DAYVIGO lemborexant 5 mg Tablet, Film Coated, 30-count

5 WARNINGS AND PRECAUTIONS CNS Depressant Effects and Daytime Impairment: Impairs alertness and motor coordination including morning impairment. Risk increases with dose and use with other central nervous system (CNS) depressants. For patients taking DAYVIGO 10 mg, caution against next-day driving and other activities requiring complete mental alertness.

( 5.1 ) Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms: May occur with use of DAYVIGO. ( 5.2 ) 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.

( 5.3 ) Compromised Respiratory Function: Effect on respiratory function should be considered. ( 5.4 , 8.8 ) Worsening of Depression/Suicidal Ideation: Worsening of depression or suicidal thinking may occur. Prescribe the lowest number of tablets feasible to avoid intentional overdosage.

( 5.5 ) Need to Evaluate for Co-morbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days of treatment. ( 5.6 )

5.1CNS Depressant Effects and Daytime Impairment DAYVIGO is a central nervous system (CNS) depressant that can impair daytime wakefulness even when used as prescribed. CNS depressant effects may persist in some patients for up to several days after discontinuing DAYVIGO. Prescribers should advise patients about the potential for next-day somnolence.

Driving ability was impaired in some subjects taking DAYVIGO 10 mg [see Clinical Studies ( 14.2 )]. 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 [see Dosage and Administration ( 2.1 )]. If DAYVIGO is taken in these circumstances, patients should be cautioned against driving and other activities requiring complete mental alertness.

Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression, which can cause daytime impairment. Dosage adjustments of DAYVIGO and of concomitant CNS depressants may be necessary when administered together because of potentially additive effects. The use of DAYVIGO with other drugs to treat insomnia is not recommended .

Patients should be advised not to consume alcohol in combination with DAYVIGO because of additive effects [see Drug Interactions ( 7.1 )]. Because DAYVIGO can cause drowsiness, patients, particularly the elderly, are at a higher risk of falls.

5.2Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy - l ike Symptoms Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions, can occur with the use of DAYVIGO. Prescribers should explain the nature of these events to patients when prescribing DAYVIGO. Symptoms similar to mild cataplexy can occur with DAYVIGO.

Such symptoms can include periods of leg weakness lasting from seconds to a few minutes, can occur either at night or during the day, and may not be associated with an identified triggering event (e.g., laughter or surprise).

5.3Complex Sleep Behaviors Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake (e.g., preparing and eating food, making phone calls, having sex), have been reported to occur with the use of hypnotics such as DAYVIGO. These events can occur in hypnotic-naïve as well as in hypnotic-experienced persons. Patients usually do not remember these events.

Complex sleep behaviors may occur following the first or any subsequent use of DAYVIGO, with or without the concomitant use of alcohol and other CNS depressants [see Drug Interactions ( 7.1 )] . Discontinue DAYVIGO immediately if a patient experiences a complex sleep behavior.

5.4 Patients with Compromised Respiratory Function DA…

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in detail in other sections of the labeling: CNS Depressant Effects and Daytime Impairment [see Warnings and Precautions ( 5.1 )] Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms [see Warnings and Precautions ( 5.2 )] Complex Sleep Behaviors [see Warnings and Precautions ( 5.3 )] Patients with Compromised Respiratory Function [see Warnings and Precautions ( 5.4 )] Worsening of Depression/Suicidal Ideation [see Warnings and Precautions ( 5.5 )] The most common adverse reaction (reported in ≥5% of patients treated with DAYVIGO and at least twice the rate of placebo) was somnolence.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888-274-2378 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of DAYVIGO was evaluated in 1418 adult patients with insomnia disorder (age 18 to 88 years) from two controlled efficacy trials (Study 1 and Study 2). Study 1 was a 6-month placebo-controlled trial assessing DAYVIGO 5 or 10 mg once nightly, followed by a 6-month parallel-group extension period in which patients initially treated with DAYVIGO continued on the same dose, and patients who received placebo were re-randomized to receive DAYVIGO 5 or 10 mg once nightly.

In Study 1, 434 patients were treated with DAYVIGO for one year. Study 2 was a 30-day placebo- and active-controlled trial assessing DAYVIGO 5 or 10 mg once nightly. Adverse Reactions Resulting in Discontinuation of Treatment The frequencies of discontinuation due to adverse reactions in Study 1 (the first 30 days) and Study 2 were 2.6% and 1.4% for patients treated with 10 mg and 5 mg DAYVIGO, respectively, compared to 1.5% for patients in the placebo group.

The most common adverse reactions leading to discontinuation of DAYVIGO were somnolence (1.0% for 10 mg, 0.7% for 5 mg, and 0.4% for placebo) and nightmares (0.3% for 10 mg, 0.3% for 5 mg, and 0% for placebo). The frequencies of discontinuation due to adverse reactions in the 6-month placebo-controlled period of Study 1 were 8.3% and 4.1% for patients treated with DAYVIGO 10 mg and 5 mg, respectively, compared to 3.8% for patients in the placebo group. The most common reasons for discontinuation of DAYVIGO and occurring in more than one patient within a treatment arm were somnolence (2.9% for 10 mg, 1.0% for 5 mg, and 0.6% for placebo), nightmares (1.3% for 10 mg, 0.3% for 5 mg, and 0% for placebo), and palpitations (0.6% for 10 mg, 0% for 5 mg, and 0% for placebo).

Most Common Adverse Reactions The most common adverse reaction (reported in 5% or more of patients treated with DAYVIGO and at least twice the rate of placebo) in Study 1 (the first 30 days) and Study 2 was somnolence (10% for DAYVIGO 10 mg, 7% for DAYVIGO 5 mg, and 1% for placebo). Table 1 presents the adverse reactions based on the pooled data from the first 30 days of Study 1 (6-month controlled efficacy trial) and Study 2 (1-month controlled efficacy trial) where the incidence was ≥2% in DAYVIGO-treated patients and greater than in placebo-treated patients.

Table 1: Adverse Reactions Reported in ≥ 2% of DAYVIGO-Treated Patients and at a Greater Frequency than Placebo-Treated Patients During the First 30 D ays of Study 1 and Study 2 DAYVIGO Placebo 5 mg 10 mg n=528 n=580 n=582 (%) (%) (%) Somnolence or fatigue * 1.3 6.9

9.6Headache 3.4 5.9

4.5Nightmare or abnormal dreams 0.9 0.9 2.2 * Combines preferred terms somnolence, lethargy, fatigue, sluggishness Other Adverse Reactions Observed During Clinical Trials (Studies 1 and 2) Other adverse reactions of <2% incidence but greater than placebo are shown below. The follow…

7 DRUG INTERACTIONS Strong or moderate CYP3A inhibitors: Avoid concomitant use. ( 7.1 ) Weak CYP3A inhibitors: The maximum recommended dose is 5 mg. ( 2.2 , 7.1 ) Strong or moderate CYP3A inducers: Avoid concomitant use. ( 7.1 )

7.1Drugs Having Clinically Important Interactions with DAYVIGO Table 2: 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 C max which may increase the risk of DAYVIGO adverse reactions [see Clinical Pharmacology ( 12.3 )]. Intervention: Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inhibitors [see Dosage and Administration ( 2.2 )].

The maximum recommended dose of DAYVIGO with weak CYP3A inhibitors is 5 mg [see Dosage and Administration ( 2.2 )]. 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 [see Clinical Pharmacology ( 12.3 )]. Intervention: Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inducers [see Dosage and Administration ( 2.2 )].

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 C max and AUC. Co-administration of DAYVIGO with alcohol produced a numerically greater negative impact on postural stability and memory as compared with alcohol alone when assessed near the t max of DAYVIGO (2 hours post-dose) [see Clinical Pharmacology ( 12.2 )].

Intervention: Avoid alcohol consumption with DAYVIGO [see Warnings and Precautions ( 5.1 )]. 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 [see Clinical Pharmacology ( 12.3 )]. Intervention: Patients receiving DAYVIGO and CYP2B6 substrates concurrently should be monitored for adequate clinical response.

Increasing the doses of CYP2B6 substrates may be considered as needed. Examples: Bupropion, methadone