Lasmiditan (Monograph)

Brand name: Reyvow
Drug class: Selective Serotonin Agonists
- Antimigraine Agents
- 5-HT1 Agonists
VA class: CN105
Chemical name: 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl]benzamide hemisuccinate
Molecular formula: C₁₉H₁₈F₃N₃O₂•½[C₄H₆O₄]
CAS number: 439239-92-6

Medically reviewed by Drugs.com on Nov 27, 2022. Written by ASHP.

Introduction

Selective agonist of serotonin (5-hydroxytryptamine; 5-HT) type 1F receptors (“ditan”).

Uses for Lasmiditan

Acute Treatment of Migraine

Acute treatment of migraine attacks with or without aura in adults.

Not indicated for prophylaxis of migraine.

Recommended by American Headache Society (AHS) as an option for acute treatment of migraine attacks in patients who have contraindications to serotonin type 1 (5-HT₁) selective receptor agonists (triptans) or who have failed to respond to or tolerate at least 2 oral triptans.

Lasmiditan Dosage and Administration

General

Patient Monitoring

Consider monitoring heart rate following administration of lasmiditan in patients in whom a decrease in heart rate may not be tolerated, including patients taking other drugs that can decrease heart rate.
Consider monitoring BP following administration of lasmiditan in patients in whom an increase in BP may not be tolerated.

Administration

Oral Administration

Administer orally without regard to food.

Swallow tablets whole; do not split, crush, or chew.

Because of risk of CNS sedation, including driving impairment, patients should not drive or operate machinery for at least 8 hours after taking lasmiditan; the drug should not be used if the patient cannot wait ≥8 hours between dosing and performing hazardous activities that require mental alertness (e.g., driving, operating machinery).

Dosage

Adults

Acute Treatment of Migraine

Oral

Administer a single dose of 50, 100, or 200 mg as needed.

Taking a second dose for same migraine attack not shown to be effective.

Prescribing Limits

Adults

Acute Treatment of Migraine

Oral

Do not take more than one dose in a 24-hour period.

Safety of treating an average of more than 4 migraine attacks in a 30-day period not established.

Special Populations

Hepatic Impairment

No dosage adjustments necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

Not recommended in patients with severe (Child-Pugh class C) hepatic impairment.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

Select dosage carefully, usually starting at the low end of the dosage range.

Cautions for Lasmiditan

Contraindications

None.

Warnings/Precautions

Driving Impairment

May cause marked driving impairment. Patients may not be able to assess their driving competence or degree of impairment after taking the drug.

Avoid using lasmiditan unless the patient can wait ≥8 hours between dosing and performing hazardous activities that require mental alertness (e.g., driving, operating machinery).

CNS Depression

May cause CNS depression (e.g., dizziness, sedation) and other adverse cognitive and/or neuropsychiatric reactions; use with caution with other CNS depressants, including alcohol.

Serotonin Syndrome

Reactions consistent with serotonin syndrome reported, including in patients not receiving other drugs associated with this adverse effect. Also may occur in patients receiving concomitant therapy with other serotonergic drugs (e.g., SSRIs, SNRIs, tricyclic antidepressants, MAO inhibitors).

Symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).

If serotonin syndrome is suspected, discontinue lasmiditan.

Medication Overuse Headache

Overuse of acute migraine drugs (e.g., 5-HT₁ receptor agonists [triptans], ergotamine derivatives, opioids, or a combination of these drugs on a regular basis for ≥10 days per month) may result in migraine-like daily headaches or a marked increase in the frequency of migraine attacks.

Detoxification, including withdrawal of the overused drugs and treatment of withdrawal symptoms (e.g., transient worsening of headaches), may be necessary.

Abuse Potential and Dependence

Euphoria and hallucination reported.

Lasmiditan associated with higher “drug liking” scores compared with placebo, but lower scores compared with alprazolam. Feeling of relaxation reported more frequently with alprazolam than lasmiditan, but incidence of euphoric mood was similar between the drugs.

Physical withdrawal not observed following abrupt cessation after 7 daily doses of lasmiditan 200 or 400 mg in healthy subjects.

Lasmiditan is subject to control as a schedule V (C-V) drug.

Carefully evaluate patients for history of drug abuse and monitor for signs of lasmiditan misuse or abuse.

Cardiovascular Effects

Decrease in heart rate of 5–10 beats per minute reported.

Consider monitoring heart rate in patients in whom a decrease in heart rate may not be tolerated, including those taking other drugs that decrease heart rate.

May cause a transient increase in BP; effect may be more pronounced in geriatric individuals.

Consider monitoring BP in patients in whom an increase in BP may not be tolerated.

Unlike triptans, lasmiditan not shown to have vasoconstrictive effects. However, not well studied in patients with ischemic cardiac disease.

Hypersensitivity

Hypersensitivity reactions (e.g., angioedema, rash, photosensitivity) reported.

If a serious or severe hypersensitivity reaction occurs, discontinue lasmiditan and initiate appropriate therapy.

Specific Populations

Pregnancy

Pregnancy registry at 833-464-4724 or [Web].

No adequate data on developmental risk associated with use of lasmiditan in pregnant females.

Adverse developmental effects (increased incidences of fetal abnormalities, increased embryofetal and offspring mortality, decreased fetal body weight) observed in animal reproduction studies.

Lactation

Distributed into milk in rats. Not known whether distributed into human milk. Effects on the breast-fed infant or on milk production also unknown.

Consider developmental and health benefits of breast-feeding, mother's clinical need for lasmiditan, and potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Insufficient numbers of patients ≥65 years of age to determine whether efficacy of the drug differs from that in younger adults.

Dizziness reported more frequently in patients ≥65 years of age compared with younger patients. In addition, greater increases in systolic BP reported in patients ≥65 years of age compared with younger adults.

Pharmacokinetic profile similar to that in younger adults.

Hepatic Impairment

Use not recommended in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

Renal impairment not expected to affect pharmacokinetics.

Common Adverse Effects

Adverse effects (≥5%): Dizziness, fatigue, paresthesia, sedation.

Drug Interactions

Metabolized primarily by non-CYP enzymes. Substrate of P-glycoprotein (P-gp).

Inhibits CYP2D6 in vitro. Also inhibits P-gp, breast cancer resistance protein (BCRP), organic cation transporter 1 (OCT1), multidrug and toxic compound extrusion protein (MATE) 1, and MATE2K in vitro.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP isoenzymes: Pharmacokinetic interactions unlikely.

Substrates of CYP isoenzymes: Pharmacokinetic interactions unlikely.

Drugs Transported by Breast Cancer Resistance Protein

Increased exposure to BCRP substrates expected. Concomitant use with BCRP substrates not recommended.

Drugs Transported by P-glycoprotein

Increased exposure to P-gp substrates expected. Concomitant use with P-gp substrates not recommended.

CNS Depressants

Additive CNS effects possible when used concomitantly with alcohol or other CNS depressants; caution advised.

Drugs that Lower Heart Rate

Additive heart rate-lowering effects can occur. Use concomitantly with caution.

Serotonergic Drugs

Increased risk of serotonin syndrome. Use concomitantly with caution.

Specific Drugs

Drug	Interaction	Comments
Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and SNRIs (e.g., duloxetine, venlafaxine)	Potential pharmacologic interaction (increased risk of serotonin syndrome)	Use concomitantly with caution
Caffeine	Daily doses of lasmiditan did not affect pharmacokinetics of caffeine
Dextromethorphan	Potential pharmacologic interaction (increased risk of serotonin syndrome) Lasmiditan unlikely to affect pharmacokinetics of dextromethorphan	Use concomitantly with caution
MAO Inhibitors	Potential pharmacologic interaction (increased risk of serotonin syndrome)	Use concomitantly with caution
Midazolam	Daily doses of lasmiditan did not affect pharmacokinetics of midazolam
Propranolol	Additive heart rate lowering effects possible Additional decrease in heart rate observed with concomitant use compared with propranolol use alone No substantial pharmacokinetic interaction	Use concomitantly with caution, particularly when decreases in heart rate of this magnitude unlikely to be well tolerated
St. John's wort (Hypericum perforatum)	Increased risk of serotonin syndrome	Use concomitantly with caution
Sumatriptan	Increased risk of serotonin syndrome No substantial pharmacokinetic interaction	Use concomitantly with caution
Tolbutamide	Pharmacokinetics of tolbutamide not affected
Topiramate	No substantial pharmacokinetic interaction
Trazodone	Increased risk of serotonin syndrome	Use concomitantly with caution

Lasmiditan Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration, with peak plasma concentrations achieved in approximately 1.8 hours.

Oral bioavailability reported to be about 40%.

Linear pharmacokinetics reported following oral administration as a liquid at doses of 25–400 mg. Accumulation of drug not observed with daily dosing.

Similar pharmacokinetics observed when administered during acute migraine attack compared with during interictal period.

Onset

Significant improvement in pain freedom compared with placebo observed within 1–1.5 or 2 hours following lasmiditan doses of 100–200 or 50 mg, respectively.

Food

Higher peak concentrations and AUC and delayed absorption observed following administration with a high-fat meal compared with fasting administration. Differences not expected to be clinically important; drug was administered without regard to meals in controlled clinical trials.

Distribution

Extent

Penetrates the blood-brain barrier.

Not known whether distributed into human milk.

Plasma Protein Binding

About 55–60%; not concentration-dependent at plasma concentrations of 15–500 ng/mL.

Elimination

Metabolism

Undergoes hepatic and extrahepatic metabolism primarily by non-CYP enzymes, with ketone reduction as major pathway.

Also metabolized to M7 via oxidation on the piperidine ring and to M18 via a combination of M7 and M8 pathways; metabolites pharmacologically inactive.

Elimination Route

Renal excretion plays minor role in lasmiditan clearance; about 3% of dose excreted unchanged in urine.

S-M8 metabolite comprises approximately 66% of the dose in urine, with majority recovered within 48 hours after oral administration.

Half-life

Approximately 5.7 hours.

Special Populations

Increases in AUC and peak plasma concentrations of 11 and 19%, respectively, in patients with mild hepatic impairment (Child-Pugh class A), and of 35 and 33%, respectively, in patients with moderate hepatic impairment (Child-Pugh class B) observed; differences not considered clinically important. Not studied in subjects with severe hepatic impairment (Child-Pugh class C).

Increased AUC (18%) and peak plasma concentrations (13%) reported in patients with severe renal impairment (estimated GFR <30 mL/minute per 1.73 m²); differences not considered clinically important.

Increased AUC (26%) and peak plasma concentrations (21%) reported in patients ≥65 years of age compared with those ≤45 years of age; differences not considered clinically important.

Age, sex, race, ethnicity, and body weight do not appear to substantially affect pharmacokinetics.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted to 15–30°C).

Actions

Binds with high affinity and selectivity to the serotonin (5-hydroxytryptamine, 5-HT) type IF receptor.
Differs structurally from selective 5-HT₁ receptor agonists (triptans); does not bind to 5-HT_1B receptors and appears to lack vasoconstrictive effects.
Precise mechanism of action not established; may ameliorate migraine through decreasing neuropeptide release (e.g., calcitonin gene-related peptide [CGRP], substance P) and inhibiting pain pathways, including those in the trigeminal nerve and ganglion. Modulation of dural neurogenic inflammation, possibly through blockade of plasma protein extravasation, also may play a role.

Advice to Patients

Importance of instructing patients to read the manufacturer's information for patients (medication guide).
Advise patients to swallow tablets whole; do not split, crush, or chew.
Importance of advising patients to avoid potentially dangerous activities requiring complete mental alertness (e.g., driving, operating machinery) for ≥8 hours after taking lasmiditan. Importance of not taking drug if unable to comply. Importance of informing patients of possible inability to assess own driving competence or degree of impairment after taking the drug.
Risk of dizziness or sedation; importance of exercising caution if taking lasmiditan concomitantly with alcohol or other CNS depressants.
Importance of informing patients of risk of serotonin syndrome, particularly with concurrent use of lasmiditan and serotonergic drugs (e.g., SSRIs, SNRIs, tricyclic antidepressants, MAO inhibitors).
Overuse (i.e., ≥10 days per month) of drugs used to treat acute migraine attacks may exacerbate headaches; importance of recording headache frequency and drug use (e.g., by keeping a headache diary).
Risk of hypersensitivity reaction; importance of seeking immediate medical attention if symptoms of serious or severe hypersensitivity reaction occur.
Importance of advising patients of lasmiditan's abuse potential and importance of keeping drug secure.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of females informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to lasmiditan during pregnancy.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lasmiditan is subject to control under the Federal Controlled Substances Act of 1970 as a schedule V (C-V) drug.