` 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)
`
`
`
`
`
`-------------------------------ADVERSE REACTIONS------------------------------
`
`
`
`
`Most common adverse reactions (≥5% and > placebo) were dizziness,
`
`
`
`
`fatigue, paresthesia, and sedation. (6.1)
`
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly
`
`
`
`and Company at 1-800-LillyRx (1-800-545-5979) or FDA at
`
`
`1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`
`------------------------------- DRUG INTERACTIONS ------------------------------
`
`
`
`• REYVOW may further lower heart rate when administered with
`
`
`heart rate lowering drugs. (7.3)
`
`
`• Avoid concomitant use with P-gp and Breast Cancer Resistant
`
`
`Protein (BCRP) substrates. (7.4)
`
`
`
`
`
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`
`
`
`
`• 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)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved Medication Guide.
`
`
`
`Revised: 1/2022
`
`
`
`
`9 DRUG ABUSE AND DEPENDENCE
`
`
`9.1 Controlled Substance
`
`
`9.2 Abuse
`
`
`9.3 Dependence
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Migraine
`
`
`14.2 Effects on Driving
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
`
`
`16.2 Storage and Handling
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`* Sections or subsections omitted from the full prescribing information
`
`
`are not listed.
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
`
` These highlights do not include all the information needed to use
` REYVOW safely and effectively. See full prescribing information
`
`
`
`
`
`
` for REYVOW.
`
`
` REYVOW (lasmiditan) tablets, for oral use, CV
`
` Initial U.S. Approval: 2020
`
`
`
`
`
`
`
`
`
`
`
`
` ---------------------------- INDICATIONS AND USAGE ---------------------------
` 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)
`
`
`
`
`
`
`
`------------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`
`
`
`
`
`
`• 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)
`
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`
`
`Tablets: 50 mg, 100 mg (3)
`
`
`
`
`
`------------------------------- CONTRAINDICATIONS ------------------------------
`
`
`
`• None. (4)
`
`
`
`
`
`
`------------------------WARNINGS AND PRECAUTIONS -----------------------
`
`
`
`
`• 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)
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Driving Impairment
`
`
`
`5.2 Central Nervous System Depression
`
`
`5.3 Serotonin Syndrome
`
`
`5.4 Medication Overuse Headache
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 CNS Depressants
`
`
`7.2 Serotonergic Drugs
`
`
`7.3 Heart Rate Lowering Drugs
`
`
`
`7.4 P-gp and Breast Cancer Resistant Protein (BCRP)
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic Impairment
`
`Reference ID: 5014152
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 2
`
` 1
`
`
` INDICATIONS AND USAGE
` REYVOW® is indicated for the acute treatment of migraine with or without aura in adults.
`
`
`Limitations of Use
`
`
`REYVOW is not indicated for the preventive treatment of migraine.
`
`
`
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`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
`
`
`CONTRAINDICATIONS
`
`
`4
`
`None.
`
`
`5
`
`
`WARNINGS AND PRECAUTIONS
`
`
`
`Driving Impairment
`5.1
`
`
`
`
`
`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.
`
`
`
`Central Nervous System Depression
`5.2
`
`
`
`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)].
`
`
`
`Serotonin Syndrome
`5.3
`
`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
`
`Reference ID: 5014152
`
`

`

`
`
`
`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.
`
`
`
`5.4 Medication Overuse Headache
`
`
`
`
`
`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.
`
`
`3
`
`
`
`ADVERSE REACTIONS
`6
`
`
`
`The following clinically significant adverse reactions are described elsewhere in the labeling:
`
`
`
`• Driving Impairment [see Warnings and Precautions (5.1)]
`
`
`
`
`• Central Nervous System Depression [see Warnings and Precautions (5.2)]
`
`
`• Serotonin Syndrome [see Warnings and Precautions (5.3)]
`
`
`• Medication Overuse Headache [see Warnings and Precautions (5.4)]
`
`
`
`
`Clinical Trials Experience
`6.1
`
`
`Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical
`
`
`
`
`studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates
`
`
`observed in practice.
`
`
`
`
`
`
`The safety of REYVOW has been evaluated in 4,878 subjects who received at least one dose of REYVOW. In 2 placebo-
`
`
`
`
`
`
`
`controlled, Phase 3 trials in adult patients with migraine (Studies 1 and 2), a total of 3,177 patients received REYVOW 50,
`
`
`
`
`
`
`100, or 200 mg [see Clinical Studies (14.1)]. Of the REYVOW-treated patients in these 2 studies, approximately 84% were
`
`
`
`
`
`
`
`female, 78% were White, 18% were Black, and 18% were of Hispanic or Latino ethnicity. The mean age at study entry
`
`
`
`was 42.4 years (range 18 to 81).
`
`
`
`
`
`Long-term safety was assessed for 2,030 patients, dosing intermittently for up to 12 months in a long-term safety study.
`
`
`
`
`
`
`
`
`
`Of these, 728 patients were exposed to 100 mg or 200 mg for at least 3 months, 361 patients were exposed to these
`
`
`
`
`
`
`
`
`
`
`doses for at least 6 months, and 180 patients were exposed to these doses for at least 12 months, all of whom treated at
`
`
`
`
`
`
`
`least 2 migraine attacks per month on average. In that study, 14% (148 out of 1,039) in the 200 mg dose group, and 11%
`
`
`
`(112 out of 991) in the 100 mg dose group withdrew from the trial because of an adverse event. The most common
`
`
`
`
`adverse event resulting in discontinuation in the long-term safety study (greater than 2%) was dizziness.
`
`
`Table 1 shows adverse reactions that occurred in at least 2% of patients treated with REYVOW and more frequently than
`
`
`
`in patients who received placebo in Studies 1 and 2. The most common adverse reactions (at least 5%) were dizziness,
`
`fatigue, paresthesia, and sedation.
`
`
`Reference ID: 5014152
`
`

`

`
` Table 1: Adverse Reactions Occurring in ≥2% and at a Frequency Greater than Placebo in Studies 1 and 2
`
` REYVOW 200 mg
`
` REYVOW 50 mg
`
`
`
`
`
`
`
` Placebo
` Adverse Reaction
` REYVOW 100 mg
`
`
`
` N=1262
`
` N=654
` N=1265
` N=1258
`
` %
`
` %
`
` %
`
` %
`
` 3
`
` 9
` 15
`
`
` 17
`
` 1
`
` 4
`
` 5
`
` 6
`
` 2
`
` 3
`
` 7
`
` 9
`
` 2
`
` 6
`
` 6
`
` 7
`
` 2
`
` 3
`
` 4
`
` 4
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4
`
`
`
` Dizziness
`
`
` Fatiguea
` Paresthesiab
`
` Sedationc
` Nausea and/or
`
`
` Vomiting
` 1
` Muscle Weakness
`
`
`
` 1
`
`
`
`
`
` a Fatigue includes the adverse reaction related terms asthenia and malaise.
`
`
`
`
`
`
`
`b Paresthesia includes the adverse reaction related terms paresthesia oral, hypoesthesia, and hypoesthesia oral.
`
`
`
`
`c Sedation includes the adverse reaction related term somnolence.
`
`
`Less Common Adverse Reactions
`
`The following adverse reactions occurred in less than 2% of REYVOW-treated patients but more frequently than in
`
`
`
`
`
`patients receiving placebo: vertigo, incoordination, lethargy, visual impairment, feeling abnormal, feeling hot or feeling
`
`
`cold, palpitations, anxiety, tremor, restlessness, sleep abnormalities including sleep disturbance and abnormal dreams,
`
`muscle spasm, limb discomfort, cognitive changes, confusion, euphoric mood, chest discomfort, speech abnormalities,
`
`
`dyspnea, and hallucinations.
`
`Hypersensitivity
`
`
`
`Events of hypersensitivity, including angioedema, rash and photosensitivity reaction, occurred in patients treated with
`
`
`
`
`
`
`
`REYVOW. In controlled trials, hypersensitivity was reported in 0.2% of patients treated with REYVOW compared to no
`
`
`
`patients who received placebo. If a serious or severe hypersensitivity reaction occurs, initiate appropriate therapy and
`
`discontinue administration of REYVOW.
`
`
`Vital Sign Changes
`
`Heart Rate Decrease
`
`
`
`
`REYVOW was associated with mean decreases in heart rate of 5 to 10 beats per minute (bpm) while placebo was
`
`
`
`
`associated with mean decreases of 2 to 5 bpm. Consider evaluating heart rate after administration of REYVOW in
`
`
`patients for whom these changes may not be tolerated, including patients taking other medications that lower heart rate
`
`[see Drug Interactions (7.3)].
`
`Blood Pressure Increase
`
`
`REYVOW may increase blood pressure following a single dose. In non-elderly healthy volunteers there was a mean
`
`
`
`
`
`
`
`
`increase from baseline in ambulatory systolic and diastolic blood pressure of approximately 2 to 3 mm Hg one hour after
`
`
`
`
`
`
`administration of 200 mg REYVOW compared to a mean increase of up to 1 mm Hg for placebo. In healthy volunteers
`
`
`
`
`
`
`
`over 65 years of age, there was a mean increase from baseline in ambulatory systolic blood pressure of 7 mm Hg
`
`
`
`
`
`
`
`
`
`
`one hour after administration of 200 mg REYVOW compared to a mean increase of 4 mm Hg for placebo. By 2 hours,
`
`
`
`
`
`there were no increases in mean blood pressure with REYVOW compared to placebo. REYVOW has not been well
`
`studied in patients with ischemic heart disease. Consider evaluating blood pressure after administration of REYVOW in
`
`
`patients for whom these changes may not be tolerated.
`
`
`
` 2
`
`
`
` 0
`
`
`7
`
`
`DRUG INTERACTIONS
`
`
`
`CNS Depressants
`7.1
`
`
`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)].
`
`Reference ID: 5014152
`
`

`

` Serotonergic Drugs
` 7.2
`
`
` 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.
`
` Heart Rate Lowering Drugs
` 7.3
`
`
`
`
` 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.
`
`
`
`
`
`
`
` 5
`
` P-gp and Breast Cancer Resistant Protein (BCRP)
` 7.4
`
`
`
`
` REYVOW inhibits P-gp and BCRP in vitro. Concomitant use of REYVOW and drugs that are P-gp or BCRP substrates
`
` should be avoided.
`
`
`
`
`
`
`
`8
`
`
`
`
` USE IN SPECIFIC POPULATIONS
`
`
`
`
`
` Pregnancy
` 8.1
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5014152
`
`

`

`
`
` Lactation
` 8.2
`
`
` 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.
`
`
`
`
`
` 6
`
` Pediatric Use
` 8.4
`
`
` Safety and effectiveness in pediatric patients have not been established.
`
`
`
`
`
`
`
`
`
` 8.5
` Geriatric Use
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
` 8.6
` Hepatic Impairment
`
`
`
`
`
`
` 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.
`
`
`
`
`
` 9
`
`
`
` DRUG ABUSE AND DEPENDENCE
`
`
`
` Controlled Substance
` 9.1
`
`
`
`
` REYVOW contains lasmiditan, a Schedule V controlled substance (CV).
`
`
`
`
`
`
`
`
`
` Abuse
` 9.2
`
`
` Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.
`
`
`
`
`
`
`
`
` In a human abuse potential (HAP) study in recreational poly-drug users (n=58), single oral therapeutic doses (100 and
`
` 200 mg) and a supratherapeutic dose (400 mg) of REYVOW were compared to alprazolam (2 mg) (C-IV) and placebo.
`
`
`
`
`
`
`
` With all doses of REYVOW, subjects reported statistically significantly higher “drug liking” scores than placebo, indicating
`
`
`
`
` that REYVOW has abuse potential. In comparison to alprazolam, subjects who received REYVOW reported statistically
`
`
`
`
` significantly lower “drug liking” scores. In the HAP study, euphoric mood occurred to a similar extent with REYVOW
`
`
` 200 mg, REYVOW 400 mg, and alprazolam 2 mg (43-49%). A feeling of relaxation was noted in more subjects on
`
`
`
`
`
` alprazolam (22.6%) than with any dose of REYVOW (7-11%).
`
`
`
` Phase 2 and 3 studies indicate that, at therapeutic doses, REYVOW produced adverse events of euphoria and
`
` hallucinations to a greater extent than placebo. However these events occur at a low frequency (about 1% of patients).
`
`
`
`
`
` Evaluate patients for risk of drug abuse and observe them for signs of lasmiditan misuse or abuse.
`
`
`
`
`
`
` 9.3
`
`
` Dependence
` Physical withdrawal was not observed in healthy subjects following abrupt cessation after 7 daily doses of lasmiditan
`
`
`
`
`
` 200 mg or 400 mg.
`
`
`
`
`
` 11
` DESCRIPTION
`
`
`
`
`
`
`
`
` 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
`
`
`Reference ID: 5014152
`
`

`

` empirical formula of C19H18F3N3O2•0.5[C4H6O4] and a molecular weight of 436.41 (hemisuccinate). Lasmiditan
`
`
`hemisuccinate has the following structural formula:
`
`
`
`
`
`
`
`
`
`
` 7
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`12
`
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`Lasmiditan binds with high affinity to the 5-HT1F receptor. Lasmiditan presumably exerts its therapeutic effects in the
`
`
`
`
`
`
`treatment of migraine through agonist effects at the 5-HT1F receptor; however, the precise mechanism is unknown.
`
`
`
`
`12.2 Pharmacodynamics
`
`
`Cardiac Electrophysiology
`
`At a dose two times the maximum recommended daily dose, REYVOW does not prolong the QTc interval to any clinically
`
`
`
`
`
`
`
`
`relevant extent.
`
`
`12.3 Pharmacokinetics
`
`
`Absorption
`
`Following oral administration, lasmiditan is rapidly absorbed with a median tmax 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 Cmax and AUC values by 22% and
`19%, respectively, and delayed the median tmax 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.
`
`
`
`Reference ID: 5014152
`
`

`

`
`
` 8
`
`
`
` Elimination
`
` Lasmiditan was eliminated with a geometric mean t½ 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 (Cmax 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 Cmax, 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 m2) demonstrated 18% greater exposure in AUC(0-∞) and 13% higher Cmax, 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 Cmax 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
`
`Lasmiditan inhibits P-gp and BCRP in-vitro [see Drug Interactions (7.4)].
`
`
`
`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.
`
`
`Reference ID: 5014152
`
`

`

`
`
` 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.
`
`
`
`
`
`
`
` 9
`
`
`
` 13
`
`
`
` NONCLINICAL TOXICOLOGY
`
`
`
`
`
`
`
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
` 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.
`
`
`
`
`
`
`
`
`
` 14
`
`
`
` CLINICAL STUDIES
`
` 14.1 Migraine
`
`
`
`
`
`
`
`
`
` 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