DRUG INTERACTIONS - summary

 Strong or moderate CYP3A inhibitors: Avoid concomitant use. 

 Weak CYP3A inhibitors:                                                                                                  The maximum recommended dose is 5 mg. 

 Strong or moderate CYP3A inducers:                                                                           Avoid concomitant use. 

 DRUG INTERACTION

 Drugs Having Clinically Important Interactions with DAYVIGO

 Clinically Important Drug Interactions with DAYVIGO

Effect of Other Drugs on DAYVIGO Strong, Moderate, and Weak CYP3A Inhibitors

Clinical Impact: Concomitant use with a strong, moderate, or weak CYP3A inhibitor increases lemborexant AUC and Cmax which may increase the risk of DAYVIGO adverse reactions 

Intervention: Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inhibitors 

The maximum recommended dose of DAYVIGO with weak CYP3A inhibitors is 5 mg 

Examples: Strong CYP3A inhibitors:                                                           itraconazole, clarithromycin Moderate CYP3A inhibitors: fluconazole, verapamil 

Weak CYP3A inhibitors: chlorzoxazone, ranitidine                                                       Strong and Moderate CYP3A Inducers

Clinical Impact: Concomitant use with a strong or moderate CYP3A inducer decreases lemborexant exposure, which may reduce DAYVIGO efficacy 

Intervention: Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inducers 

Examples: Strong CYP3A inducers:                                                                   rifampin, carbamazepine, St. John’s wort                                                                      Moderate CYP3A inducers:                                                                                          bosentan, efavirenz, etravirine, modafinil Alcohol

Clinical Impact:                                                                                                Concomitant use of alcohol increases lemborexant Cmax and AUC.

Coadministration of DAYVIGO with alcohol produced a numerically greater negative impact on postural stability and memory as compared with alcohol alone when assessed near the tmax of DAYVIGO (2 hours post-dose) 

Intervention: Avoid alcohol consumption with DAYVIGO 

Effect of DAYVIGO on Other Drugs CYP2B6 Substrates                                           Clinical Impact: Concomitant use of DAYVIGO decreases the AUC of drugs that are CYP2B6 substrates, which may result in reduced efficacy for these concomitant medications 

Intervention: Patients receiving DAYVIGO and CYP2B6 substrates concurrently should be monitored for adequate clinical response.

Increasing the doses of CY2B6 substrates may be considered as needed.

Examples: Bupropion, methadone

CI-    DAYVIGO is contraindicated in patients with narcolepsy.  

ADVERSE REACTIONS

 The most common adverse reaction (reported in =5% of patients treated with DAYVIGO and at least twice the rate of placebo) was somnolence.

 Sleep Paralysis, Hypnogogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms:                                                                                                                     May occur with use of DAYVIGO. 

Complex Sleep Behaviors:                                                                                         Behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur. Discontinue immediately if a complex sleep behavior occurs.

Compromised Respiratory Function:                                                                      Effect on respiratory function should be considered. 

Worsening of Depression/Suicidal Ideation:                                                          Worsening of depression or suicidal thinking may occur. Prescribe the lowest number of tablets feasible to avoid intentional overdosage.

 Need to Evaluate for Co-morbid Diagnoses:                                                                  Reevaluate if insomnia persists after 7 to 10 days of treatment. 

 PATIENT COUNSELING INFORMATION

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

Administration Instructions                                                                                            Advise patients to take DAYVIGO only when preparing for or getting into bed and only if they can stay in bed for a full night (at least 7 hours) before being active again 

Advise patients that the effect of DAYVIGO may be delayed if taken with or soon after a meal 

CNS Depressant Effects and Daytime Impairment                                                           Advise patients that DAYVIGO can impair daytime wakefulness even when used as prescribed.

The risk of daytime impairment is increased if DAYVIGO is taken with less than a full night of sleep remaining or if a higher than recommended dose is taken.

If DAYVIGO is taken in these circumstances, caution patients against driving and other activities requiring complete mental alertness.

Advise patients that increased drowsiness may increase the risk of falls in some patients 

Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-Like Symptoms                                                                                                                   Advise patients and their families that DAYVIGO may cause sleep paralysis, which is an inability to move or speak for several minutes during sleep-wake transitions, despite being aware of  surroundings; hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions; and symptoms similar to mild cataplexy 

Complex Sleep Behaviors                                                                                          Instruct patients and their families that DAYVIGO may cause complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake.

Tell patients to discontinue DAYVIGO and notify their healthcare provider immediately if they develop any of these symptoms 

Worsening of Depression/Suicidal Ideation                                                                  Tell patients to report any worsening of depression or suicidal thoughts immediately 

Pregnancy                                                                                                                 Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DAYVIGO during pregnancy 

Concomitant Medications                                                                                            Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription.

Advise patients not to consume alcohol in combination with DAYVIGO 

Tolerance, Abuse, and Dependence                                                                               Tell patients not to increase the dose of DAYVIGO on their own, and to inform you if they believe the drug “does not work” 

. Distributed by: Eisai Inc. Woodcliff Lake, NJ 07677 DAYVIGOTM is a trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc. © 2019 Eisai Inc.

 CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                                                      The mechanism of action of lemborexant in the treatment of insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system plays a role in wakefulness.

Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.

2. Pharmacodynamics                                                                                   Lemborexant binds to orexin receptors OX1R and OX2R and acts as a competitive antagonist (IC50 values of 6.1 nM and 2.6 nM, respectively).

Cardiac Electrophysiology                                                                                                In a concentration-QTcF analysis using the data from two randomized, double-blind, placebocontrolled, multiple ascending dose studies in healthy subjects, lemborexant does not prolong the QTcF interval to any clinically relevant extent at a dose 5 times the maximum recommended dose.

Drug Interactions                                                                                                     Lemborexant co-administered with alcohol produced a numerically greater negative impact on postural stability and memory as compared with alcohol alone at approximately 2 hours post-dose 

3. Pharmacokinetics                                                                                             Following single doses of lemborexant 2.5 to 75 mg, geometric mean Cmax and AUC0-24h increased slightly less than in proportion to dose.

The extent of accumulation of lemborexant at steady-state is 1.5- to 3-fold across this dose range.

Absorption                                                                                                                     The time to peak concentration (tmax) of lemborexant is approximately 1 to 3 hours.

Effect of Food                                                                                                            Lemborexant Cmax decreased by 23%, AUC0-inf increased by 18%, and tmax was delayed by 2 hours following administration of a high-fat and high-calorie meal (containing approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively).

Distribution                                                                                                                    The volume of distribution of lemborexant is 1970 L. Protein binding of lemborexant is approximately 94% in vitro. The blood to plasma concentration ratio of lemborexant is 0.65.

Elimination                                                                                                                 

 Metabolism-Lemborexant is primarily metabolized by CYP3A4, and to a lesser extent by CYP3A5. The major circulating metabolite is M10.

Excretion                                                                                                                       Following administration of an oral dose, 57.4% of the dose was recovered in the feces and 29.1% in the urine (<1% as unchanged).

The effective half-life for lemborexant 5 mg and 10 mg is 17 and 19 hours, respectively.

Specific Populations                                                                                                      No clinically significant differences in the pharmacokinetics of lemborexant were observed based on age, sex, race/ethnicity, or body mass index.

No studies have been conducted to investigate the pharmacokinetics of lemborexant in pediatric patients.

 USE IN SPECIFIC POPULATIONS

1 Pregnancy                                                                                                            Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to DAYVIGO during pregnancy.

Healthcare providers are encouraged to register patients in the DAYVIGO pregnancy registry by calling 1-888-274-2378.

Risk Summary                                                                                                            There are no available data on DAYVIGO use in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage or adverse maternal or fetal outcomes. 

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.

2. Lactation Risk Summary

There are no data on the presence of lemborexant in human milk, the effects on the breastfed infant, or the effects on milk production. Lemborexant and its metabolites are present in the milk of lactating rats.

When a drug is present in animal milk, it is likely that the drug will be present in human milk. Infants exposed to DAYVIGO through breastmilk should be monitored for excessive sedation.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DAYVIGO and any potential adverse effects on the breastfed infant from DAYVIGO or from the underlying maternal condition.

3. Pediatric Use

The safety and effectiveness of DAYVIGO have not been established in pediatric patients.

4. Geriatric Use

Of the total number of patients treated with DAYVIGO (n=1418) in controlled Phase 3 studies, 491 patients were 65 years and over, and 87 patients were 75 years and over.

Overall, efficacy results for patients <65 years of age were similar compared to patients =65 years. In a pooled analysis of Study 1 (the first 30 days) and Study 2, the incidence of somnolence in patients =65 years with DAYVIGO 10 mg was higher (9.8%) compared to 7.7% in patients <65 years.

The incidence of somnolence with DAYVIGO 5 mg was similar in patients =65 years (4.9%) and <65 years (5.1%). The incidence of somnolence in patients treated with placebo was 2% or less regardless of age 

Because DAYVIGO can increase somnolence and drowsiness, patients, particularly the elderly, are at a higher risk of falls . Exercise caution when using doses higher than 5 mg in patients =65 years old.

5. Renal Impairment

No dose adjustment is required in patients with mild, moderate, or severe renal impairment. DAYVIGO exposure (AUC) was increased in patients with severe renal impairment.

Patients with severe renal impairment may experience an increased risk of somnolence 

6. Hepatic Impairment

DAYVIGO has not been studied in patients with severe hepatic impairment. Use in this population is not recommended 

Dosage adjustment is recommended in patients with moderate hepatic impairment (Child-Pugh class B)

DAYVIGO exposure (AUC) was increased in patients with mild hepatic impairment (Child-Pugh class A), but the terminal half-life was not changed.

Patients with mild hepatic impairment may experience an increased risk of somnolence 

7. Patients with Compromised Respiratory Function

In a study of patients with mild OSA (apnea-hypopnea index <15 events per hour of sleep), DAYVIGO did not increase the frequency of apneic events or cause oxygen desaturation. DAYVIGO has not been studied in patients with COPD or moderate to severe OSA. Clinically meaningful respiratory effects of DAYVIGO in COPD or moderate to severe OSA cannot be excluded [see Warnings and Precautions (5.4)]. 9 Reference ID: 4538172

8. DRUG ABUSE AND DEPENDENCE

1. Controlled Substance DAYVIGO contains lemborexant. (Controlled substance schedule to be determined after review by the Drug Enforcement Administration).

2 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 study conducted in recreational sedative abusers (n=29), lemborexant 10 mg, 20 mg (two times the maximum recommended dose), and 30 mg (three times the maximum recommended dose) produced responses on positive subjective measures such as “Drug Liking,” “Overall Drug Liking,” “Take Drug Again,” and “Good Drug Effects” that were statistically similar to those produced by the sedatives zolpidem (30 mg) and suvorexant (40 mg), and statistically greater than the responses on these measures that were produced by placebo.

Because individuals with a history of abuse or addiction to alcohol or other drugs may be at increased risk for abuse and addiction to DAYVIGO, follow such patients carefully.

3. Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

OVERDOSAGE

There is limited clinical experience with DAYVIGO overdose. In clinical pharmacology studies, healthy patients who were administered multiple doses of up to 75 mg (7.5 times the maximum recommended dose) of DAYVIGO showed dose-dependent increases in the frequency of somnolence.

There is no available specific antidote to an overdose of DAYVIGO.

In the event of overdose, standard medical practice for the management of any overdose should be used. In managing overdose, provide supportive care, including close medical supervision and monitoring and consider the possibility of multiple drug involvement.

Consult a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222 or www.poison.org).

The value of dialysis in the treatment of overdosage has not been determined with lemborexant. As lemborexant is highly protein-bound, hemodialysis is not expected to contribute to elimination of lemborexant.