Dayvigo
(Lemborexant)Dosage & Administration
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Dayvigo Prescribing Information
DAYVIGO is indicated for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance
DAYVIGO was evaluated in two clinical trials in patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance (Study 1, NCT02952820 and Study 2, NCT02783729).
Study 1 was a 6-month, randomized, double-blind, placebo-controlled, multi-center trial in adult patients age 18 or older who met DSM-5 criteria for insomnia disorder. Patients were randomized to placebo (n=325), DAYVIGO 5 mg (n=323), or DAYVIGO 10 mg (n=323) once nightly. The primary efficacy endpoint was the mean change from baseline to end of treatment at 6 months for log-transformed patient-reported (subjective) sleep onset latency (sSOL), defined as the estimated minutes from the time that the patient attempted to sleep until sleep onset. Pre-specified secondary efficacy endpoints for sleep maintenance were change from baseline to end of treatment at 6 months for patient-reported sleep efficiency (sSEF) and wake after sleep onset (sWASO). sSEF is defined as the proportion of time spent asleep per time in bed. sWASO is defined as the minutes of wake from the onset of sleep until wake time. The primary and pre-specified secondary efficacy endpoints were measured by sleep diary.
The demographic characteristics of patients in Study 1 were similar across the treatment arms. Patients had a median age of 55 years (range 18 to 88) and were 68% female, 72% White, 8% Black or African American, 17% Japanese, and 3.5% other; 28% were elderly (≥65 years).
Examination of subgroups by age, race, and sex did not suggest differences in response to DAYVIGO. In Study 1, DAYVIGO 5 mg and 10 mg demonstrated statistically significant superiority on the primary efficacy measure, sSOL, compared to placebo (Table 3). DAYVIGO 5 mg and 10 mg also showed statistically significant superiority in sSEF and sWASO.
Endpoint | Treatment Group | Number of Patients ITT | Baseline Mean a(SD) | Month 6 LS Mean a(SE) | Treatment Effect (95% CI) |
Sleep Onset sSOL (minutes) | DAYVIGO 5 mg* | 316 | 43.0(31.5) | 20.0(1.1) | 0.7(0.6, 0.8) |
| DAYVIGO 10 mg* | 315 | 45.0(33.4) | 19.2(1.1) | 0.7(0.6, 0.8) | |
| Placebo | 318 | 45.0(31.8) | 27.3(1.4) | (ratio vs placebo)b | |
Sleep Maintenance sSEF (%) | DAYVIGO 5 mg* | 316 | 63.1 (18.2) | 75.9 (0.9) | 4.5(2.2, 6.9) |
| DAYVIGO 10 mg* | 315 | 62.0 (17.2) | 75.9 (0.9) | 4.7(2.4, 7.0) | |
| Placebo | 318 | 61.3 (17.8) | 71.4 (0.8) | (%)c | |
Sleep Maintenance sWASO (minutes) | DAYVIGO 5 mg* | 316 | 132.8 (82.5) | 87.9 (3.7) | -17.5(-27.3, -7.6) |
| DAYVIGO 10 mg* | 315 | 136.8 (87.4) | 92.7 (3.7) | -12.7(-22.4, -3.0) | |
| Placebo | 318 | 132.5 (80.2) | 105.3 (3.6) | (minutes)c | |
| ITT (intention to treat); sSOL (subjective sleep onset latency); SD (standard deviation); LS (least squares); SE (standard error); CI (unadjusted confidence interval); sSEF (subjective sleep efficiency); sWASO (subjective wake after sleep onset) aFor the sleep onset sSOL endpoint, the mean refers to geometric mean, which was used due to the approximately log normal distribution of the outcomes; SD for the geometric mean is calculated as GM*SD (log transformed sSOL); SE for the least squares geometric mean is calculated in the same way as the SD. bFor the sleep onset sSOL endpoint, treatment effect refers to the ratio of [Month 6 sSOL / Baseline sSOL] for DAYVIGO versus placebo, such that a smaller ratio corresponds to a greater improvement. cTreatment effect refers to the treatment difference between DAYVIGO versus placebo, such that a larger value for sSEF and smaller value for sWASO correspond to greater improvement. *Doses that were statistically significantly superior (p<0.05) to placebo after multiplicity adjustment. | |||||
Study 2 was a 1-month, randomized, double-blind, placebo- and active-controlled, multi-center, parallel-group clinical trial in adult female patients age 55 and older and male patients 65 years and older who met DSM-5 criteria for insomnia disorder. Patients were randomized to placebo (n=208), DAYVIGO 5 mg (n=266) or 10 mg (n=269), or active comparator (n=263) once nightly.
The primary efficacy endpoint was the mean change in log-transformed latency to persistent sleep (LPS) from baseline to end of treatment (Days 29/30), as measured by overnight polysomnography (PSG) monitoring. LPS was defined as the number of minutes from lights off to the first 10 consecutive minutes of non-wakefulness. The pre-specified secondary efficacy endpoints in Study 2 were the mean change from baseline to end of treatment (Days 29/30) in sleep efficiency (SEF) and wake after sleep onset (WASO) measured by PSG.
The demographic and baseline characteristics of patients in Study 2 were similar across the treatment arms. Patients had a median age of 63 years (range 55 to 88) and were 86% female, 72% White, 25% Black or African American, and 2% other; 45% were elderly (≥65 years).
In Study 2, DAYVIGO 5 mg and 10 mg demonstrated statistically significant superiority on the primary efficacy measure, LPS, compared to placebo (Table 4). DAYVIGO 5 mg and 10 mg demonstrated statistically significant improvement in SEF and WASO compared to placebo.
Endpoint | Treatment Group | Number of Patients ITT | Baseline Mean a(SD) | Day 29/30 LS Mean a(SE) | Treatment Effect (95% CI) |
Sleep Onset LPS (minutes) | DAYVIGO 5 mg* | 266 | 33.0(27.2) | 15.5(0.8) | 0.8 (0.7, 0.9) |
| DAYVIGO 10 mg* | 269 | 33.3(27.2) | 14.5(0.7) | 0.7(0.6, 0.8) | |
| Placebo | 208 | 33.6(25.9) | 20.0(1.1) | (ratio vs. placebo)b | |
Sleep Maintenance SEF (%) | DAYVIGO 5 mg* | 266 | 68.4 (11.3) | 80.7 (0.5) | 7.1 (5.6, 8.5) |
| DAYVIGO 10 mg* | 269 | 67.8 (10.8) | 82.7 (0.5) | 8.0(6.6, 9.5) | |
| Placebo | 208 | 68.9 (9.6) | 74.6 (0.6) | (%)c | |
Sleep Maintenance WASO (minutes) | DAYVIGO 5 mg* | 266 | 113.4 (39.0) | 68.3 (2.2) | -24.0 (-30.0, -18.0) |
| DAYVIGO 10 mg* | 269 | 114.8 (40.0) | 66.9 (2.2) | -25.3(-31.4, -19.3) | |
| Placebo | 208 | 111.7 (37.2) | 92.2 (2.5) | (minutes)c | |
| ITT (intention to treat); LPS (latency to persistent sleep); SD (standard deviation); LS (least squares); SE (standard error); CI (unadjusted confidence interval); SEF (sleep efficiency); WASO (wake after sleep onset) aFor the sleep onset LPS endpoint, the mean refers to geometric mean, which was used due to the approximately log normal distribution of the outcomes; SD for the geometric mean is calculated as GM*SD (log transformed LPS); SE for the least squares geometric mean is calculated in the same way as the SD. bFor the LPS endpoint, treatment effect refers to the ratio of [Day 29/30 LPS / Baseline LPS] for DAYVIGO versus placebo, such that a smaller ratio corresponds to a greater improvement. cTreatment effect refers to the treatment difference between DAYVIGO versus placebo, such that a larger value for SEF and smaller value for WASO correspond to greater improvement. *Doses that were statistically significantly superior (p<0.05) to placebo after multiplicity adjustment. | |||||
The effects of DAYVIGO at the beginning of treatment were generally consistent with later timepoints.
- 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. ()2.1Dosing 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)]. - The maximum recommended dose is 10 mg once daily. ()2.1Dosing 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)]. - Time to sleep onset may be delayed if taken with or soon after a meal. ()2.1Dosing 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)]. - Hepatic Impairment: ()2.3Dosage Recommendations forPatients 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)].
○ Moderate hepatic impairment: Initial and maximum recommended dosage is 5 mg no more than once per night.
○ Severe hepatic impairment: Not recommended.
DAYVIGO (lemborexant) tablets are available as:
- 5 mg tablets: pale yellow, round, biconvex, film-coated tablets, and debossed with "5" on one side and "LЄM" on the other side.
- 10 mg tablets: orange, round, biconvex, film-coated tablets, and debossed with "10" on one side and "LЄM" on the other side.
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.
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
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.
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.
DAYVIGO is contraindicated in patients with narcolepsy.
- 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. ()5.1CNS 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.
- Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms: May occur with use of DAYVIGO. ()5.2Sleep 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).
- 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. ()5.3Complex 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. - Compromised Respiratory Function: Effect on respiratory function should be considered. (,5.4Patients 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 SpecificPopulations (8.8)].)8.8Patients with Compromised Respiratory FunctionObstructive 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)]. - Worsening of Depression/Suicidal Ideation: Worsening of depression or suicidal thinking may occur. Prescribe the lowest number of tablets feasible to avoid intentional overdosage. ()5.5Worsening 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.
- Need to Evaluate for Co-morbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days of treatment. ()5.6Need 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.