DAYVIGO: Package Insert and Label Information (Page 2 of 4)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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.

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 Warning s 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 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

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)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

DAYVIGO contains lemborexant, a Schedule IV controlled substance.

9.2 Abuse

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.

9.3 Dependence

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.

10 OVERDOSAGE

There is limited clinical experience with DAYVIGO overdose. In clinical pharmacology studies, healthy patients who were administered multiple doses of up to 75 mg (7.5 times the maximum recommended dose) of DAYVIGO showed dose-dependent increases in the frequency of somnolence.

There is no available specific antidote to an overdose of DAYVIGO. In the event of overdose, standard medical practice for the management of any overdose should be used. In managing overdose, provide supportive care, including close medical supervision and monitoring and consider the possibility of multiple drug involvement. Consult a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222 or www.poison.org).

The value of dialysis in the treatment of overdosage has not been determined with lemborexant. As lemborexant is highly protein-bound, hemodialysis is not expected to contribute to elimination of lemborexant.

11 DESCRIPTION

DAYVIGO contains lemborexant, an orexin receptor antagonist. The chemical name of lemborexant is (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N -(5-fluoropyridin-2-yl) cyclopropanecarboxamide. The molecular formula is C₂₂ H₂₀ F₂ N₄ O₂ . The molecular weight is 410.42.

The structural formula is:

(click image for full-size original)

Lemborexant is a white to off-white powder that is practically insoluble in water.

DAYVIGO tablets are intended for oral administration. Each film coated tablet contains 5 mg or 10 mg of lemborexant. The inactive ingredients are: hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, and magnesium stearate.

In addition, the film coating contains the following inactive ingredients: hypromellose 2910, polyethylene glycol 8000, talc, titanium dioxide, and either (a) ferric oxide yellow for the 5 mg tablet; or, (b) both ferric oxide yellow and ferric oxide red for the 10 mg tablet.

12 CLINICAL PHARMACOLOGY

Figure 1. Effects of Hepatic and Renal Impairment on Lemborexant PharmacokineticsFigure 2. Effects of Co-administered Drugs on the Pharmacokinetics of Lemborexant 10 mgFigure 3. Effects of Lemborexant 10 mg on the Pharmacokinetics of Co-Administered Drugs

12.1 Mechanism of Action

The mechanism of action of lemborexant in the treatment of insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system plays a role in wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.

12.2 Pharmacodynamics

Lemborexant binds to orexin receptors OX1R and OX2R and acts as a competitive antagonist (IC₅₀ values of 6.1 nM and 2.6 nM, respectively). A major metabolite of lemborexant, M10, binds with comparable affinity as the parent drug to orexin receptors OX1R and OX2R (IC₅₀ values of 4.2 nM and 2.9 nM), respectively.

Cardiac Electrophysiology

In a concentration-QTcF analysis using the data from two randomized, double-blind, placebo-controlled, multiple ascending dose studies in healthy subjects, lemborexant does not prolong the QTcF interval to any clinically relevant extent at a dose 5 times the maximum recommended dose.

Drug Interactions

Lemborexant co-administered with alcohol produced a numerically greater negative impact on postural stability and memory as compared with alcohol alone at approximately 2 hours post-dose [see Drug Interactions 7.1].

12.3 Pharmacokinetics

Following single doses of lemborexant 2.5 to 75 mg, geometric mean C_max and AUC_0-24h increased slightly less than in proportion to dose. The extent of accumulation of lemborexant at steady-state is 1.5- to 3-fold across this dose range.

Absorption

The time to peak concentration (t_max ) of lemborexant is approximately 1 to 3 hours.

Effect of Food

Lemborexant C_max decreased by 23%, AUC_0-inf increased by 18%, and t_max was delayed by 2 hours following administration of a high-fat and high-calorie meal (containing approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively).

Distribution

The volume of distribution of lemborexant is 1970 L. Plasma protein binding of lemborexant is approximately 88% in vitro and 94% in clinical samples. The blood to plasma concentration ratio of lemborexant is 0.65.

Elimination

Metabolism

Lemborexant is primarily metabolized by CYP3A4, and to a lesser extent by CYP3A5. The major circulating metabolite is M10.

Excretion

Following administration of an oral dose, 57.4% of the dose was recovered in the feces and 29.1% in the urine (<1% as unchanged). The effective half-life for lemborexant 5 mg and 10 mg is 17 and 19 hours, respectively.

Specific Populations

No clinically significant differences in the pharmacokinetics of lemborexant were observed based on age, sex, race/ethnicity, or body mass index. No studies have been conducted to investigate the pharmacokinetics of lemborexant in pediatric patients. Exposures of lemborexant in patients with hepatic and renal impairment are summarized in Figure 1.

Figure 1. Effects of Hepatic and Renal Impairment on Lemborexant Pharmacokinetics

Drug Interaction Studies

The effects of other drugs on the exposures of lemborexant are summarized in Figure 2. The effects of lemborexant on the exposures of other drugs are summarized in Figure 3. Based on these results, drug interactions between lemborexant and strong CYP3A inducers, strong CYP3A inhibitors, moderate CYP3A inhibitors, and CYP2B6 substrates are clinically significant [see Dosage and Administration ( 2.2), Drug Interactions ( 7.1)].

Physiologically-based pharmacokinetic (PBPK) modeling predicted that concomitant use of weak CYP3A inhibitors increased lemborexant exposure by less than 2-fold [see Dosage and Administration ( 2.2), Drug Interactions ( 7.1)] , and that lemborexant is expected to have minimal effect on the pharmacokinetics of CYP2C8, CYP2C9, or CYP2C19 substrates.

Figure 2. Effects of Co-administered Drugs on the Pharmacokinetics of Lemborexant 10 mg

Figure 3. Effects of Lemborexant 10 mg on the Pharmacokinetics of Co-Administered Drugs

In Vitro Studies

In vitro metabolism studies demonstrated that lemborexant and M10 have the potential to induce CYP3A and a weak potential to inhibit CYP3A and induce CYP2B6. Lemborexant and M10 do not inhibit other CYP isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1) or transporters (P-gp, BCRP, BSEP, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, and MATE2-K). Lemborexant and M10 do not induce CYP2C8, CYP2C9, and CYP2C19 at clinically relevant concentrations.

Lemborexant is a potential poor substrate of P-gp, but M10 is a substrate of P-gp. Lemborexant and M10 are not substrates of BCRP, OATP1B1, or OATP1B3.