DRUG INTERACTIONS

Summary

­ • REYVOW may further lower heart rate when administered with heart rate lowering drugs. 

• Avoid concomitant use with P-gp and Breast Cancer Resistant Protein (BCRP) substrates. 

Details

1. CNS Depressants

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

2. Serotonergic Drugs

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

 Use REYVOW with caution in patients taking medications that increase serotonin.

3. Heart Rate Lowering Drugs

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.

4. P-gp and Breast Cancer Resistant Protein (BCRP)

REYVOW inhibits P-gp and BCRP in vitro. Concomitant use of REYVOW and drugs that are P-gp or BCRP substrates should be avoided.

ADVERSE REACTIONS

­ Most common adverse reactions (=5% and > placebo) were dizziness, fatigue, paresthesia, and sedation. 

• 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. 

• Serotonin Syndrome:

Reactions consistent with serotonin syndrome were reported in patients treated with REYVOW. Discontinue REYVOW if symptoms of serotonin syndrome occur. 

• Medication Overuse Headache:

Detoxification may be necessary. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Driving Impairment

 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 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.

CNS Depression

Inform patients that REYVOW may cause dizziness and sedation. Advise patients to use caution if taking REYVOW in combination with alcohol or other CNS depressants

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with the use of REYVOW, particularly during combined use with serotonergic medications such as SSRIs, SNRIs, TCAs, or MAO inhibitors

Medication Overuse Headache

 Inform patients that use of drugs to treat migraine attacks for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary)

Hypersensitivity

Advise patients to seek immediate medical attention if they experience any symptoms of serious or severe hypersensitivity reaction.

Abuse and Dependence

There is a pending DEA decision for control of REYVOW (lasmiditan) under the Controlled Substances Act. A statement about abuse and dependence risks cannot be completed at this time.

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant

Nursing Mothers

Inform patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed

Marketed by:

Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2019, Eli Lilly and Company. All rights reserved. 6.0-REY-0000-USPI-YYYYMMDD Reference ID: 4505262

 CLINICAL PHARMACOLOGY

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.

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.

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

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.

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(0-8) and 21% higher Cmax, compared to subjects 45 years of age or less.

This difference in exposure is not expected to be clinically significant

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(0-8) 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(0-8)] 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 

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 .

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.

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.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy

 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 

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.

2. Lactation

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.

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. 

3. Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

4.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.

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 

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.

5. 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.

6. DRUG ABUSE AND DEPENDENCE

 Controlled Substance REYVOW contains lasmiditan. (Controlled substance schedule to be determined after review by the Drug Enforcement Administration.)

 Abuse

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.

 Dependence

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