New Migraine Drugs Target Triptan Contraindication Population

Migraines are a chronic neurobiological condition that are among the most common disabling health conditions affecting people worldwide. This disorder peaks in prevalence between 25 and 55 years of age and the patient population is approximately 75% female.

The current acute migraines treatments have shown efficacy and safety , however, approximately one-third of people do not respond, cannot use these options due to contraindications, or report dissatisfaction in therapy. Triptans are considered the gold standard for the acute treatment of moderate to severe migraine, with strong evidence in support of their efficacy.

However, triptans are not efficacious in all patients and are contraindicated in people with coronary artery disease, peripheral vascular disease, or uncontrolled hypertension. They are also not recommended in patients with risk factors for undiagnosed coronary artery disease.

With this barrier to triptans in certain populations, researchers decided to explore classes of medications that could be used in these target patients and for people with these contraindications. With a high demand for new treatment options, ubrogepant (Ubrelvy, Allergan), rimegepant (Nurtec, Biohaven), and lasmiditan (Reyvow, Elli Lilly) came to market.

Table 1 details the drug information about each medication and vital data for prescribing these new formulations.

Table 1.

Drug

Mechanism of Action

Dosing

Adverse Reactions

Pharmacokinetics

Ubrelvy (Ubrogepant)

calcitonin gene-related peptide receptor antagonist

• Recommended dose: 50 mg or 100 mg A second dose may be administered at least 2 hours after the initial dose. Max dose: 200 mg/24 hours Safety of treating more than 8 migraines in a 30-day period has not been established.

2%: nausea and somnolence

• Onset: 1 hour (maximum efficacy seen between 3-8 hours)
• Half-life: 5-7 hours
• Peak plasma concentration: 1.5 hours

Reyvow (Lasmiditan)

5-HT1F receptor agonist

• Recommended dose: 50 mg or 100 mg or 200 mg
• No more than one dose in 24 hours (2^nd dose not proven effective)
• Max dose: 200 mg/24 hours
• Safety of treating more than 4 migraines in a 30-day period has not been established.

≥ 5%: dizziness, fatigue, paresthesia, numbness and sedation

Warning/precautions

• Driving Impairment: Advise patients not to drive or operate machinery until at least 8 hours after taking each dose
• Abuse potential: Schedule C-V medication

• Onset: 30-60 minutes
• Half-life: 5-7 hours
• Time to peak: 1.8 hours

Nurtec (Rimegepant)

calcitonin gene-related peptide receptor antagonist

• Recommended dose: 75 mg
• Max dose: 75 mg/24 hours
• The safety of treating more than 15 migraines in a 30-day period has not been established

2%: nausea

• Onset: <2 hours (migraine pain free as early as 1 hour and MBS-free as early as 0.5 hours)
• Half-life: 11 hours
• Time to Peak: 1.5 hours (delayed 1 hour following high fat meal)

The research of rimegepant and ubrogepant resulted from the observation that calcitonin gene-related peptide (CGRP) administration can cause acute headaches and even delayed migraine-like attacks. It has also been found to be released during these attacks as well. These 2 medications reduce CGRP activity and help to prevent it from binding to its receptors.

Following this research, ubrogepant was approved by the FDA on December 23, 2019, and rimegepant was approved on February 27, 2020. These 2 medications are classified as CGRP antagonists and are options for the acute treatment of migraine in patients who do not respond to triptans or are contraindicated to triptan treatment. An orally disintegrating form of rimegepant was developed to also target the population who experience nausea and vomiting with migraine and cannot administer liquids.

Another class of medication to target this population and can be used as a potential treatment alternative are selective 5-HT1F agonists. During a migraine, the nerves in the brain can over simulate and cause pain.

It is believed that when 5-HT1F receptors are triggered in the brain, they can suppress the pain. The medication in this class, lasmiditan, is a selective serotonin 1F receptor agonist that lacks vasoconstrictor activity. Lasmiditan was approved by the FDA on October 11, 2019.

Dose Modifications for Drug Interactions and Specific Populations

The prescribing of these 3 new migraine medications comes with some dose modifications for specific populations and also for interactions with other drugs patients might be taking.

Ubrogepant use should be avoided with strong CYP3A inhibitors and inducers and also with patients with end-stage renal disease (CrCl <15 mL/min). A starting dose of 50 mg is recommended with concurrent use of weak/moderate CYP3A4 inhibitors, BCRP and/or P-gp only inhibitors and with severe renal or hepatic impairment.

If a second dose is needed, a 50 mg dose can be repeated. With moderate CYP3A4 inducers, a second dose within 24 hours should be avoided. With weak or moderate CYP3A4 inducers, a starting dose of 100 mg is recommended and if a second dose is needed, 100 mg can be taken again.

The use of lasmiditan should be avoided in severe hepatic impairment and with concurrent use of P-gp or breast cancer-resistant protein substrates (BCRP). Lasmiditan should be used with caution in patients who use alcohol/central nervous system depressants, or who take serotonergic drugs or heart rate-lowering medications.

It is also recommended to use this medication with caution in the geriatric population at a suggested starting dose of 50 mg. This is because of more frequent increases in systolic blood pressure and increased prevalence of dizziness reported in older adults.

Patients taking moderate CYP3A4 inhibitors along with Nurtec are recommended to only take one dose (75 mg) and to avoid a second dose within 48 hours. Also, with this medication, use should be avoided with moderate/strong CYP3A4 inhibitors, strong/moderate inducers

Since more research has been conducted since the FDA approved these medications, additional information about the efficacy has been found. Based on a comparative analysis trial, no statically significant difference was shown between lasmiditan, rimegepant, or ubrogepant in achieving pain freedom or the absence of the most bothersome symptoms at 2 hours.

It was also discovered in an evaluation of these medications that all interventions showed lower odds of achieving pain freedom compared with eletriptan and sumatriptan. To achieve pain freedom at 2 hours, the recommended dose for rimegepant was 10 for 75 mg, ubrogepant’s was 14 for 50 mg and 11 for 100 mg, and lasmiditan’s was 14 for 50 mg, 9 for 100 mg, and 6 for 200 mg, compared with sumatriptan’s number needed to treat of 5.

With such a recent approval date, the exact place in treatment guidelines for these 3 medications has not yet been defined. Since these treatments do not result in constriction of blood vessels, they may have a distinct role in patients with cardiovascular contraindications to triptans and may find a place there in therapy.

The opinion and conclusions presented herein are those of the author and do not necessarily represent the views of the school or facility.

About the Author

Melissa Yokoyama is a PharmD candidate at Pacific University’s School of Pharmacy, anticipated to graduate in spring 2021.

Jonathan Ogurchak, PharmD, CSP, is the CEO and Co-Founder of STACK, a pharmacy

Information management platform, and serves as preceptor for a virtual Advanced Pharmacy Practice Experiential Rotation for specialty pharmacy, during which this article was composed.

References

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