DAYVIGO Film-coated tablet Ref.[10116] Active ingredients:

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 [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.

5.2 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 [see Drug Interactions (7.1)]. Discontinue DAYVIGO immediately if a patient experiences a complex sleep behavior.

5.4 Patients with Compromised Respiratory Function

The effect of DAYVIGO on respiratory function should be considered if prescribed to patients with compromised respiratory function. DAYVIGO has not been studied in patients with moderate to severe obstructive sleep apnea (OSA) or in patients with chronic obstructive pulmonary disease (COPD) [see Use in Special Populations (8.8)].

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.

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)]

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 Days of Study 1 and Study 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 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 [see Warnings and Precautions (5.2)].
• Two events of complex sleep behavior were reported, both in patients receiving DAYVIGO 10 mg [see Warnings and Precautions (5.3)].

Table 2. Clinically Important Drug Interactions with DAYVIGO:

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.

In animal reproduction studies, oral administration of lemborexant to pregnant rats and rabbits during the period of organogenesis caused toxicities only at high multiples of the human exposure at the maximum recommended human dose (MRHD) based on AUC. The no observed adverse effect levels (NOAEL) are approximately >100 and 23 times the MRHD based on AUC in rats and rabbits, respectively. Similarly, oral administration of lemborexant to pregnant and lactating rats caused toxicities only at high multiples of the human exposure at the MRHD based on AUC. The NOAEL is 93 times the MRHD based on AUC [see Data].

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.

Data

Animal Data

Lemborexant was administered orally to pregnant rats during the period of organogenesis in 2 studies at doses of 60, 200, and 600 mg/kg/day or 20, 60, and 200 mg/kg/day, which are approximately 6 to >300 times the MRHD based on AUC. Lemborexant caused maternal toxicity, manifested by decreased body weight and food consumption, decreased mean fetal body weight, an increased number of dead fetuses, and skeletal, external and visceral malformations (omphalocele, cleft palate, and membranous ventricular septal defect) at >300 times the MRHD based on AUC. The NOAEL of 200 mg/kg/day is approximately 143 times the MRHD based on AUC.

Lemborexant was administered orally to pregnant rabbits during the period of organogenesis at doses of 10, 30, and 100 mg/kg/day, which are approximately 7 to 139 times the MRHD based on AUC. Lemborexant caused maternal toxicity that consisted of decreased body weight and food consumption and a higher incidence of skeletal variations (presence of cervical ribs and supernumerary lung lobes) at approximately 139 times the MRHD based on AUC. The NOAEL of 30 mg/kg/day is approximately 23 times the MRHD based on AUC.

Lemborexant was administered orally to pregnant rats during pregnancy and lactation at doses of 30, 100, and 300 mg/kg/day, which are approximately 15 to 206 times the MRHD based on AUC. Lemborexant caused maternal toxicity that consisted of decreased body weight and food consumption and toxicity to offspring consisting of decreased pup body weights, decreased femur length, and decreased acoustic startle responses at 206 times the MRHD based on AUC. The NOAEL of 100 mg/kg/day is approximately 93 times the MRHD based on AUC.

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.

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

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 [see Clinical Studies (14.2)]. Because DAYVIGO can increase somnolence and drowsiness, patients, particularly the elderly, are at a higher risk of falls [see Warning and Precautions (5.1)]. Exercise caution when using doses higher than 5 mg in patients ≥65 years old.

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 [see Clinical Pharmacology (12.3)].

DAYVIGO has not been studied in patients with severe hepatic impairment. Use in this population is not recommended [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

DAYVIGO exposure (AUC and C_max) and terminal half-life were increased in patients with moderate hepatic impairment (Child-Pugh class B). Dosage adjustment is recommended in patients with moderate hepatic impairment (Child-Pugh class B) [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

8.8 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)].

DAYVIGO contains lemborexant, a Schedule IV controlled substance.

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.

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. In animal studies and clinical trials evaluating physical dependence, chronic administration of lemborexant did not produce withdrawal signs or symptoms upon drug discontinuation. This suggests that lemborexant does not produce physical dependence.