Dayvigo

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 [see Clinical Pharmacology ( 12.3)].

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 [see Drug Interactions ( 7.1), Clinical Pharmacology ( 12.3)].

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 [see Drug Interactions ( 7.1), Clinical Pharmacology ( 12.3)].

Co-administration with Strong or Moderate CYP3A Inducers

Avoid concomitant use of DAYVIGO with strong or moderate CYP3A inducers [see Drug Interactions ( 7.1), Clinical Pharmacology ( 12.3)].

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 [see Use in Specific Populations ( 8.7), Clinical Pharmacology ( 12.3)].

DAYVIGO is not recommended in patients with severe hepatic impairment [see Use in Specific Populations ( 8.7)].

8.1        Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to psychiatric medications, including DAYVIGO, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Psychiatric Medications, at1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry.

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.

8.2        Lactation

Risk Summary

Available data from a lactation study in 8 women indicates that lemborexant is transferred into the breastmilk of nursing mothers, and the results have established a mean daily infant dose of 0.0029 mg/kg/day and a relative infant dose of less than 2% of the maternal dose. These data support that transfer of lemborexant into breastmilk is low (see Data). There are no data on the effects of lemborexant on the breastfed infant, or the effects on milk production. 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.

Data

A single dose milk-only lactation study was conducted in 8 healthy adult lactating women. The mean amount of lemborexant recovered in human milk was 0.0174 mg following a 10 mg maternal dose. The mean calculated daily infant oral dosage was 0.0029 mg/kg/day based on nominal infant body weight of 6 kg. Approximately 70% of the total amount of lemborexant excreted in milk was excreted by 24 hours after a single maternal dose administration. There are no data on the effects of lemborexant on the breastfed infant, the effects on milk production, or infant exposure after repeated maternal dosing of lemborexant.

8.4        Pediatric Use

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

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

8.6        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 [see Clinical Pharmacology ( 12.3)].

8.7        Hepatic Impairment

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 Cmax) 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

Obstructive Sleep Apnea (OSA)

The respiratory depressant effect of DAYVIGO was evaluated after 8 consecutive nights of treatment with DAYVIGO 10 mg in a randomized, placebo-controlled, two-period crossover study in 37 patients with mild OSA (apnea-hypopnea index < 15 events per hour of sleep). Following once daily dosing of 10 mg, the mean treatment difference (DAYVIGO – placebo) on Day 8 for the apnea-hypopnea index was -0.06 (95% CI: -1.95 to 1.83).

DAYVIGO was also evaluated after 8 consecutive nights of treatment with DAYVIGO 10 mg in a randomized, placebo-controlled, two-period crossover study in 33 patients with moderate to severe OSA (apnea-hypopnea index ≥ 15 events per hour of sleep). Following once daily dosing of 10 mg, the mean treatment difference (DAYVIGO – placebo) on Day 8 for the apnea-hypopnea index was -0.80 (95% CI: -4.88 to 3.29).

Due to study limitations, including the short duration of the study, clinically meaningful respiratory effects of DAYVIGO in OSA cannot be excluded, including for long-term treatment [see Warnings and Precautions ( 5.4)].

Chronic Obstructive Pulmonary Disease (COPD)

The respiratory depressant effect of DAYVIGO was evaluated after 8 consecutive nights of treatment with DAYVIGO 10 mg in a randomized, placebo-controlled, two-period crossover study in 30 patients with moderate to severe COPD (Forced expiratory volume in the first second (FEV1)/Forced vital capacity (FVC) ratio ≤ 70% and 30% ≤ FEV1 < 80% of predicted). Following once-daily dosing of 10 mg, the mean treatment difference (DAYVIGO – placebo) on Day 8 for the mean peripheral capillary oxygen saturation during sleep was 0.47 (95% CI: 0.07 to 0.87).

DAYVIGO has not been studied in COPD patients with a FEV1 < 30% of predicted.

Clinically meaningful respiratory effects of DAYVIGO in patients with compromised respiratory function cannot be excluded [see Warnings and Precautions ( 5.4)].

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-like 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

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 [see Use in Specific 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-morbid 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.