Summary Basis of Decision for Dayvigo

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Dayvigo is located below.

Recent Activity for Dayvigo

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Dayvigo, a product which contains the medicinal ingredient Lemborexant. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Updated: 2025-08-19

Drug Identification Number (DIN):

  • DIN 02507366 - 5 mg lemborexant, tablet, oral administration
  • DIN 02507374 - 10 mg lemborexant, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 281784

2023-12-05

Issued NOC 2025-01-30

Submission filed as a Level I – Supplement to update the PM with new safety and efficacy information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, Dosage and Administration, Overdosage, Action and Clinical Pharmacology, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 280394

2023-10-26

Issued NOC 2024-05-29

Submission filed as a Level I – Supplement to add a manufacturing site for the drug substance. The information was reviewed and considered acceptable and an NOC was issued.

SNDS # 274602

2023-04-21

Issued NOC  2023-12-15

Submission filed as a Level I – Supplement to revise the outer carton and inner bottle labels. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 266529

2022-07-28

Issued NOC 2023-06-22

Submission filed as a Level I – Supplement to migrate the PM to the 2020 format and to update the PM with new safety information from studies 010 (Lactation), 113 (OSA+COPD), 21-303, and SUNBAE2019-007. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Drug Interactions, and Action and Clinical Pharmacology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

Drug product (DINs 02507366, 02507374) market notification

Not applicable

Date of first sale 2020-11-06

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 231286

2019-09-03

Issued NOC 2020-11-04

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Dayvigo

Date SBD issued: 2021-05-13

The following information relates to the New Drug Submission for Dayvigo.

Lemborexant

Drug Identification Number (DIN):

  • DIN 02507366 - 5 mg lemborexant, tablet, oral administration
  • DIN 02507374 - 10 mg lemborexant, tablet, oral administration

Eisai Ltd.

New Drug Submission Control Number: 231286

 

On November 4, 2020, Health Canada issued a Notice of Compliance to Eisai Limited for the drug product Dayvigo.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit‑harm-uncertainty profile of Dayvigo is favourable for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance.

 

1 What was approved?

 

Dayvigo, a hypnotic agent, was authorized for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance.

The efficacy and safety of Dayvigo have not been established in pediatric patients (<18 years of age). Dayvigo is therefore not recommended in this population.

There were no clinically meaningful differences in efficacy or safety observed between elderly patients (≥65 years of age) and adult patients at the recommended doses.

Dayvigo is contraindicated in patients with narcolepsy and patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Dayvigo was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Dayvigo (5 mg and 10 mg lemborexant) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, hypromellose 2910, polyethylene glycol 8000, talc, titanium dioxide, ferric oxide yellow, and ferric oxide red (10 mg tablet only).

For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Dayvigo Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Dayvigo approved?

 

Health Canada considers that the benefit-harm-uncertainty profile of Dayvigo is favourable for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance.

Insomnia, as per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM‑5), is a predominant complaint of dissatisfaction with sleep quantity or quality, associated with one or more of the following symptoms: difficulty initiating sleep, difficulty maintaining sleep (frequent awakenings or problems returning to sleep after awakenings), and/or early-morning awakening with inability to return to sleep. The sleep disturbance causes clinically significant distress or impairment in functioning, it occurs at least three nights per week, it is present for at least three months, and it occurs despite adequate opportunity for sleep.

Insomnia is often subclassified by the predominant symptom, i.e., sleep onset versus sleep maintenance. Generally, sleep onset insomnia is more common among younger individuals and is more likely to be associated with psychiatric comorbidities, whereas sleep maintenance insomnia is more prevalent in older individuals. However, histories of multiple sleep symptoms are more common than any single symptom, both cross-sectionally and longitudinally.

The course of insomnia is variable. For many individuals, situational insomnia may last a few days or weeks before resolving once the precipitating situation has subsided. However, a substantial proportion of individuals with insomnia (45% to 75%) experience it chronically. Chronic insomnia is associated with medical comorbidities, including diabetes, coronary heart disease, and chronic obstructive pulmonary disease. Persistent sleep disturbances (both insomnia and excessive sleepiness) are also risk factors for the subsequent development of mental illnesses and substance use disorders. Sleep disorders are often accompanied by depression, anxiety, and cognitive changes. In addition, the daytime impairments frequently associated with insomnia include fatigue, decreased cognitive performance, mood disturbances, and disruptions in social and occupational functioning.

The prevalence of insomnia disorder has been reported as approximately 12% to 20% in the general adult population and up to 25% in the elderly. There is also a higher prevalence in females compared to males (ratio of about 1.44:1). Prevalence in Canada based on different surveys in adults is between 13% to 24%, and the resulting individual economic burden is estimated to be  5,010 per person per year. Nearly 90% of this amount is attributed to indirect costs such as work absenteeism and reduced productivity. Further, the trend for experiencing nighttime insomnia symptoms appears to be increasing in the general Canadian population.

Current pharmacologic options for insomnia include gamma‑aminobutyric acid (GABA) type‑A receptor agonists, such as sedative-hypnotic benzodiazepines and benzodiazepine-like Z‑drugs, melatonin receptor agonists, sedating antidepressants, sedating antihistamines, and dual orexin receptor antagonists (DORA).

Lemborexant, the medicinal ingredient in Dayvigo, belongs to the DORA class of drugs. The two variants of the orexin molecule (orexin A and orexin B) play an important role in the human sleep-wake cycles. Unlike most current medications used to treat insomnia, which act on the GABA receptor, lemborexant exerts its hypnotic effects through reversible competitive binding to, and inhibition of, the wakefulness effects of orexin on the orexin‑1 receptor (OX1R) and orexin‑2 receptors (OX2R). Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.

Dayvigo has been shown to be efficacious in the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. The market authorization of Dayvigo was based, in part, on efficacy and safety data from two Phase III studies (Study 303 [Study 1 in the Dayvigo Product Monograph] and Study 304 [Study 2 in the Dayvigo Product Monograph]).

Study 303 was a 6‑month, double-blind, randomized, placebo-controlled study in patients ≥18 years of age who met DSM‑5 criteria for insomnia disorder, with a 6‑month safety extension period. Patients were randomized and received Dayvigo 5 mg (number of participants [n] = 319), Dayvigo 10 mg (n = 319), or placebo (n = 321) once nightly. The demographic characteristics of patients were similar across the treatment arms.

Study 304 was a double-blind, randomized, active- and placebo-controlled 1‑month study conducted in female patients ≥55 years of age and male patients ≥65 years of age who met DSM‑5 criteria for insomnia disorder. Patients were randomized and received Dayvigo 5 mg (n = 266), 10 mg (n = 269), placebo (n = 208), or active comparator (n = 263) once nightly. The demographic and baseline characteristics of patients were similar across the treatment arms.

Both studies met their primary efficacy endpoint to demonstrate a reduction in time to sleep onset. In Study 303, this 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. Results demonstrated a reduction in sSOL of ‑12 minutes (95% Confidence Interval [CI]: ‑18, ‑8; p<0.001) and ‑15 minutes (95% CI: ‑17, ‑7; p<0.001) for Dayvigo 5 mg and Dayvigo 10 mg, respectively, compared to placebo.

In Study 304, 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), measured by overnight polysomnography (PSG) monitoring and defined as the number of minutes from lights off to the first 10 consecutive minutes of non-wakefulness. Results demonstrated a reduction in LPS of ‑11 minutes (95% CI: ‑15, ‑6; p<0.001) and ‑13 minutes (95% CI: ‑17, ‑9; p<0.001) for Dayvigo 5 mg and Dayvigo 10 mg, respectively, compared to placebo.

Both doses met pre-defined secondary efficacy endpoints, as demonstrated by improvements in sleep efficiency and sleep maintenance compared to placebo. These findings were observed both early in treatment and at the end of treatment. The robustness of these findings was supported by responder analyses.

The clinical safety of Dayvigo was based on data from 20 clinical studies involving 3,371 participants. Overall, of the 2,825 participants with sleep disorders who were studied, 1,848 received Dayvigo, 714 received placebo, and 263 received an active-comparator. In a pooled safety analysis of Study 303 and Study 304 (Phase III Pool), as of the Day 120 safety update, when adjusted by duration of exposure (patients per patient-year), the overall incidence of treatment-emergent adverse events (TEAEs) for participants treated with Dayvigo 5 mg, Dayvigo 10 mg, and placebo was 1.1, 1.2, and 1.6 patients per patient-year, respectively. Similarly, when adjusted by duration of exposure, the overall rate (events per patient-year) of TEAEs was 3.1, 3.1, and 3.3 events per patient-year, for Dayvigo 5 mg, Dayvigo 10 mg, and placebo, respectively. The most frequently reported TEAE in the Phase III Pool was somnolence, which appeared to be dose-dependent and occurred at a higher incidence in the Dayvigo 5 mg and Dayvigo 10 mg groups (6.9% and 11.2%, respectively) compared to placebo (1.7%). This was also the most frequently reported reason for study discontinuation. The incidence and rate of treatment-emergent serious adverse events (SAEs), when adjusted by duration of exposure, did not differ between participants treated with Dayvigo or placebo (both <0.1 events per patient-year). There also appeared to be a dose-related signal for parasomnias (such as confusional arousals, sleep terrors, sleep-related eating disorders, sleep paralysis, nightmare disorder, exploding head syndrome, sleep-related hallucinations, and somnambulism) that occurred solely in the Dayvigo groups. There were two incidences of potential complex sleep behaviors. This has been added to the Warnings and Precautions section of the Product Monograph.

When participants were awakened in the middle of the night, Dayvigo (10 mg) impaired postural stability and worsened performance on tests of attention and memory. Next day driving may be affected in some individuals. A blinded independent adjudication committee evaluated potential events of cataplexy and seizure. No cases of cataplexy or potential cataplexy were adjudicated as cataplexy, however, the adjudicators could not reach agreement on one case. One patient experienced seizure following administration of a 25 mg (supratherapeutic) dose. Abuse liability was similar to other sleep aids. However, no evidence of abuse or diversion was observed. Overall, there did not appear to be a difference in the safety profile based on the age or sex of the participants.

Notable uncertainties include the effect of exposure to Dayvigo during pregnancy on the fetus, to infants of breast-feeding women, and in patients with severe hepatic impairment, moderate to severe obstructive sleep apnea or chronic obstructive pulmonary disease.

A Risk Management Plan (RMP) for Dayvigo was submitted to Health Canada. Upon review, the RMP was considered to be acceptable with revisions and follow-up required.

Overall, the studies provided evidence of safety and efficacy of Dayvigo, at both 5 mg and 10 mg doses, as measured by shorter time to sleep onset, improvement in sleep maintenance, and more time spent asleep compared to placebo.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Dayvigo Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name assessment was conducted, including testing for look‑alike sound‑alike attributes, and the proposed name Dayvigo was accepted.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Dayvigo?

 

Submission Milestones: Dayvigo

Submission Milestone Date
Pre-submission meeting 2019-05-23
Submission filed 2019-08-30
Screening  
Screening Deficiency Notice issued 2019-10-17
Response filed 2019-11-26
Screening Acceptance Letter issued 2020-01-10
Review  
Review of Risk Management Plan complete 2020-09-16
Quality Evaluation complete 2020-10-19
Labelling Review complete 2020-10-30
Clinical/Medical Evaluation complete 2020-11-02
Notice of Compliance issued by Director General, Therapeutic Products Directorate 2020-11-04

 

The Canadian regulatory decision on the review of Dayvigo was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration was used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Dayvigo?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Dayvigo is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Lemborexant, the medicinal ingredient in Dayvigo, belongs to the pharmacologic class of dual orexin receptor antagonists. The two variants of the orexin molecule (orexin A and orexin B) play an important role in the human sleep-wake cycles. Orexin A acts nonselectively on both the orexin‑1 receptor (OX1R) and orexin‑2 receptor (OX2R), while Orexin B acts more selectively on OX2R. Unlike most current medications used to treat insomnia, which act on the gamma-aminobutyric acid receptor, lemborexant exerts its hypnotic effects through reversible competitive binding to, and inhibition of, the wakefulness effects of orexin on OX1R and OX2R, with a stronger affinity to OX2R. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.

In healthy participants, the pharmacokinetic profile of lemborexant was examined after the administration of single doses ranging from 1 mg to 200 mg and multiple doses ranging from 2.5 mg to 75 mg given once daily for 14 days. Lemborexant was rapidly absorbed, with a time to peak plasma concentration (tmax) of approximately 1 to 3 hours. Absorption characteristics were approximately linear with the extent of accumulation of lemborexant at steady state being 1.5‑ to 2‑fold across the dose range. A multi-exponential decline in plasma concentration was observed after peak plasma concentration (Cmax) was reached.

The ingestion of Dayvigo with a high-fat meal resulted in a slight decrease in the rate of absorption, as demonstrated by a 23% decrease in the Cmax of lemborexant, a delay in tmax of 2 hours, and an 18% increase in total exposure (area under the plasma concentration versus time curve [AUC] from zero to infinite time [AUC0‑inf]). Therefore, time to sleep onset may be delayed if Dayvigo is taken with or soon after a meal.

In population pharmacokinetic analyses, the apparent volume of distribution of lemborexant was approximately 1,970 L. Protein binding of lemborexant and its major circulating metabolite, M10, ranged from 87.4% to 88.7% and 91.5% to 92.0%, respectively, at concentrations of 100 ng/mL to 1,000 ng/mL. At these concentrations in vitro, lemborexant was bound primarily to human serum albumin, low-density lipoprotein, and high-density lipoprotein. In vitro blood to plasma concentration ratios of lemborexant and M10 in humans were 0.610 to 0.656 and 0.562 to 0.616, respectively, at concentrations of 100 ng/mL to 1,000 ng/mL.

Lemborexant metabolism is primarily metabolized by cytochrome P450 (CYP) 3A4, and to a lesser extent by CYP3A5. The contribution of the major circulating metabolite, M10 (12% of parent drug), to the pharmacologic activity of lemborexant is thought to be minimal given that the unbound systemic exposure of M10 is significantly lower and that it is a P‑glycoprotein substrate with less brain penetration compared to lemborexant.

Following oral administration of a radiolabeled dose of lemborexant, the primary route of elimination was through the feces, with 57.4% of the dose recovered in the feces and 29.1% in the urine. The percent of lemborexant excreted unchanged in the urine is negligible (<1% of the dose). The effective half-life for lemborexant 5 mg and 10 mg is 17 hours and 19 hours, respectively.

Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic insufficiency increased lemborexant AUC0‑inf and Cmax by approximately 1.2‑ to 1.5‑fold. The terminal half-life was 1.1‑ and 1.6‑fold longer in patients with mild and moderate hepatic impairment, respectively. The maximum recommended dose for patients with moderate hepatic insufficiency is 5 mg per day. No dose adjustment is recommended for mild hepatic insufficiency. Since no data are available for patients with severe hepatic insufficiency, lemborexant is not recommended for use in this population.

Severe renal impairment (urinary creatinine clearance ≤30 mL/min/1.73m2) increased lemborexant exposure (AUC0‑inf) 1.5‑fold but had no effect on Cmax and terminal half-life. No dose adjustment is required in patients with renal impairment.

The co-administration of lemborexant with moderate or strong inhibitors of CYP3A is not recommended due to potential drug interactions. When co-administered with weak CYP3A inhibitors, the maximum recommended dose of Dayvigo is 5 mg no more than once per night. Co-administration of Dayvigo with CYP3A inducers is not recommended due to the potential for a decrease in Dayvigo efficacy.

Lemborexant weakly induces CYP2B6 based on a study with bupropion as a CYP2B6 substrate. Substrates of CYP3A and CYP2B6 can be co-administered with Dayvigo; however, physicians should monitor patients for changes related to reduced efficacy of CYP2B6 substrates.

Sex, body mass index, and race had no clinically meaningful changes on lemborexant pharmacokinetics. Therefore, no dose adjustment is required based on these factors.

Co-administration with alcohol is not recommended due to additive effects on lemborexant concentrations. Lemborexant can be co-administered with gastric acid-reducing agents and oral contraceptives.

Overall, the clinical pharmacological data support the use of Dayvigo for the recommended indication.

For further details, please refer to the Dayvigo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Dayvigo was demonstrated in two pivotal multicentre, randomized, double-blind, placebo-controlled Phase III studies (Study 303 [Study 1 in the Dayvigo Product Monograph] and Study 304 [Study 2 in the Dayvigo Product Monograph]) in patients who met the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM‑5) criteria for insomnia disorder.

Study 303 was a 6‑month study conducted in patients ≥18 years of age that compared the efficacy of Dayvigo on subjective sleep measures, as recorded daily by study patients in a sleep diary. Patients were randomized to receive Dayvigo 5 mg (number of patients [n] = 319), Dayvigo 10 mg (n = 319), or placebo (n = 321) once daily. The demographic and baseline characteristics of patients were similar across treatment arms. Overall, patients had a median age of 55 years (range: 18 to 88 years of age) with 28% being ≥65 years of age. Further, 68% were female, 72% were White, 8% were Black or African American, 17% were Japanese, and 3.5% were another race. In addition to measuring subjective efficacy parameters, Study 303 included a 6‑month extension period to assess the safety in participants taking Dayvigo for up to one year (see Clinical Safety).

Study 304 was a 1‑month study conducted in female patients ≥55 years of age and male patients ≥65 years of age. Patients were randomized to receive Dayvigo 5 mg (n = 266), Dayvigo 10 mg (n = 269), placebo (n = 208), or active comparator (n = 263) once nightly. The demographic and baseline characteristics of participants were similar across treatment arms. Overall, patients had a median age of 63 years (range: 55 to 88 years) with 45% being ≥65 years of age. Further, 86% were female, 72% were White, 25% were Black or African American, and 2% were another race.

The primary efficacy endpoint of both studies was to demonstrate a reduction in time to sleep onset. In Study 303, this was measured by 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. In Study 304, time to sleep onset was measured by the mean change from baseline to end of treatment (Days 29/30) in log-transformed latency to persistent sleep (LPS), defined as the number of minutes from lights off to the first 10 consecutive minutes of non-wakefulness. This was measured by overnight polysomnography (PSG) monitoring. Both sSOL and LPS are measured in minutes, with a decrease in value indicating improvement in terms of taking less time to fall asleep.

In Study 303, the pre-specified secondary efficacy endpoints that were controlled for Type I error were change from baseline to end of treatment (at 6 months) for patient-reported (subjective) sleep efficiency (sSEF), defined as the proportion of time spent asleep per time spent in bed, and patient-reported (subjective) wake after sleep onset (sWASO), defined as the minutes of wake from the onset of sleep until wake time. In Study 304, the pre-specified secondary efficacy endpoints, measured objectively using PSG monitoring, were mean change from baseline to end of treatment (Days 29/30) in sleep efficiency (SEF), defined as the proportion of time spent asleep per time spent in bed, and wake after sleep onset (WASO), defined as the minutes of wake from the onset of sleep until wake time.

Study 303 and Study 304 demonstrated statistical significance in their primary efficacy endpoints, with improved (reduced) time to sleep onset for patients with insomnia, regardless of dose (5 mg or 10 mg) or age. In Study 303, the mean change from baseline in time for sSOL at 6 months, compared to placebo, for Dayvigo 5 mg and Dayvigo 10 mg was ‑12 minutes (95% Confidence Interval [CI]: ‑18, ‑8; p<0.001) and ‑15 minutes (95% CI: ‑17, ‑7; p<0.001), respectively. In Study 304, the mean change from baseline in time for LPS at Days 29/30, compared to placebo, for Dayvigo 5 mg and Dayvigo 10 mg was ‑11 minutes (95% CI: ‑15, ‑6; p<0.001) and ‑13 minutes (95% CI: ‑17, ‑9; p<0.001), respectively. The robustness of these findings was supported by responder analyses. In Study 303, a responder for sSOL was defined as an sSOL value at baseline of ≥30 minutes and a mean sSOL at 6 months of ≤20 minutes. For both doses of Dayvigo, there was a significantly greater number of responders compared to placebo. In Study 304, the inclusion criteria did not require patients to have sleep onset complaints; therefore, approximately 40% of patients were not eligible for the responder analysis. There were no statistically significant differences in the proportion of responders on LPS for either dose of Dayvigo compared to placebo after either of the first two doses or at the end of one month of treatment. However, when data from these patients' sleep diaries were assessed, the difference in the proportion of responders on sSOL was significantly higher for both doses of Dayvigo compared to placebo after both the first two doses and at the end of one month of treatment.

In both studies, the secondary endpoint of sleep efficiency demonstrated statistically significant improvement and was clinically meaningful. In Study 303, the least squares mean (LSM) change from baseline for sSEF as a percentage at 6 months, compared to placebo, for Dayvigo 5 mg and Dayvigo 10 mg was 5% (95% CI: 2.2, 6.9; p<0.001) and 5% (95% CI: 2.4, 7.0; p<0.01), respectively. In Study 304, the LSM change from baseline for SEF as a percentage on Days 29/30, compared to placebo, for Dayvigo 5 mg and Dayvigo 10 mg was 7% (95% CI: 5.6, 8.5; p<0.001) and 8 % (95% CI: 6.6, 9.5; p<0.001), respectively. In addition, improvements in sleep efficiency were also observed early in treatment (Days 1/2 in Study 304 and at one week in Study 303).

For the secondary endpoint of sleep maintenance, the number of minutes of wake time after sleep onset was reduced significantly in both studies. In study 303, the LSM change from baseline in time for sWASO at 6 months, compared to placebo, for Dayvigo 5 mg and Dayvigo 10 mg was ‑17 minutes (95% CI: ‑27, ‑8; p<0.001) and ‑13 minutes (95% CI: ‑22, ‑3; p<0.05), respectively. In Study 304, the LSM change from baseline in time for WASO at Days 29/30, compared to placebo, for Dayvigo 5 mg and Dayvigo 10 mg was ‑24 minutes (95% CI: ‑30, ‑18; p<0.001) and ‑25 minutes (95% CI: ‑31, ‑19; p<0.001), respectively. This effect was also observed both early in the study (after one week in Study 303 and on Days 1/2 in Study 304), as well as throughout the 6 months of Study 303 (i.e., at Month 3 and Month 6; no significant difference was found at Month 1). A sleep maintenance responder in Study 303 was defined as a sWASO at baseline of ≥60 minutes and a mean sWASO at 6 months of ≤60 minutes, as well as a reduction of >10 minutes compared to baseline. In Study 304, a similar 10‑minute improvement in sleep was required to be considered a responder. For both studies, the difference in the proportion of responders on sWASO and WASO was significantly higher for both doses of Dayvigo compared to placebo after both the first two doses and at the end of one month of treatment.

Overall, the results from the primary and key secondary efficacy endpoints, as well as exploratory endpoints, provide consistent and complementary evidence for the effectiveness of Dayvigo at both 5 mg and 10 mg doses. Patients treated with Dayvigo reported shorter time to sleep onset, improvement in sleep maintenance, and more time spent asleep compared to those treated with placebo. This was demonstrated consistently throughout the entire study period of both pivotal studies, further demonstrating the persistence of effect. The results from these studies were statistically significant, clinically meaningful, and were supported by both objective and patient-reported measures. In addition, responder analyses supported the robust effects of both doses of Dayvigo compared to placebo on sleep onset and sleep maintenance.

The elderly population (patients ≥65 years of age) was well represented in the Dayvigo development program, and efficacy results were generally consistent for elderly and nonelderly populations. Both pivotal studies had a much higher proportion of females to males; however, this imbalance is representative of the general population, which sees higher rates of insomnia disorder amongst females. In general, the results favoured Dayvigo treatment in most subgroups (male/female/body mass index/age, etc.) and for most endpoints analyzed.

The results in Study 303 and Study 304 on the primary endpoint (sSOL/LPS) did not demonstrate that the higher dose, 10 mg, performed better than the lower dose, 5 mg. The reason for this is unclear. However, it is possible that efficacy of this product plateaus somewhere between the 5 mg and 10 mg doses due to adequate receptor occupancy to elicit sleep. This explanation is supported by a Phase II proof-of-concept study, using objective PSG measurements, where there did not appear to be an added efficacy benefit between the 10 mg and 25 mg doses. Although Dayvigo 10 mg was not markedly more beneficial than Dayvigo 5 mg when comparing mean treatment effects, the proportion of patients with different magnitudes of response suggests that, for some patients, the 10 mg dose may provide the optimal benefit. This finding, taken together with the pharmacokinetic/pharmacodynamic analysis, which demonstrated incremental benefit in efficacy for higher doses, supports the benefit of having both doses available to the public. As such, the Dosing and Administration section of the Dayvigo Product Monograph states that patients should use the lowest effective dose. The recommended dose is 5 mg, which may be increased to 10 mg based on clinical response and tolerability.

In summary, sufficient evidence was provided to support the efficacy of both 5 mg and 10 mg of Dayvigo for use in patients for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance.

Indication

The New Drug Submission for Dayvigo was filed by the sponsor with the following indication:

  • Dayvigo (lemborexant) is indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance, with or without associated impairment in daily functioning.

Health Canada approved the following indication:

  • Dayvigo (lemborexant) is indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance.

Consistent with this class of drugs, the indication includes a statement to specify that sleep disturbance may be the presenting manifestation of a physical and/or psychiatric disorder. Consequently, a decision to initiate symptomatic treatment of insomnia should only be made after the patient has been carefully evaluated.

For more information, refer to the Dayvigo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Dayvigo was based on data from 20 clinical studies involving 3,371 participants. Of these studies, 16 were Phase I and evaluated single or multiple doses of Dayvigo (1 mg to 200 mg), 1 was a Phase II proof-of-concept/dose-selection study, 1 was a Phase II study conducted in participants not related to the indicated population, and 2 were Phase III studies (Study 303 and Study 304; see Clinical Efficacy).

Overall, of the 2,825 participants studied with sleep disorders, 1,848 received Dayvigo, 714 received placebo, and 263 received an active-comparator. In this group, there was a total of 685.6 patient-years of exposure to Dayvigo (5 mg: 344.6 patient-years, 10 mg: 328.8 patient-years), with 434 participants (5 mg: 230 participants, 10 mg: 204 participants) having been exposed for ≥12 months. The mean duration of Dayvigo exposure was 135.8 days (5 mg: 150.7 days, 10 mg: 137.2 days). This database was sufficient in exposure and exceeded the International Council for Harmonisation guidelines (ICH E1) for assessment of drugs intended for long-term treatment of non-life threatening conditions. Approximately 40% of participants in the development program were elderly (≥65 years of age).

In a pooled safety analysis of Study 303 and Study 304 (Phase III Pool), as of the Day 120 safety update, the overall incidence of treatment-emergent adverse events (TEAEs) for participants treated with Dayvigo 5 mg, Dayvigo 10 mg, and placebo was 52.3%, 52.6%, and 47.9%, respectively. It should be noted that due to study designs, the duration of exposure for Dayvigo 5 mg and Dayvigo 10 mg was longer (up to 12 months) compared to placebo (up to 6 months). Therefore, TEAEs unrelated to the study drug were more likely to be reported in the Dayvigo treatment groups. When adjusted by duration of exposure (patients per patient-year), the overall incidence of TEAEs for Dayvigo 5 mg, Dayvigo 10 mg, and placebo was 1.1, 1.2, and 1.6 patients per patient-year, respectively. Similarly, when adjusted by duration of exposure, the overall rate (events per patient-year) of TEAEs was 3.1, 3.1, and 3.3 events per patient-year, respectively. The most frequently reported TEAE in the Phase III Pool was somnolence, which appeared to be dose-dependent and occurred at a higher incidence in the Dayvigo 5 mg and Dayvigo 10 mg groups (6.9% and 11.2%, respectively) compared to placebo (1.7%). There were no differences in safety profile based on age or sex of the participants.

In the Phase III Pool, the overall incidence and rate of treatment-emergent serious adverse events (SAEs), when adjusted by duration of exposure, did not differ between participants treated with Dayvigo or placebo (both <0.1 events per patient-year). There were no differences in treatment-emergent SAEs based on intrinsic factors, including age, sex, and body mass index of patients. Notably, the incidence of treatment-emergent SAEs in the elderly (≥65 years of age) was consistent with that in younger patients. There was one event of seizure in the Phase II dose-ranging study at a dose of 25 mg, discussed further below. In the Phase III Pool, there was a low overall incidence of TEAEs leading to discontinuation for participants treated with Dayvigo 5 mg, Dayvigo 10 mg, and placebo (3.5%, 6.2%, and 2.7%, respectively), with somnolence being the most common.

Due to the different durations of Study 303 and Study 304, it was determined that simple pooling of the adverse events from both studies would be difficult to interpret. Therefore, Health Canada's review of TEAEs relied heavily on the United States Food and Drug Administration's (FDA) review of pooled data from the first 30 days of both studies. In the FDA safety review, a number of preferred terms for related events were pooled together in a single analysis to determine if a safety signal existed. A signal was confirmed for somnolence-related events (somnolence, fatigue, and sedation) that was dose-related, with a risk difference (all Dayvigo vs. placebo) of 18.9 events per 100 patient-years. Parasomnias (confusional arousals, sleep terrors, sleep-related eating disorders, sleep paralysis, nightmare disorder, exploding head syndrome, sleep-related hallucinations, and somnambulism) were also dose-related, at a rate of 4.3 events per 100 patient-years, compared to none in the placebo group.

Additionally, a number of events of clinical interest were selected for the clinical program based on labelled safety concerns for other marketed hypnotic medications, and due to theoretical safety considerations for lemborexant. Some of these events were studied specifically in separate Phase I studies, while other events were assessed more in depth as TEAEs occurring within clinical studies. These TEAEs are described below and included next-day impairment, middle of the night safety, suicidality, abuse liability, falls and fractures, cataplexy, complex sleep behaviors, and seizure. Adverse events suggestive of cataplexy or seizure were submitted to a blinded external committee of experts for evaluation and adjudication as potential cataplexy.

Next-day impairment

When mean treatment group differences were compared, mean driving performance was not impaired in an on-road driving study that took place the next morning approximately 9 hours after a single dose of Dayvigo or after multiple doses (eight consecutive nights of treatment) of Dayvigo. However, some participants receiving Dayvigo 10 mg demonstrated driving impairment, suggesting variability in effects at this dose. Notably, this test did not measure reaction time or effects on executive functioning (decision-making), nor did it measure the effects of Dayvigo use after shorter periods of sleep. The variability observed at the 10 mg dose was reported in the Dayvigo Product Monograph. No clinically meaningful group differences between Dayvigo and placebo were observed on morning postural stability. Based on self-reported daily assessments using the Sleep Diary, participants generally rated themselves as more alert after treatment. No differences in tests of memory upon awakening were observed between patients who had received Dayvigo versus those who had received placebo. Reaction time tests of performance showed no impairment across the day. However, a greater reaction time was noted on the psychomotor vigilance test in participants who received Dayvigo 10 mg. These effects primarily appeared in the first few days of treatment and diminished thereafter.

Middle of the night safety (measured approximately 4 hours post-dose upon awakening)

Dayvigo did not impair the ability to awaken to an auditory stimulus. Participants receiving Dayvigo 5 mg and Dayvigo 10 mg showed higher body sway than those who received placebo upon a scheduled awakening. For patients treated with Dayvigo 5 mg, there was no impact on the performance of any tests of attention or memory in the middle of the night. Performance was worse for these tasks in patients treated with Dayvigo 10 mg when compared with placebo. Results in the elderly (≥65 years of age) were consistent with those in younger participants.

Safety Issues of Special Interest

There was no signal of suicidality during Dayvigo treatment. There was also no evidence for abuse or diversion of study medication in the Dayvigo clinical studies. In a human abuse liability study, recreational sedative users rated Dayvigo with similar scores on positive subject measures to other common sleep aids. Thus, the Dayvigo Product Monograph includes information on the increased risk for abuse and/or addiction for those with a history of substance abuse or addiction. There was no signal of withdrawal symptoms following Dayvigo discontinuation (from 1 month to 1 year of use). Upon discontinuation of Dayvigo use, no evidence for rebound insomnia was observed. That is, symptoms of insomnia were no worse than those reported prior to initiating Dayvigo use, indicating that insomnia was not worsened. No safety signal was found for falls and fractures. However, a general warning about the increased potential for falls with the use of hypnotics, particularly in the elderly, was added to the Dayvigo Product Monograph, consistent with labelling for this class of drug.

An independent adjudication committee blinded to treatment groups assessed cases of cataplexy and potential cataplexy in the development program. No cases were adjudicated as cataplexy, however, agreement was not reached on one case. As this is a known concern for orexin receptor antagonists, language was included in the Dayvigo Product Monograph, in line with other orexin receptor antagonists about the potential risks for this event.

There were two incidences of potential complex sleep behaviors in Dayvigo-treated participants: one incident where a participant awoke during a vivid dream to find that she was acting out writing a letter and one participant who reported an event of somnambulism. A warning is included in the Dayvigo Product Monograph for the risk of complex sleep behaviors.

There was one event (two episodes on the same night) of seizure in the development program in a participant who received a 25 mg dose of Dayvigo (2.5‑fold the highest recommended dose) with no prior history of seizure. A positive dechallenge was reported and the investigator and adjudication committee reported the event as drug-related. However, a follow-up appointment with a neurologist suggested the event was not related to Dayvigo use.

A dedicated QT study was not conducted, however, electrocardiogram and Holter monitoring in Phase I studies and modeling suggested no QT effects are anticipated. Further, suvorexant, a similar compound to lemborexant, showed no QT prolonging effects. The Dayvigo Product Monograph includes information about the predicted QT response based on modelling data.

The respiratory safety of Dayvigo was assessed in patients with mild obstructive sleep apnea (OSA) where there were no significant differences observed compared to those treated with placebo. Dayvigo was not studied in patients with moderate to severe OSA or chronic obstructive pulmonary disease (COPD), therefore, it is unknown if any respiratory effects of Dayvigo would occur in these patients. In addition, no data on pregnant or lactating women or in pediatric populations were provided. These issues have been addressed through appropriate labelling in the Dayvigo Product Monograph.

A Risk Management Plan (RMP) for Dayvigo was submitted to Health Canada. Upon review, the RMP was considered to be acceptable with revisions and follow-up required.

The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

Overall, the Dayvigo safety profile supports its use for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. The approval of Dayvigo is acceptable from a safety perspective.

Appropriate warnings and precautions are in place in the approved Dayvigo Product Monograph to address the identified safety concerns.

For more information, refer to the Dayvigo Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

No mortality was observed in single-dose toxicity studies in rats and primates at oral doses of up to 1,000 mg/kg, which resulted in systemic exposures that were 106‑ to 217‑times (in rats) and 193‑ to 219‑times (in primates) the clinical exposure (measured as area under the plasma concentration versus time curve [AUC]) at the maximum recommended human dose (MRHD) of 10 mg.

In repeat-dose toxicity studies in rodents, lemborexant induced minor changes in clinical pathology parameters and decreases in body weight gain and food consumption. Increased liver weights and hepatocyte hypertrophy were consistent with microsomal enzyme induction, which is well described to be rodent-specific. Adverse changes were observed in bone (histologic structural changes, decreased bone mineral density, and bone fracture) and teeth (discoloration and histologic changes in ameloblasts) consistent with fluorosis at ≥100 mg/kg/day in females and at 1,000 mg/kg/day in males. Several investigational studies revealed that these changes were a result of animal-specific defluorination of lemborexant during metabolism. Defluorinated metabolites were not reported to have been identified in humans. No adverse effects were observed in rats at exposures 41‑times (males) and 12‑times (females) the clinical exposure at the MRHD of 10 mg.

In repeat-dose studies in primates, lemborexant-related findings included vomiting or abnormal stool, minor changes in clinical pathology parameters, and hepatocellular hypertrophy at doses ≥100 mg/kg/day. A minor but dose-dependent increase in urinary fluoride excretion was observed without any adverse changes in the bone. No adverse effects were observed in primates at 12‑times the clinical exposure at the MRHD of 10 mg.

Lemborexant was negative in in vitro and in vivo genotoxicity assays, and did not result in an increase in tumors in a 26‑week study in Tg‑rasH2 mice or a 2‑year study in rats.

In developmental and reproductive toxicity studies, treatment with lemborexant resulted in maternal toxicity at the highest doses of 100 mg/kg/day and 1,000 mg/kg/day, with embryotoxicity and fetal malformations in the presence of maternal toxicity in rats and skeletal variations, but no embryotoxicity or malformations, in rabbits. Lemborexant had no effect on male fertility, but did decrease female fertility. This was likely related to both maternal toxicity as well as the potential for orexin inhibition. Oral administration to pregnant rats during gestation and lactation resulted in decreases in body weights, femur lengths, and acoustic startle responses in offspring. The no-observed-adverse-effect level (NOAEL) doses in the developmental and reproductive toxicity studies provide an adequate exposure ratio (i.e., >10) relative to exposure at the MRHD.

Lemborexant did not induce physical or reinforcing effects in rats or rhesus monkeys, suggesting low potential for drug abuse.

In vitro and in vivo studies supported the proposed mechanism of action of lemborexant. Its main metabolites, M4, M9, and M10, are found in humans and animals, and have similar antagonistic effects on orexin receptors. Off-target effects include inhibition of melatonin 1A receptors.

Lemborexant caused emotion-induced cataplexy in mice at therapeutic doses when co-administered with a strong positive emotional stimulus (such as chocolate).

Neither tolerance of pharmacologic effect nor rebound effect were observed in rats within 2 days of chronic (24 day) daily treatment of lemborexant at 30 mg/kg/day.

Lemborexant at therapeutic and high doses (30, 100, and 300 mg/kg) did not affect motor coordination on accelerating rotarod with trained mice.

Potential cardiovascular issues were noted. Lemborexant and its metabolites decreased human ether-à-go-go-related gene (hERG) ion channel currents in a concentration-dependent manner. Lemborexant prolonged field potential duration in stem cell-derived cardiomyocytes in a concentration-dependent manner and had a partial inhibition on slowly activating delayed rectifier potassium (IKs) currents that was not concentration-dependent. In a cardiovascular study using monkeys, lemborexant resulted in significantly increased QTc intervals at high doses.

The pharmacokinetic profile of lemborexant was different between rats and cynomolgus monkeys. In both, lemborexant showed low bioavailability. However, in rats, peak plasma concentration (Cmax) was not linear and area under the plasma concentration versus time curve from time zero to the last measurable concentration (AUC0-t) and from zero to infinite time (AUC0‑inf) increased more than dose proportionally. In monkeys, Cmax, AUC0-t, and AUC0‑inf were dose-proportional. After a single intravenous administration, lemborexant had a moderately high clearance in rats (2,730 to 2,870 mL/h/kg), while in monkeys, clearance was moderate (1,210 to 1,190 mL/h/kg). The steady state volume of distribution was moderate and similar between species.

Pharmacokinetic studies were generally performed in fasted animals, which may have increased absorption rate. Lemborexant was rapidly absorbed and distributed in all tissues within an hour of oral administration, with plasma concentrations decreasing rapidly thereafter. It easily crossed the blood-brain barrier. Metabolites M4, M9, and M10 had high plasma concentrations that reached cerebrospinal fluid (CSF) one hour after administration in both rats and monkeys. However, in rats, the CSF to unbound plasma concentration ratio was higher for lemborexant than its metabolites. This was not the case in monkeys, suggesting a species-specific distribution profile. Lemborexant crossed the placental barrier on gestation day 13 and 18, reaching the fetal brain.

The major metabolic pathways for lemborexant are the oxidation of demethylpyrimidine moiety or fluorophenyl moiety of lemborexant and subsequent further oxidation or glutathione conjugation of metabolites in rats or subsequent sulfation or glucuronidation of metabolites in monkeys.

Lemborexant is primarily eliminated in the feces. It is also excreted in rat milk, along with its metabolites, at concentrations higher than maternal plasma, with a Cmax milk/plasma ratio of 6 and an AUC milk/plasma ratio of 3.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Dayvigo Product Monograph. In view of the intended use of Dayvigo, there are no pharmacological/toxicological issues within this submission that preclude authorization of the product. Appropriate warnings and precautionary measures are in place in the Dayvigo Product Monograph to address the identified safety concerns.

No evidence of lemborexant abuse liability was found in the non-clinical studies.

For more information, refer to the Dayvigo Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Dayvigo has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e. within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

Lactose monohydrate is the only excipient of animal origin used in the manufacture of Dayvigo tablets. The lactose monohydrate used in production of Dayvigo tablets is derived from bovine milk and is manufactured in accordance with compendial monographs. A letter of attestation confirming that the materials are in accordance with Public Statement EMEA/CPMP/571/02 of February 27, 2002 has been provided, indicating that the BSE risk in pharmaceutical grade lactose is negligible and that it is considered to be safe for human use.

 

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