Lasmiditan

Usage

• Lasmiditan is prescribed for the acute treatment of migraine with or without aura in adults. It is not intended for preventative use.
• Pharmacological Classification: Serotonin 5-HT_1F receptor agonist, antimigraine agent.
• Mechanism of Action: Lasmiditan selectively activates 5-HT_1F receptors within the central nervous system, believed to inhibit the release of vasoactive neuropeptides thought to be involved in migraine initiation and pain transmission. It is distinct from triptans and does not cause vasoconstriction.

Alternate Names

• International Nonproprietary Name (INN): Lasmiditan
• Brand Name: Reyvow

How It Works

• Pharmacodynamics: Lasmiditan selectively binds to and activates 5-HT_1F receptors in the trigeminal nervous system, leading to inhibition of dural vasodilation and neuronal firing associated with migraine pain. It does not cause vasoconstriction, unlike triptans.
• Pharmacokinetics:
  • Absorption: Rapidly absorbed after oral administration, with a bioavailability of approximately 40%. Food does not significantly affect absorption.
  • Metabolism: Metabolized primarily in the liver and extra-hepatic sites, involving multiple CYP enzymes and non-CYP pathways.
  • Elimination: Primarily eliminated through renal excretion of metabolites, with a half-life of approximately 5.7 hours.
• Mode of Action (Cellular/Molecular): Lasmiditan acts as an agonist at the 5-HT_1F receptor, a G-protein coupled receptor. Activation inhibits adenylate cyclase, reducing cyclic AMP levels and subsequently modulating neuronal activity.
• Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Selective agonist at 5-HT_1F receptors. May inhibit the release of vasoactive neuropeptides, like calcitonin gene-related peptide (CGRP), involved in migraine pathophysiology.
• Elimination Pathways: Primarily renal excretion of metabolites; some hepatic metabolism by various CYP enzymes (CYP3A4, CYP2C19, CYP2C9, CYP2D6) and non-CYP pathways.

Dosage

Standard Dosage

Adults:

• 50 mg, 100 mg, or 200 mg orally as needed for acute migraine.
• Maximum single dose: 200 mg.
• Maximum daily dose: 200 mg (no more than one dose in 24 hours).
• If migraine recurs within 24 hours, a second dose of the same strength may be taken, but not within 2 hours of the initial dose.
• The recommended initial dose is generally 100 mg. This may be adjusted up to 200 mg or down to 50 mg based on individual response and tolerability.

Children:

• Safety and efficacy not established in pediatric patients under 18 years of age.

Special Cases:

• Elderly Patients: Dose selection should be cautious, starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function.
• Patients with Renal Impairment: No dose adjustment needed.
• Patients with Hepatic Dysfunction: No dose adjustment needed for mild or moderate impairment (Child-Pugh A or B). Use is not recommended in patients with severe hepatic impairment (Child-Pugh C).
• Patients with Comorbid Conditions: Use with caution in patients with cardiovascular disease, as bradycardia has been reported. Caution is advised in patients taking other CNS depressants.

Clinical Use Cases

• Lasmiditan is not indicated for clinical settings such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest. Its sole indicated use is for the acute treatment of migraine attacks.

Dosage Adjustments

• Adjustments may be necessary based on individual patient response and tolerability. Start with the lowest effective dose and titrate upwards as needed.

Side Effects

Common Side Effects:

• Dizziness
• Somnolence/fatigue
• Paresthesia
• Nausea

Rare but Serious Side Effects:

• Serotonin syndrome
• Severe hypersensitivity reactions (angioedema, anaphylaxis)
• Bradycardia
• Syncope
• Seizures

Long-Term Effects:

• Medication overuse headache may occur with frequent use.

Adverse Drug Reactions (ADR):

• Angioedema
• Anaphylaxis
• Serotonin syndrome

Contraindications

• Hypersensitivity to lasmiditan or any of its components.

Drug Interactions

• CYP450 Interactions: Lasmiditan is metabolized by multiple CYP enzymes (CYP3A4, CYP2C19, CYP2C9, and CYP2D6) and non-CYP pathways. However, it is not a significant inhibitor or inducer of these enzymes.
• Other Interactions:
  • CNS depressants (alcohol, benzodiazepines, opioids): May enhance CNS depression.
  • Serotonergic drugs (SSRIs, SNRIs, MAO inhibitors, triptans): Increased risk of serotonin syndrome.
  • P-gp and BCRP inhibitors/substrates: Lasmiditan inhibits P-gp and BCRP transporters and may affect the concentrations of drugs transported by these proteins (e.g. dabigatran).
  • Beta-blockers and Calcium Channel Blockers: May increase risk of bradycardia.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Data are limited. Animal studies show potential adverse developmental effects. Not recommended during pregnancy unless the potential benefit justifies the potential risk to the fetus. A pregnancy registry is available for monitoring outcomes.
• Breastfeeding: Excretion into human milk is unknown but likely based on animal data. Due to potential risks to the infant, alternative medications may be preferred, or breastfeeding should be temporarily discontinued.

Drug Profile Summary

• Mechanism of Action: Selective 5-HT_1F receptor agonist, leading to inhibition of dural vasodilation and neuronal activation without vasoconstriction.
• Side Effects: Dizziness, somnolence, paresthesia, nausea; rarely serotonin syndrome, hypersensitivity reactions, bradycardia.
• Contraindications: Hypersensitivity to lasmiditan.
• Drug Interactions: CNS depressants, serotonergic drugs, P-gp and BCRP substrates, beta-blockers, calcium channel blockers.
• Pregnancy & Breastfeeding: Limited data, not recommended.
• Dosage: 50-200 mg orally once every 24 hours as needed.
• Monitoring Parameters: Heart rate, blood pressure, signs of serotonin syndrome.

Popular Combinations

• Lasmiditan is generally used as monotherapy for acute migraine treatment. Combination with other acute migraine medications (e.g., triptans, NSAIDs) is not routinely recommended.

Precautions

• General Precautions: Assess patients for cardiovascular disease and concurrent use of CNS depressants or serotonergic medications.
• Specific Populations: As detailed in the sections above.
• Lifestyle Considerations: Avoid alcohol, driving, or operating machinery for at least 8 hours after taking lasmiditan.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Lasmiditan?

A: The recommended dosage for adults is 50 mg, 100 mg, or 200 mg orally as needed, not to exceed 200 mg in 24 hours. The initial recommended dose is 100 mg.

Q2: How does Lasmiditan differ from triptans?

A: Lasmiditan is a 5-HT_1F receptor agonist, while triptans are 5-HT_1B/1D agonists. Lasmiditan does not cause vasoconstriction, making it a potential option for patients with cardiovascular disease where triptans are contraindicated.

Q3: Can Lasmiditan be used to prevent migraines?

A: No, Lasmiditan is only indicated for the acute treatment of migraine attacks, not for prevention.

Q4: What are the most common side effects of Lasmiditan?

A: The most common side effects are dizziness, somnolence/fatigue, paresthesia, and nausea.

Q5: Are there any serious drug interactions with Lasmiditan?

A: Yes, co-administration with other serotonergic medications can increase the risk of serotonin syndrome. Concomitant use with CNS depressants may enhance CNS depression. Using with beta-blockers or calcium channel blockers can increase the risk of bradycardia.

Q6: Can Lasmiditan be used during pregnancy or breastfeeding?

A: Lasmiditan is generally not recommended during pregnancy or breastfeeding due to limited safety data and potential risks to the fetus/infant.

Q7: How long should patients wait to drive or operate machinery after taking Lasmiditan?

A: Patients should wait at least 8 hours after taking Lasmiditan before driving or operating machinery, or longer if they still feel impaired.

Q8: What should be done if a patient experiences signs of serotonin syndrome while taking Lasmiditan?

A: Discontinue Lasmiditan immediately and provide supportive care as needed. Serotonin syndrome can be life-threatening.

Q9: Can Lasmiditan be used in patients with hepatic or renal impairment?

A: No dose adjustment is necessary for patients with mild or moderate hepatic or renal impairment. Use in patients with severe hepatic impairment is not recommended. No information on use in patients undergoing dialysis is available.

Q10: Is there potential for abuse or dependence with Lasmiditan?

A: Limited evidence suggests some potential for abuse, although it is a Schedule V controlled substance in the United States. Prescribers should assess patients for risk of drug abuse and monitor for misuse.