Comprehensive Monograph: Lasmiditan (Reyvow)

Section 1: Executive Summary & Therapeutic Context

1.1 Introduction to Lasmiditan

Lasmiditan, marketed under the brand name Reyvow, is a first-in-class, orally administered small molecule medication developed for the acute treatment of migraine.[1] It represents a new therapeutic category known as "ditans" and functions as a selective serotonin 5-hydroxytryptamine receptor 1F (

5−HT1F​) agonist.[3] Its approved indication is for the immediate, abortive treatment of migraine attacks, with or without aura, in adult patients.[1] It is critical to note that Lasmiditan is not indicated for the prophylactic, or preventive, treatment of migraine.[1]

1.2 The Unmet Need in Migraine Therapy

The development of Lasmiditan was driven by a significant unmet need within the landscape of migraine therapeutics. Migraine is a highly prevalent and debilitating neurological disorder, recognized as one of the leading causes of disability globally, affecting a substantial portion of the population and imposing a heavy healthcare burden.[6] For decades, the therapeutic cornerstone for acute migraine has been the triptan class of drugs, such as sumatriptan.[2] While effective for many, the utility of triptans is fundamentally limited by their mechanism of action. Triptans exert their primary therapeutic effect through agonism at

5−HT1B​ and 5−HT1D​ receptors.[1] The activation of

5−HT1B​ receptors, which are expressed on vascular smooth muscle, induces vasoconstriction of cranial arteries.[8] This vasoconstrictive property, while once thought to be central to their anti-migraine effect, results in a profile of cardiovascular side effects and contraindications. Consequently, triptans are unsuitable for a significant subset of migraine sufferers, including those with a history of, or risk factors for, cardiovascular, cerebrovascular, or peripheral vascular diseases, such as ischemic heart disease or previous myocardial infarction.[2] This created a critical therapeutic gap for patients in need of an effective acute treatment but for whom triptans posed an unacceptable cardiovascular risk.

1.3 Synopsis of a Novel Mechanism

Lasmiditan introduces a paradigm shift in the acute treatment of migraine through its novel, targeted mechanism. It is classified as a neurally-acting anti-migraine medication (NAAMA), a designation that highlights its primary action on the nervous system rather than the vasculature.[8] The success of Lasmiditan provides strong clinical validation for a modern understanding of migraine pathophysiology, which has evolved from a primarily vascular theory to one centered on neuronal hyperexcitability within the trigeminovascular system. The older vascular model posited that the pain of a migraine attack stemmed from the acute dilation of cerebral blood vessels, and therefore, treatments like triptans were designed to constrict these vessels.[2] Lasmiditan, by contrast, was engineered to be highly selective for the

5−HT1F​ receptor, which is predominantly located on trigeminal neurons, not on cranial blood vessels.[1] By achieving effective migraine abortion through a purely neuronal mechanism—the inhibition of neuronal firing—Lasmiditan's efficacy demonstrates that the primary driver of migraine pain is neuronal hyperactivity, not vasodilation. This mechanistic distinction is the cornerstone of its innovation and has significant implications for future drug development, steering the field toward neuronal targets.

1.4 Summary of Efficacy and Safety Profile

Lasmiditan has demonstrated robust and statistically significant efficacy in large-scale, pivotal Phase III clinical trials, including the SAMURAI and SPARTAN studies.[1] In these trials, Lasmiditan met its co-primary endpoints, showing superiority over placebo in achieving both pain freedom and freedom from the patient-identified most bothersome symptom (MBS) at two hours post-administration.[1] While it successfully addresses the cardiovascular concerns associated with triptans, its clinical use is defined by a distinct safety profile dominated by central nervous system (CNS) effects. The most common adverse reactions are dizziness, sedation, and paresthesia.[11] These CNS effects are significant enough to warrant a stringent warning advising patients not to drive or operate heavy machinery for at least eight hours following a dose.[1] This creates a clear clinical trade-off: for a patient with cardiovascular disease, the risk of a vascular event from a triptan is unacceptable, making the risk of CNS sedation from Lasmiditan a medically sound alternative. Conversely, for a patient who must remain mentally alert for occupational or personal reasons, the CNS effects of Lasmiditan may be prohibitive. Therefore, the drug's therapeutic niche is not as a universal replacement for triptans but as an essential option for a well-defined patient subpopulation. Furthermore, due to evidence of euphoric effects and a low potential for misuse observed in human abuse studies, Lasmiditan is regulated as a Schedule V controlled substance in the United States.[1]

Section 2: Chemical Identity and Physicochemical Properties

2.1 Nomenclature and Identifiers

The precise identification of a pharmaceutical agent is paramount for scientific, clinical, and regulatory accuracy. Lasmiditan is identified by a comprehensive set of names and codes across various chemical and drug databases.

• Generic Name: Lasmiditan [1]
• Brand Name: Reyvow (United States and European Union) [1]
• DrugBank ID: DB11732 [2]
• CAS Registry Number: 439239-90-4 [14]
• Type: Small Molecule [2]
• Systematic Chemical Names:
• 2,4,6-trifluoro-N-[(1-methyl-4-piperidinyl)carbonyl]-2-pyridinyl]-benzamide [15]
• Benzamide, 2,4,6-trifluoro-N-[(1-methyl-4-piperidinyl)carbonyl]-2-pyridinyl]- [15]
• Synonyms and Developmental Codes: COL-144, LY573144, CS-2381 [14]

2.2 Molecular and Structural Formulae

The molecular structure and composition of Lasmiditan define its chemical behavior and interaction with biological targets.

• Molecular Formula: C19​H18​F3​N3​O2​ [16]
• Molecular Weight: 377.36 g/mol [14]
• Chemical Structure Identifiers:
• InChI: 1S/C19H18F3N3O2/c1-25-7-5-11(6-8-25)18(26)15-3-2-4-16(23-15)24-19(27)17-13(21)9-12(20)10-14(17)22/h2-4,9-11H,5-8H2,1H3,(H,23,24,27) [1]
• InChIKey: XEDHVZKDSYZQBF-UHFFFAOYSA-N [1]
• Canonical SMILES: CN1CCC(CC1)C(=O)C1=CC=CC(NC(=O)C2=C(F)C=C(F)C=C2F)=N1 [18]

2.3 Physicochemical Properties

The physical and chemical properties of the Lasmiditan active pharmaceutical ingredient (API) are crucial for its formulation, stability, and handling.

• Appearance: White to off-white solid [14]
• Melting Point: 255 °C [14]
• Solubility: Lasmiditan is sparingly soluble in water.[17] It demonstrates good solubility in several organic solvents, which is relevant for laboratory and analytical applications:
• Dimethylformamide (DMF): 25 mg/ml [16]
• Dimethyl sulfoxide (DMSO): 25 mg/ml [16]
• Ethanol: 30 mg/ml [16]
• Storage and Stability: For the pure API, long-term stability (≥ 5 years) is achieved with storage at -20 °C, preferably under an inert atmosphere.[14] The final formulated product, Reyvow tablets, is stored at controlled room temperature between 20 °C to 25 °C (68 °F to 77 °F).[20]
• Formulation: Lasmiditan is formulated as an oral tablet for administration.[8] The tablets contain several inactive ingredients (excipients) to ensure proper formulation and delivery, including croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sodium lauryl sulfate. The film coating contains polyvinyl alcohol, talc, titanium dioxide, and various ferric oxides to provide color differentiation between dosages.[20]

Table 1: Drug Identification and Physicochemical Properties

Property	Value	Source(s)
Generic Name	Lasmiditan	1
Brand Name	Reyvow	1
DrugBank ID	DB11732	2
CAS Registry Number	439239-90-4	14
Molecular Formula	C19​H18​F3​N3​O2​	16
Molecular Weight	377.36 g/mol	14
Appearance	White to Off-White Solid	14
Melting Point	255 °C	14
Key Solubilities	DMSO: 25 mg/ml; Ethanol: 30 mg/ml	16
InChIKey	XEDHVZKDSYZQBF-UHFFFAOYSA-N	1

Section 3: Clinical Pharmacology

3.1 Mechanism of Action

Lasmiditan's therapeutic utility is rooted in its highly specific and novel mechanism of action, which distinguishes it from all prior classes of acute migraine treatments.

• Primary Target: Lasmiditan is a high-affinity, selective agonist of the serotonin 5−HT1F​ receptor.[2] Its binding affinity ( Ki​) for this receptor is exceptionally potent, measured in the low nanomolar range at 2.2–3.1 nM.[1]
• Neuronal Inhibition: The therapeutic effect of Lasmiditan is believed to be mediated entirely through its agonist activity at 5−HT1F​ receptors expressed on neurons of the trigeminal system. These receptors are located both peripherally on nerve endings in the dura mater and centrally within key pain-processing regions like the trigeminal nucleus caudalis.[7] Activation of these receptors by Lasmiditan is thought to produce two primary anti-migraine effects:

1. Inhibition of Neuropeptide Release: It suppresses the release of pro-inflammatory neuropeptides that are pivotal in generating and propagating migraine pain. These include Calcitonin Gene-Related Peptide (CGRP) and Glutamate.[7]
2. Inhibition of Pain Signal Transmission: It directly dampens the electrical activity (firing) of trigeminal neurons. This action effectively blocks the transmission of pain signals from the periphery into the central nervous system, thereby aborting the headache.[2] This mechanism has been validated in preclinical models, where Lasmiditan was shown to potently inhibit dural plasma protein extravasation and the expression of c-Fos in the trigeminal nucleus caudalis, both established biomarkers of trigeminal nerve activation during a migraine attack.[17]

• Distinction from Triptans: It is essential to contrast this mechanism with that of the triptan class. While triptans also possess some activity at 5−HT1F​ receptors, their principal anti-migraine effects are attributed to their potent agonism at 5−HT1B​ and 5−HT1D​ receptors.[1] Specifically, agonism at the 5−HT1B​ receptor, which is highly expressed on the smooth muscle of cranial blood vessels, is responsible for the vasoconstriction that characterizes triptan action.[8] Lasmiditan was specifically designed to have minimal affinity for the 5−HT1B​ receptor, which is the molecular foundation for its lack of vasoconstrictive activity and its improved cardiovascular safety profile.[1]

3.2 Receptor Selectivity and Pharmacodynamics

The clinical profile of Lasmiditan is a direct result of its precisely engineered receptor selectivity.

• Binding Affinity Profile: Quantitative binding assays reveal Lasmiditan's remarkable selectivity for the 5−HT1F​ receptor. While its affinity for 5−HT1F​ is 2.2–3.1 nM, its affinity for other key serotonin receptor subtypes involved in triptan action is several hundred-fold weaker: Ki​ values are 955–1,043 nM for 5−HT1B​ and 490–1,357 nM for 5−HT1D​.[1] Its affinity for other serotonin receptors (e.g., 5−HT2A​, 5−HT2B​) and other major neurotransmitter receptors, including adrenergic and dopaminergic receptors, is negligible, with Ki​ values typically greater than 10,000 nM.[1] This high degree of selectivity minimizes the potential for off-target effects mediated by these other receptors.
• Cardiovascular Pharmacodynamics: The most significant pharmacodynamic consequence of Lasmiditan's selectivity is its lack of vasoconstrictive activity. This makes it a viable and important therapeutic option for patients with stable cardiovascular disease or those with significant cardiovascular risk factors, for whom triptans are contraindicated.[6] It is important to note, however, that Lasmiditan is not entirely devoid of cardiovascular effects. Clinical studies have shown that it can cause a transient and modest decrease in heart rate (mean of 5-10 beats per minute) and a small increase in blood pressure, which necessitates caution in patients with pre-existing bradycardia or uncontrolled hypertension.[13]
• CNS Pharmacodynamics: Lasmiditan is a centrally acting agent that readily penetrates the blood-brain barrier, which is a prerequisite for its central mechanism of action but also the source of its most prominent adverse effects.[24] The dose-dependent CNS depression, manifesting as dizziness, sedation, and somnolence, is a direct pharmacodynamic effect of the drug.[1] Furthermore, dedicated human abuse potential studies demonstrated that therapeutic doses of Lasmiditan produced subjective effects, including a euphoric mood and "drug-liking" scores that were significantly higher than placebo, though lower than the positive control alprazolam. These findings were the basis for its scheduling as a controlled substance.[1]

Table 2: Receptor Binding Affinity and Functional Activity Profile of Lasmiditan

Target Receptor	Binding Affinity (Ki​, nM)	Functional Activity (EC50​, nM)	Maximal Efficacy (Emax​, %)
5-HT1F	2.2–3.1	3.7–43	81
5-HT1A	407–1,053	>10,000	16
5-HT1B	955–1,043	≥10,000	49
5-HT1D	490–1,357	229–>1,000	73
5-HT1E	594–1,450	676–~10,000	55
5-HT2A	>10,000	>10,000	-
5-HT2B	6,030	>10,000	-
5-HT7	>10,000	>10,000	-

Data compiled from source.[1]

3.3 Pharmacokinetics (ADME)

The absorption, distribution, metabolism, and excretion (ADME) profile of Lasmiditan influences its onset of action, duration of effect, and potential for drug-drug interactions.

• Absorption: Following oral administration, Lasmiditan is absorbed rapidly, reaching median peak plasma concentrations (Tmax​) in approximately 1.8 hours.[2] This rapid absorption profile is highly advantageous for an acute migraine therapy, as it facilitates a quick onset of action. Anecdotal and clinical reports suggest some patients experience therapeutic benefit within as little as 20 to 30 minutes of dosing.[2] The pharmacokinetic properties that enable this rapid absorption and central nervous system penetration are the same properties that drive its primary dose-limiting side effects. The drug's ability to quickly cross the blood-brain barrier is essential for its therapeutic action on central trigeminal neurons, but this same property is inextricably linked to the high incidence of CNS adverse events like dizziness and sedation.[12] This represents a fundamental link between the drug's beneficial pharmacokinetics and its challenging pharmacodynamics.
• Distribution: While specific parameters like volume of distribution are not detailed in the available materials, the most critical distributional characteristic of Lasmiditan is its ability to effectively cross the blood-brain barrier to engage its central targets.[24]
• Metabolism: Lasmiditan is cleared primarily through extensive metabolism. A key and highly favorable feature of its metabolic profile is that it is mediated by non-cytochrome P450 (CYP) enzymes.[2] Prescribing information explicitly states that major metabolic pathways such as monoamine oxidases and the CYP450 system are not involved in its clearance.[2] This characteristic is a significant clinical advantage, as it substantially reduces the potential for a wide range of drug-drug interactions (DDIs) that are common with medications metabolized by the CYP system. While Lasmiditan is subject to other types of interactions, its "clean" metabolic profile with respect to CYP enzymes is beneficial, particularly in patients on polypharmacy. Two of its metabolites, designated M7 and M18, have been identified but are considered to be pharmacologically inactive.[2]
• Excretion: Specific details regarding the routes and proportions of excretion (e.g., renal vs. fecal) of the parent drug and its metabolites are not provided in the source materials.
• Half-life: The geometric mean terminal elimination half-life (t1/2​) of Lasmiditan is approximately 5.7 hours.[23]

Section 4: Clinical Efficacy in Acute Migraine Treatment

4.1 Pivotal Phase III Trials: SAMURAI (NCT02439320) and SPARTAN (NCT02605174)

The approval of Lasmiditan by regulatory agencies was primarily based on the robust efficacy and safety data generated from two large-scale, pivotal Phase III trials: SAMURAI and SPARTAN.[1]

• Study Design: Both SAMURAI and SPARTAN were prospective, randomized, double-blind, placebo-controlled studies designed to evaluate the efficacy of a single dose of Lasmiditan for the acute treatment of a migraine attack.[6] Adult patients with a well-established history of migraine, with or without aura, were randomized to receive an oral dose of Lasmiditan (100 mg or 200 mg in both trials; an additional 50 mg arm was included in SPARTAN) or a matching placebo, to be taken at the onset of a moderate to severe migraine attack.[6]
• Patient Population: A strategically important feature of these trials was the deliberate enrollment of patients with cardiovascular risk factors. In the SAMURAI trial, for instance, over 77% of the enrolled subjects had at least one cardiovascular risk factor, such as hypertension, hyperlipidemia, or diabetes.[6] This approach was critical, as the primary therapeutic niche for Lasmiditan is precisely this patient population for whom triptans are often contraindicated. By generating robust efficacy and safety data directly in its target demographic, the trials provided clinicians with a high degree of confidence, supported by Class I evidence, for prescribing Lasmiditan to these higher-risk patients.[6] The trials collectively involved thousands of patients, treating a large number of migraine attacks and providing a substantial evidence base.[1]
• Primary Efficacy Endpoints: The studies shared two co-primary efficacy endpoints, both assessed at 2 hours after the dose was administered:

1. Pain Freedom: Defined as the proportion of patients whose headache severity, rated on a 4-point scale (none, mild, moderate, severe), was reduced from moderate or severe at baseline to none.[6]
2. Most Bothersome Symptom (MBS) Freedom: Defined as the proportion of patients who were free of their self-identified MBS. At baseline, each patient selected one of three common migraine-associated symptoms (nausea, photophobia, or phonophobia) as their most bothersome.[6]

• Efficacy Results: Across both trials, all tested doses of Lasmiditan demonstrated statistically significant superiority over placebo for both co-primary endpoints.[1] In the SAMURAI trial, pain freedom at 2 hours was achieved by 28.2% of patients in the 100 mg group and 32.2% in the 200 mg group, compared to only 15.3% in the placebo group (p < 0.001 for both doses vs. placebo).[6] Similarly, MBS freedom at 2 hours was achieved by approximately 41% of patients treated with either dose of Lasmiditan, compared to about 30% of patients on placebo (p < 0.001).[6] The results clearly established a dose-dependent effect and confirmed the efficacy of Lasmiditan in aborting migraine attacks.

Table 3: Summary of Pivotal Phase III Clinical Trial Efficacy Outcomes at 2 Hours Post-Dose

Efficacy Endpoint	Placebo	Lasmiditan 100 mg	Lasmiditan 200 mg
Pain Freedom (% of Patients)	15.3%	28.2%	32.2%
Odds Ratio vs. Placebo (95% CI)	--	2.2 (1.6–3.0)	2.6 (2.0–3.6)
p-value vs. Placebo	--	<0.001	<0.001
Most Bothersome Symptom (MBS) Freedom (% of Patients)	29.5%	40.9%	40.7%
Odds Ratio vs. Placebo (95% CI)	--	1.7 (1.3–2.2)	1.6 (1.3–2.1)
p-value vs. Placebo	--	<0.001	<0.001

Data representative of the SAMURAI trial results.[6]

4.2 Onset and Sustainability of Effect

• Onset of Action: For an acute migraine medication, the speed of therapeutic onset is a critical determinant of its clinical value. Pooled analyses of the Phase III trials demonstrated that Lasmiditan has a rapid onset of action. Statistically significant separation from placebo for pain relief and MBS freedom was observed as early as 30 to 60 minutes after administration of the 100 mg and 200 mg doses.[10]
• Sustained Efficacy: The durability of the initial therapeutic response was also assessed. Key measures included the rate of headache recurrence and the need for rescue medication in the 2 to 48-hour period following the initial dose.[6] Data indicated that patients treated with Lasmiditan were significantly less likely to require a second dose of study medication for either rescue from a non-responding headache or for a recurring headache compared to those who received placebo.[6]

4.3 Long-Term Safety and Efficacy: The GLADIATOR Study

The GLADIATOR study (NCT02565186) was an open-label, long-term (up to 1 year) study designed to assess the safety and consistency of efficacy of Lasmiditan over multiple, intermittent uses.[9]

• Key Findings: The study provided reassuring data on both long-term safety and efficacy. The efficacy of Lasmiditan remained consistent over the 1-year treatment period. For all attacks treated, 26.7% of those treated with the 100 mg dose and 32.2% of those treated with the 200 mg dose were pain-free at the 2-hour mark, mirroring the results seen in the single-attack pivotal trials.[30] No new or unexpected safety signals emerged during prolonged, intermittent use.[30] A particularly important finding from GLADIATOR related to tolerability. The data suggested that the incidence of treatment-emergent adverse events (TEAEs), most notably dizziness, appeared to decrease with subsequent treated attacks.[30] This observation is clinically significant, as it suggests a potential for patient acclimatization or tolerance to the CNS side effects over time. This information is invaluable for patient counseling, as it allows clinicians to manage expectations and encourage adherence. Patients can be informed that while the side effects from an initial dose may be pronounced, they are likely to become more manageable with continued use, which may prevent premature discontinuation of an otherwise effective therapy.

Section 5: Safety Profile, Warnings, and Precautions

5.1 Common and Serious Adverse Reactions

The safety profile of Lasmiditan is well-characterized and is distinct from that of triptans, with a predominance of CNS-related effects.

• Most Common TEAEs: Across clinical trials, the most frequently reported adverse reactions, occurring at an incidence of ≥2% and more often than with placebo, were consistently identified as dizziness, fatigue (including sedation and somnolence), paresthesia (sensations of tingling or "pins and needles"), nausea, and muscle weakness.[11] Dizziness is the most common of these, with reported incidences as high as 17–18.5% in some studies.[23] These adverse events are known to be dose-dependent.[24]
• Serious Adverse Events: Serious adverse events were uncommon in the clinical development program. In the long-term GLADIATOR study, no serious TEAEs were considered by investigators to be related to the study drug.[30] Post-marketing reports include rare but serious hypersensitivity reactions, such as angioedema and rash.[23]

Table 4: Common Adverse Reactions (Incidence ≥2% and > Placebo) in Pooled Phase III Trials

Adverse Reaction	Placebo (%)	Lasmiditan 50 mg (%)	Lasmiditan 100 mg (%)	Lasmiditan 200 mg (%)
Dizziness	3%	9%	15%	17%
Fatigue	2%	4%	6%	7%
Paresthesia	1%	3%	5%	7%
Sedation	2%	3%	6%	7%
Nausea	2%	3%	4%	5%
Muscle weakness	<1%	1%	1%	2%

Data adapted from prescribing information and clinical trial summaries.[12]

5.2 Central Nervous System Effects and Driving Impairment

The most significant safety concern associated with Lasmiditan is its impact on the central nervous system, which has led to a prominent warning regarding driving.

• Warning: Lasmiditan causes significant CNS depression.[1] The prescribing information contains a clear and stringent warning that patients must not drive a motor vehicle or operate other potentially hazardous machinery for at least 8 hours after taking each dose.[1] This restriction applies even if the patient feels subjectively well enough to perform these tasks.[5] The labeling further states that patients who are unable to consistently adhere to this 8-hour restriction should not be prescribed the medication.[1]
• Clinical Evidence: This warning is not based on theoretical risk but on data from dedicated clinical studies. Driving simulation studies conducted in healthy volunteers demonstrated that single oral doses of 50 mg, 100 mg, or 200 mg of Lasmiditan caused a statistically significant and dose-dependent impairment in the ability to drive.[12]
• Patient Perception: A critical aspect of this impairment is that patients may not be able to accurately assess their own level of functional impairment caused by the drug.[12] This finding underscores the necessity of the strict 8-hour rule, as a patient's subjective feeling of alertness is not a reliable indicator of their ability to drive safely.

5.3 Serotonin Syndrome

• Risk: As a serotonergic agent, Lasmiditan is associated with a risk of serotonin syndrome, a rare but potentially life-threatening condition caused by excessive serotonergic activity in the nervous system.[5] The risk is highest when Lasmiditan is co-administered with other serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and triptans.[31] Notably, cases consistent with serotonin syndrome have been reported in clinical trials even in patients who were not taking any other serotonergic medications.[12]
• Symptoms: Clinicians and patients should be aware of the hallmark symptoms of serotonin syndrome, which include a combination of mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), and neuromuscular abnormalities (e.g., hyperreflexia, tremor, incoordination).[4] If serotonin syndrome is suspected, Lasmiditan should be discontinued immediately.

5.4 Medication Overuse Headache (MOH)

• Risk: In line with other medications used for the acute treatment of migraine, frequent and prolonged use of Lasmiditan can lead to a paradoxical increase in headache frequency, a condition known as medication overuse headache (MOH) or rebound headache.[4] This is generally defined as using acute medication on 10 or more days per month. The safety of treating, on average, more than four migraine attacks within a 30-day period has not been formally established.[12]

5.5 Drug-Drug and Disease Interactions

Lasmiditan is subject to several clinically significant drug and disease interactions that require careful management.

• CNS Depressants: Due to its own CNS depressant effects, co-administration of Lasmiditan with other CNS depressants can lead to additive effects, significantly increasing the risk of sedation, dizziness, and functional impairment. This includes alcohol, benzodiazepines (e.g., alprazolam), opioids, and prescription or over-the-counter sleep aids. Concomitant use should be approached with extreme caution, or preferably, avoided.[1]
• Serotonergic Drugs: As detailed above, concurrent use with other serotonergic agents (e.g., SSRIs, SNRIs, triptans, dextromethorphan) increases the risk of serotonin syndrome.[31] The herbal supplement St. John's wort can also contribute to this risk.[34]
• Heart Rate Lowering Drugs: Lasmiditan can cause a modest, transient decrease in heart rate. Therefore, caution is advised when it is used concomitantly with other medications that lower heart rate, such as beta-blockers (e.g., propranolol, metoprolol) and certain calcium channel blockers (e.g., verapamil, diltiazem).[20]
• P-gp and BCRP Substrates: In vitro studies have shown that Lasmiditan is an inhibitor of the efflux transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).[35] Co-administration of Lasmiditan with drugs that are sensitive substrates of these transporters could lead to increased plasma concentrations and potential toxicity of the substrate drug. Caution is advised, and co-administration with sensitive P-gp substrates like digoxin or dabigatran is generally not recommended.[33]
• Disease Interactions: Caution should be exercised when prescribing Lasmiditan to patients with pre-existing conditions such as bradycardia (low heart rate) or hypertension.[13] The use of Lasmiditan is not recommended in patients with severe hepatic impairment (Child-Pugh Class C), as it has not been studied in this population.[13]

5.6 Use in Specific Populations

• Pediatric Population: The safety and effectiveness of Lasmiditan have not been established in pediatric patients (under 18 years of age).[13] The FDA has waived the requirement for studies in children younger than 6 years but has deferred the submission of pediatric studies for children and adolescents aged 6 to less than 18 years.[37]
• Geriatric Population: Clinical trial data suggest that patients aged 65 and older may experience a higher incidence of dizziness compared to younger patients. Furthermore, a larger transient increase in systolic blood pressure was observed in this age group following Lasmiditan administration. Therefore, cautious dose selection is recommended for elderly patients.[13]
• Pregnancy and Lactation: There are no adequate and well-controlled studies of Lasmiditan in pregnant women. Based on data from animal reproduction studies, which showed evidence of developmental toxicity, the drug may cause fetal harm.[8] To monitor maternal and fetal outcomes, a pregnancy exposure registry has been established (1-833-464-4724).[20] It is unknown whether Lasmiditan is excreted in human breast milk, and the potential effects on a breastfed infant are unknown.[20]

Section 6: Dosing, Administration, and Clinical Considerations

6.1 Recommended Dosing

• Available Strengths: Lasmiditan is commercially available as film-coated oral tablets in three strengths: 50 mg, 100 mg, and 200 mg.[12]
• Administration: The recommended dose is a single tablet (50 mg, 100 mg, or 200 mg) taken orally as needed at the first sign of a migraine attack. The choice of starting dose may be guided by attack severity and patient tolerability. The tablet should be swallowed whole and should not be split, crushed, or chewed. Lasmiditan may be taken with or without food.[20]
• Frequency of Use: No more than one dose of Lasmiditan should be taken within a 24-hour period.[4] Clinical studies have not demonstrated additional benefit from taking a second dose to treat the same migraine attack.[23] To mitigate the risk of medication overuse headache, patients should be counseled on appropriate use. The safety of treating an average of more than four migraine attacks in a 30-day period has not been established.[22]

6.2 Key Patient Counseling Points

Effective and safe use of Lasmiditan relies heavily on thorough patient education regarding its unique safety profile.

• Driving Restriction: The most critical counseling point is the absolute restriction on driving or operating heavy machinery for at least 8 hours after taking a dose. It must be emphasized that this applies regardless of how the patient feels subjectively.[1]
• CNS Effects: Patients must be warned about the high probability of experiencing dizziness and sleepiness. They should be strongly advised to avoid consuming alcohol and other CNS depressant medications concurrently with Lasmiditan.[20]
• Medication Overuse: Patients should be educated about the risk of developing medication overuse headache if they use Lasmiditan or other acute treatments too frequently. The use of a headache diary to track headache frequency and medication use is strongly recommended.[4]
• Serotonin Syndrome: Patients should be made aware of the signs and symptoms of serotonin syndrome (e.g., agitation, sweating, rapid heartbeat, muscle twitching) and instructed to seek immediate medical attention if they occur.[4]

6.3 Patient Selection

Careful patient selection is key to maximizing the benefit and minimizing the risk of Lasmiditan therapy.

• Ideal Candidates: The ideal candidate for Lasmiditan is an adult patient with a clear diagnosis of migraine who meets one or more of the following criteria:

1. Has known cardiovascular disease, multiple cardiovascular risk factors, or other contraindications to the use of triptans.[2]
2. Has experienced a lack of efficacy or intolerable side effects with triptan medications. Some insurance formularies may require documented trial and failure of at least two different triptans before authorizing Lasmiditan.[36]
3. Has a lifestyle and occupation that allows for strict adherence to the 8-hour post-dose restriction on driving and operating machinery.

• Patients Requiring Caution: Special consideration and caution are warranted in several populations, including the elderly (due to increased risk of dizziness and blood pressure changes), patients taking other CNS depressants or heart rate-lowering medications, and individuals with a history of substance abuse, given the drug's controlled substance status.[8]

Section 7: Regulatory History and Controlled Substance Status

7.1 Development and Approval Timeline

• Discovery and Development: Lasmiditan was originally discovered by Eli Lilly and Company. The intellectual property was licensed to CoLucid Pharmaceuticals in 2006 for further development, and in 2017, Eli Lilly reacquired the asset by purchasing CoLucid.[1]
• FDA Submission and Approval: Eli Lilly submitted a New Drug Application (NDA) for Lasmiditan to the U.S. Food and Drug Administration (FDA) in November 2018.[1] Following a priority review, the FDA approved Reyvow (lasmiditan) on October 11, 2019, for the acute treatment of migraine with or without aura in adults.[3] The FDA designated it as a first-in-class medication, recognizing its novel mechanism of action.[1]
• EMA Approval: In Europe, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion recommending marketing authorization in June 2022. Full approval in the European Union was granted in August 2022.[1]

7.2 Controlled Substance Status

• Classification: In the United States, the Drug Enforcement Administration (DEA) officially placed Lasmiditan into Schedule V of the Controlled Substances Act in January 2020.[1] Schedule V is the least restrictive category for controlled substances and is reserved for drugs with a demonstrated low potential for abuse relative to substances in other schedules.[8]
• Rationale: The decision to schedule Lasmiditan was not arbitrary but was based on a comprehensive evaluation of its abuse potential. This included preclinical studies in animals that showed reinforcing effects, as well as dedicated human abuse potential studies.[1] In these clinical studies, human subjects reported "drug-liking" scores for Lasmiditan that were statistically significantly higher than for placebo, although they were lower than for the positive control, alprazolam (a Schedule IV drug).[1] The studies also documented subjective effects such as euphoric mood, somnolence, and a feeling of being "drunk".[1] While most acute migraine medications are not controlled substances, this regulatory classification for Lasmiditan serves as an important signal to prescribers. It underscores the drug's CNS activity and potential for misuse, reinforcing the need for cautious prescribing. This regulatory flag complements the clinical warnings by prompting clinicians to assess a patient's history of substance use and to be more deliberate in their counseling regarding the drug's psychoactive effects.

Section 8: Conclusion and Future Perspectives

8.1 Synthesis of Therapeutic Profile

Lasmiditan represents a landmark achievement in the pharmacological treatment of acute migraine. Its development and approval mark the successful clinical application of a therapeutic strategy that decouples potent anti-migraine efficacy from the vasoconstrictive activity that has long limited the use of triptans. By selectively targeting the neuronal 5−HT1F​ receptor, Lasmiditan provides a critically needed treatment option for a large and previously underserved population of migraine patients with cardiovascular disease or significant cardiovascular risk factors.

This therapeutic innovation, however, is accompanied by a unique and challenging safety profile dominated by CNS adverse effects. The high incidence of dizziness and sedation, and the resulting strict 8-hour prohibition on driving, define its clinical use and necessitate careful patient selection and comprehensive counseling. Consequently, Lasmiditan is best understood not as a universal replacement for triptans, but as a highly valuable, mechanistically distinct tool within the therapeutic armamentarium. Its optimal use is in specific clinical scenarios where the clear benefit of avoiding vascular risk outweighs the significant inconvenience and potential danger of its CNS depressant effects.

8.2 Future Research and Ongoing Trials

The journey of Lasmiditan and the "ditan" class is still unfolding. Ongoing and future research will be essential to further refine its place in therapy. Real-world effectiveness and tolerability studies, such as the TRIDIGEP (NCT06267664) and DART (NCT05903040) trials, are currently underway.[39] The data from these studies will be invaluable for understanding how Lasmiditan performs in diverse, everyday clinical settings outside the rigorous confines of registration trials.

Future research should also aim to address key remaining questions. Investigating strategies to mitigate the prominent CNS side effects could significantly broaden the drug's applicability. The results of the deferred pediatric studies will determine its potential role in younger populations.[37] Furthermore, the validation of the

5−HT1F​ receptor as a viable anti-migraine target, pioneered by Lasmiditan, has irrevocably shifted the focus of migraine research. This success will undoubtedly spur the development of a new generation of neurally-acting therapies, potentially with improved tolerability profiles, promising a more targeted and safer future for the treatment of this debilitating condition.

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