table 2: Migraine Efficacy Endpoints after Treatment for Studies 1 and 2 Study 1 Study 2 REYVOW 100 mg REYVOW 200 mg Placebo REYVOW 50 mg REYVOW 100 mg REYVOW 200 mg Placebo Pain Free at 2 hours      N 498 503 515 544 523 521 534      % Responders 28.3 31.8 15.3 28.3 31.4 38.8 21.0      Difference from placebo (%) 13 16.5 7.3 10.4 17.8       p -value <0.001 <0.001 0.006 <0.001 <0.001 MBS Free at 2 hours      N 464 467 480 502 491 478 509      % Responders 41.2 40.7 29.6 40.8 44.0 48.7 33.2      Difference from placebo (%) 11.6 11.1 7.6 10.8 15.5       p -value <0.001 <0.001 0.014 <0.001 <0.001 Pain relief at 2 hours, defined as a reduction in migraine pain from moderate or severe to mild or none, was also evaluated (see Table 3 ). Table 3: Additional Migraine Efficacy Endpoint after Treatment for Studies 1 and 2 a The analysis of pain relief was descriptive and was not controlled for Type I error. Study 1 Study 2 REYVOW 100 mg REYVOW 200 mg Placebo REYVOW 50 mg REYVOW 100 mg REYVOW 200 mg Placebo Pain Relief at 2 hours a      N 498 503 515 544 523 521 534      % Responders 54.0 55.3 40.0 55.9 61.4 61.0 45.1      Difference from placebo (%) 14.0 15.3 10.8 16.3 15.9 Figure 1 presents the percentage of patients achieving migraine pain freedom within 2 hours following treatment in Studies 1 and 2. Figure 1: Percentage of Patients Achieving Migraine Pain Freedom within 2 Hours in Pooled Studies 1 and 2 a The 50 mg arm was only included in Study 2. Figure 2 presents the percentage of patients achieving MBS freedom within 2 hours in Studies 1 and 2. Figure 2: Percentage of Patients Achieving MBS Freedom within 2 Hours in Pooled Studies 1 and 2 a The 50 mg arm was only included in Study 2. Figure 1 Figure 2 Driving performance was assessed at 90 minutes after administration of REYVOW 50 mg, 100 mg, 200 mg, alprazolam 1 mg, and placebo in a randomized, double-blind, placebo- and active-controlled, five-period crossover study in 90 healthy volunteers (mean age 34.9 years) using a computer-based driving simulation. Driving performance was evaluated using a validated threshold established in a population with blood alcohol concentration of 0.05%. The primary outcome measure was the difference from placebo in the Standard Deviation of Lateral Position (SDLP), a measure of driving performance. A dose-dependent impairment of computer-based simulated driving performance was seen with all doses of REYVOW at 90 minutes after administration. Driving performance was also assessed at 8, 12, and 24 hours after administration of REYVOW 100 mg or 200 mg, in a separate randomized, double-blind, placebo- and active-controlled, four-period crossover study in 67 healthy volunteers (mean age 32.8 years) evaluating computer-based simulated driving performance using SDLP as the primary endpoint. Diphenhydramine 50 mg was used as a positive control. The mean SDLP did not reach the threshold for driving impairment at 8 hours or later after administration of REYVOW 100 or 200 mg.

PACKAGE LABEL - REYVOW 50 mg 8ct carton NDC 0002-4312-08 8 tablets (2 cards of 4 tablets) REYVOW ® (lasmiditan) CV tablets 50 mg Each tablet contains 50 mg of lasmiditan. Rx only www.REYVOW.com 50 mg Dispense enclosed Medication Guide to each patient. Lilly PDP Text – REYVOW 50 mg 8ct carton