LEMBOREXANT: 989 Adverse Event Reports & Safety Profile

DAYVIGO contains lemborexant, an orexin receptor antagonist. The chemical name of lemborexant is (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)- N -(5-fluoropyridin-2-yl) cyclopropanecarboxamide. The molecular formula is C 22 H 20 F 2 N 4 O 2 . The molecular weight is 410.42. The structural formula is: Lemborexant is a white to off-white powder that is practically insoluble in water. DAYVIGO tablets are intended for oral administration. Each film coated tablet contains 5 mg or 10 mg of lemborexant. The inactive ingredients are: hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose 2910, polyethylene glycol 8000, talc, titanium dioxide, and either (a) ferric oxide yellow for the 5 mg tablet; or, (b) both ferric oxide yellow and ferric oxide red for the 10 mg tablet. The structural formula for DAYVIGO contains lemborexant, an orexin receptor antagonist. The chemical name of lemborexant is (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl) cyclopropanecarboxamide. The molecular formula is C22H20F2N4O2. The molecular weight is 410.42.

AND USAGE DAYVIGO is indicated for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance [see Clinical Studies ( 14.1 )] . DAYVIGO is an orexin receptor antagonist indicated for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. ( 1 )

AND ADMINISTRATION Recommended dose is 5 mg taken no more than once per night, immediately before going to bed, with at least 7 hours remaining before the planned time of awakening. Dosage may be increased to 10 mg based on clinical response and tolerability. ( 2.1 ) The maximum recommended dose is 10 mg once daily. ( 2.1 ) Time to sleep onset may be delayed if taken with or soon after a meal. ( 2.1 )

Hepatic

Impairment: ( 2.3 ) ○ Moderate hepatic impairment: Initial and maximum recommended dosage is 5 mg no more than once per night. ○ Severe hepatic impairment: Not recommended.

2.1 Dosing Information The recommended dosage of DAYVIGO is 5 mg taken no more than once per night, immediately before going to bed, with at least 7 hours remaining before the planned time of awakening. The dose may be increased to the maximum recommended dose of 10 mg based on clinical response and tolerability. Time to sleep onset may be delayed if taken with or soon after a meal <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

2.2 Dosage Recommendations for Concomitant Use with CYP3A Inhibitors or CYP3A Inducers Co-administration with Strong or Moderate CYP3A Inhibitors Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inhibitors <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]</span>. Co-administration with Weak CYP3A Inhibitors The maximum recommended dosage of DAYVIGO is 5 mg no more than once per night when co-administered with weak CYP3A inhibitors <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]</span>. Co-administration with Strong or Moderate CYP3A Inducers Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inducers <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]</span>.

2.3 Dosage Recommendations for Patients with Hepatic Impairment The maximum recommended dose of DAYVIGO is 5 mg no more than once per night in patients with moderate hepatic impairment <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]</span>. DAYVIGO is not recommended in patients with severe hepatic impairment <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.7 )]</span>.

DAYVIGO is contraindicated in patients with narcolepsy. DAYVIGO is contraindicated in patients with narcolepsy. ( 4 )

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.

6.1 Clinical 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

9.6 Headache 3.4 5.9

4.5 Nightmare 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 &lt;2% incidence but greater than placebo are shown below. The following list does not include adverse reactions 1) for which a drug cause was remote, 2) that were so general to be uninformative, or 3) that were not considered to have clinically significant implications. Sleep paralysis was reported in 1.6% and 1.3% of patients receiving DAYVIGO 10 mg and 5 mg, respectively, compared to no reports for placebo. Hypnagogic hallucinations were reported in 0.7% and 0.1% of patients receiving DAYVIGO 10 mg and 5 mg, respectively, compared to no reports for placebo <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span>. Two events of complex sleep behavior were reported, both in patients receiving DAYVIGO 10 mg <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span>.

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 )

5.1 CNS 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span>. 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span>. 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>. Because DAYVIGO can cause drowsiness, patients, particularly the elderly, are at a higher risk of falls.

5.2 Sleep 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).

5.3 Complex 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> . Discontinue DAYVIGO immediately if a patient experiences a complex sleep behavior.

5.4 Patients with Compromised Respiratory Function DAYVIGO has been studied in mild to severe Obstructive Sleep Apnea (OSA) and moderate to severe Chronic Obstructive Pulmonary Disease (COPD) in short-term clinical trials. The effect of DAYVIGO on respiratory function should be considered if prescribed to patients with compromised respiratory function <span class="opacity-50 text-xs">[see Use in Speci fic Populations ( 8.8 )]</span>.

5.5 Worsening of Depression/Suicidal Ideation In clinical studies of DAYVIGO in patients with insomnia, the incidence of suicidal ideation or any suicidal behavior, as assessed by questionnaire, was higher in patients receiving DAYVIGO than in those receiving placebo (0.3% for DAYVIGO 10 mg, 0.4% for DAYVIGO 5 mg, and 0.2% for placebo). In primarily depressed patients treated with hypnotics, worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed at any one time. The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

5.6 Need to Evaluate for Co-m orbid Diagnoses Because sleep disturbances may be the presenting manifestation of a medical and/or psychiatric disorder, treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new cognitive or behavioral abnormalities may be the result of an unrecognized underlying psychiatric or medical disorder and can emerge during the course of treatment with sleep-promoting drugs such as DAYVIGO.

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 )

7.1 Drugs 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Intervention: Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inhibitors <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span>. The maximum recommended dose of DAYVIGO with weak CYP3A inhibitors is 5 mg <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span>. 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Intervention: Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inducers <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span>. 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) <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span>. Intervention: Avoid alcohol consumption with DAYVIGO <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>. 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. 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