1 

### U.S. Department of Justice Drug Enforcement Administration

Schedules of Controlled Substances: Placement of Suvorexant into Schedule IV Background, Data, and Analysis: Eight Factors Determinative of Control And Findings Pursuant to 21 U.S.C. 812(b)

Prepared by

Office of Diversion Control, Drug and Chemical Evaluation Section

Washington, D.C. 20537

January 20142

BASIS FOR THE RECOMMEND ATION TO PLACE SUVOREXANT IN SCH EDULE

IV OF THE CONTROLLED SUBSTANCES ACT



### I . BACKGROUND Suvorexant ( [(7 R )

- 4

- (5

- c hloro

- 1,3

- benzo x azol

- 2

- yl)

- 7

- methyl

- 1,4

- diazepan

- 1

- yl][5

- methyl

- 2

- (2 H

- 1,2,3

- triazol

- 2

- yl)phenyl]methanone; MK

- 4305), is a new chemical substa nce that is being developed by Merck for the treatment of insomnia

. S uvorexant, a novel, first in class, orexin receptor antagonist with a mechanism of action distinct from any marketed drug, acts via inhibition of the orexin 1 (OX1) and orexin 2 (OX2) receptors. Suvorexant is an oral ly active, selective, dual orexin receptor antagonist

. Clinical studies suggest s uvorexant at 10 and 40 milligrams (mg) administered orally produces sedative and sleep promoting effects. A buse liability stud ies in humans show that s uvorexant produces reinforcing effects and has a potential for abuse that is similar to that of zolpidem (Sc hedule IV). Thus, t he relative abuse potential of

s uvorexant can be evaluated by comparing with zolpidem (Schedule IV) as the comparator drug

. On J une 27, 2013 , the Department of Human Health Service (HHS) provided to the Drug Enforcement Administration (DEA) a scientific and medical evaluation entitled “Basis for the Recommendation to Place Suvorexant in Schedule I V of the Controlled Substances Act” and a scheduling recommendation. Following consideration of the eight factors and findings related to the substance’s abuse potential, legitimate medical use, and dependence liability, HHS recommended that suvorexant be controlled in Schedule I V of the C ontrolled Substances Act (CSA) under 21 U.S.C. 812(b).3

The Controlled Substances Act ( CSA ) requires DEA, as delegated by the Attorney General 1 , to determine whether HHS’s scientific and medical evaluation and all other relevant data constitute substantia l evidence of potential for abuse such that the substance should be scheduled. 21 U.S.C. 811(b).



### II . Eight Factors Determinative of Control Pursuant to 21 U.S.C. 811(c), DEA must consider eight factors in making any finding of substantial evidence of potential for abuse, including the data and law enforcement information relevant thereto.

Factor 1: Suvorexant's Actual or Relative Potential for Abuse In addition to the information HHS provided in its scientific and medical e valuation document for suvorexant , DEA considers all other r elevant data regarding suvorexant’s actual or relative poten tial for abuse. Since suvorexant is a new chemical entity and has not been marketed in the United States or in any other country, informat ion on actual abuse of suvorexant is not available. However, the legislative history of the CSA offers the following criterion for assessing a new drug or substance’s potential for abuse:

The drug or drugs containing such a substance are new drugs so related in their action to a drug or drugs already listed as having a potential for abuse to make it likely that the drug will have the same potentiality for abuse as such drugs, thus making it reasonable to assume that there may be significant diversions from legitimate channels , significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community. 2

1 28 CFR 0.100(b) 2 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91

- 1444, 91 st Cong., Sess. 1 (1970); as reprinted in 1970 U.S.C.C.A.N. 4566, 4601.4

D ata from clinical studies investigating the abuse potential of suvorexant s uggest that its effect is similar to Zolpidem. As stated in the HHS review, s uvorexant is indicated for the treatment of insomnia. With a mechanism of action that is distinct from any other marketed drug, including those marketed for insomnia (i.e. benzodiazepines , zolpidem , eszopiclone 3 and zaleplon [Schedule IV]) ,
s uvorexant acts as a n antagonist at the OX1 and OX2 receptors. A more det ailed description of the in vitro binding of suvorexant to the orexin receptors and its pharmacological effects are presented in Factor 2 and in HHS review

. The HHS review described a human abuse potential study conducted by Merck in subjects with histori es of recreational sedative use. Simi lar to zolpidem (Schedule IV), suvorexant produced reinforcing subjective effects. Through the use of visual analog scale s (VAS), the study used several assessments to characterize the subjective effects of suvorexant and zolpidem. The VAS assessments were performed by using a 100 millimeter line on a computer screen anchored at opposing ends with phrases such as “very much” and “not at all”. Foll owing a series of questions regarding the drug effects, the subjects responded to each question by placing a mark along the line indicating their response to each question. In the same human abuse potential study, doses of 40, 80 and 150 mg of suvo rexant were compared to 15 and 3 0 mg of zolpidem (Schedule IV). Suvorexant produced effects that were statistically indistinguishable from zolpidem on the primary outcome measure of the study (“at the moment” Drug Liking as assessed via a VAS). Specifically, 40, 80 and 150 mg doses of suvorexant produced peak VAS Drug Liking scores of 76.4, 75.5 and 74.0 , respectively

. The 15 and 30 mg doses of Zolpidem (Schedule IV) produced Drug Liking scores of 87.4 and 81.6 , respectively

. When tested on secondary measures of abuse potential such as Overall Drug

3 Eszopiclone is the dextrarotory stereoi somer, i.e., an isomer, of zoplicone (schedule IV).5

Liking, Take Drug Again, Any Drug Effect, assessment of subjective drug value, and overall familiarity , s uvorexant produced effects similar to zolpidem on VAS assessments. Similarl y, the effects of all doses of suvorexant o n VAS assessments of High and Good Effects were statistically indistinguishable from that of the 15 mg dose of zolpidem (Schedule IV). Similar ly, the 15 mg dose of zolpidem and suvorexant (40, 80 and 150 mg) produ ced effects that were statistically similar on the Bowdle VAS (a measure of perceptual and hallucinogenic effects)

. As stated in the HHS review, suvorexant produced less dysphoria and adverse effects than zolpidem , suggesting that suvorexant may have an i ncreased abuse potential relative to zolpidem. Study results showed that the maximum dose of zolpidem produced a significantly greater VAS rating of Bad Effects than the low (40mg) and high (150 mg) doses of suvorexant. Similarly, the highest dose of zolpidem (30 mg) produced statistically greater scores than suvorexant (40, 80 and 150 mg) on the Addiction Center Research Inventory (ARCI) LSD subscale 4 (a measure of dysphoric effects and/or anxiety), suggesting increased levels of bad or dysphoric effe cts. In the human abuse potential study, measures to evaluate cognitive and psychomotor impairment (e.g., reaction time, attention, and vigilance) showed that suvorexant produced levels of impairment that were similar to the low dose of zolpidem (15 mg) (Schedule IV). This data suggest that both zolpidem and suvorexant present a similar risk to the public health, and that suvorexant impairs cognition at both therapeutic (e.g., 40 mg) and supra therapeutic doses.

4 The Addiction Research Center Inventory (ARCI) is a standardized questionnaire used for assessing the psychoactive effects of drugs. It is a 40 item true/false questionnaire with five empirically derive d scales: 1) Morphine

- benzedrine group scale (MBG), as an index of euphoria, 2) Lysergic Acid Diethylamide (LSD) scale as an index of dysphoria and somatic (i.e., physical) symptoms, 3) Pentobarbital

- chlorpromazine

- alcohol (PCAG) scale as an index of sedat ion, 4) Amphetamine (A) scale, and 5) Benzedrine group BG scale. The A and the BG scales are both indices of amphetamine

- like effects.6

Similar levels of impairment o n the Sternberg Short Term Memory Test and the choice reaction time task were observed following either suvorexant (40, 80 and 150 mg) or the low dose of zolpidem (15 mg). T he maximum dose of suvorexant (150 mg) produced a significantly greater degree of i mpairment than any dose of zolpidem o n the mean RMS (mean root square distance) distance component of the divided attention task (one of three outcomes which also include the number of target hits and the number of false alarms) . In addition, the reduction in the number of target hits following low dose of zolpidem (15 mg) was similar to those following 40, 80 and 150 mg doses of suvorexant. Interestingly, as the dose of suvorexant increased , t here was no increase in drug effects. This is especially important since the lowest dose of suvorexant examined in the human abuse potential study (40 mg) is the maximum planned therapeutic dose. This would suggest that therapeutic doses of suvorexant (e.g. 40 mg) will have a significant abuse liability and prod uce cognitive and psychomotor impairment.
As mentioned in the HHS review, it is important to note that h uman abuse potential studies are believed to have both high predictive and face validity in terms of the likelihood of abuse in recreational drug abus ers (Carter and Griffiths, 2009). Hence, the results observed with suvorexant are unlikely to be spurious . Examples of previous clinical abuse potential assessments include ramelteon, an unscheduled sleep aid devoid of abuse potential and methylphenidate (S chedule II) or intravenous opioids such as morphine (Schedule II). Studies found no differences between placebo and ramelteon on a variety of abuse potential measures similar to those assessed in the clinical abuse potential study with suvorexant (Johnso n et al., 2006) , while results for studies involving either methylphenidate or morphine showed that7

recreational stimulant users indicate d that they like the drug and would pay money for it (Parasrampuria et al., 2007; Stoops et al., 2010). Further, s tudies in rodents also suggest that suvorexant produces effects similar to that of zolpidem (Schedule IV). In preclinical studies, suvorexant (10, 20, 30 and 60 mg/kg) dose dependently reduced locomotor activity in rats, an effect that is similar to other sedative drugs, including zolpidem (Murphy et al., 2011; Vlainic and Pericic, 2010). As stated in the HHS review, these data suggest that suvorexant and zolpidem (Schedule IV) hav e a similar abuse potential

. These s imilarities between suvorexant and zolp idem indicate that there will be significant diversions of these substances from legitimate channels and significant use contrary to or without medical advice. In addition, the long half

- life (see factor 3) of suvorexant may be a critical factor in the dru g’s safety profile, where the duration of action of suvorexant may create significant hazards to the health of the user or to the safety of the community and result in “next day” effects in patients.

Factor 2: Scientific Evidence of Suvorexant's Pharmaco logical Effects As stated in the HHS review, t he orexin signaling system was discovered in 1998 and has been implicated in numerous physiological functions involving the central nervous system ( CNS ) such as sleep and wakefulness, appetite/metabolism, stress response, reward/addiction and analgesia (Kukkonen, 2013). Orexin A and orexin B are peptide neurotransmitters that are produc ed through cleavage of a prepro hormone. These neurotransmitters bind with a high degree of selectivity to two different G

- protein coupled receptors (GPCR’s) namely OX1 and OX2. These orexin receptors are b roadly expressed in cortical, thalamic and hypothalamic8

neuronal circuits

. Suvorexant blocks the wakefulness promoting effec ts o f the orexins, facilitating the sleep process. Receptor Binding and in vitro Activity As stated in the HHS review, many drugs exert their pharmacological and physiological effects by binding with a molecular target known as a receptor. Affinity is a measure of the probability that a drug will bind with a receptor to form a drug

- receptor complex (Smith and Reynard, 1995) and is typically expressed as a K i value. In in vitro studies, suvorexan t showed high affinity and selectivity for OX1 and OX 2 receptors

. The binding data also suggest that it is unlikely to affect receptor subtypes other than the orexin receptors. When a drug or compound binds to a receptor and does not cause an effect and/or blocks the effects of another drug, it is considered an antagonist. In pharmacological studies , suvorexant functioned as an antagonist as demonstrated by its ability to block agonist

- induced calcium (Ca 2+ ) release. Receptor binding studie s used a stably transfected Chinese Hamster Ovary cell line (CHO) that expressed human orexin receptors to determine binding affinity as assess ed by the ability of suvorexant to displace a reference compound (expressed as a K i value). Suvorexant produced K i values of 0.55 nM and 0.35 nM for the OX1 and OX2 receptors, indicating a high affinity for these receptor subtypes (Winrow et al., 2011). In in vitro functional studies, suvorexant blocked the effects of orexin receptor agonist in CHO cells expressing OX1 and OX2 receptors. The concentrations of suvorexant inhibiting 50% of response (known as IC50) were 49.9 nM at the OX1 receptors and 54.8 nM at OX2 receptors. As stated in the HHS review, similar results were obtained when suvorexant was assessed using cloned orexin receptors from rodent and several other animal species. General Behavioral Responses and Safety Studies9

As mentioned in the HHS review, l ocomotor testing is use d to assess an animal ’s stimulant or sedating response to a drug. Locomotor studies usually involve placing a rodent inside of a chamber that can monitor and/or track a variety of movements and behaviors. Suvorexant (10, 20, 30 and 60 mg/kg) dose dependently reduced locomotor activity in rats, an expected characteristic of a sedative drug. Other sedative

- like drugs indicated for insomnia, such

as z olpidem (Schedule IV), also reduce locomotor activity in rodents (Murphy et al., 2011; Vlainic and Pericic, 2010). Locomotor activity was significantly reduced following 30 and 60 mg/kg intraperitoneally (i.p.) administered suvorexant (29 and 44%, respec tively). Maximal effects occurred at either the four hour (30 mg/kg) or one hour (60 mg/kg) time point as compared to controls. In most cases, the effects of suvorexant on locomotor activity were time

- dependent and returned to non

- significant levels by the 6 hour time point. As stated in the HHS review, canine studies noted effects following suvorexant associated with cataplexy (a sudden and transient loss of muscle tone, often triggered by emotions such as laughing, crying or terror). S igns and s ymptoms i nc luded transient limb buckling, u nstead y gait and recumbency following the presentation of daily food enrichment. The involvement of the orexin/hypocretin system in narcolepsy and cataplexy may be responsible for this behavior. Self
- Administration Study The HHS review stated that when determining the abuse potential of a drug, animal self

administration studies have a proven predicative and face validity. It has been shown previously that drugs that are self

- administered by animals are typically self

- administered by humans, and/or have a potential for abuse (Ator and Griffiths, 2003; Brady, 1988; Carter and Griffiths,10

2009). Some examples include stimulants such as cocaine and amphetamine, opioid analgesics such as morphine, and sedative drugs like zolpidem ( Brady, 1988; O’Connor et al., 2011). During self

- administration studies, “reinforcement” pertains to the ability of an animal to control whether or not it receives a repeated infusion of specific drug. Rhesus monkeys trained to self

- administer methohexital (Schedule IV) did not self

- administer suvorexant, suggesting that suvorexant does not have reinforcing effects and has a low potential for abuse. However, the predictive validity of self

- administration studies in evaluating the abuse potential of drugs acting via orexin recept ors is unknown. Studies have demonstrated that gamma hydroxybutyrate (GHB) is only self

- administered under a relatively narrow range of experimental conditions (Goodwin et al., 2011) while serotonergic hallucinogens are not typically self

- administered by l aboratory animals. (Fantegrossi et al., 2008; Nichols, 2004). Results have shown that parameters including drug delivery schedules, time

- out periods, dosing, species and prior drug history can all influence the outcome of self

- administration studies (Ator and Griffiths, 2003; Beardsley et al., 1990; Carter and Griffiths, 2009; Collins and Woods, 2007; Goodwin et al., 2011; Hiranita et al., 2013; Young and Woods, 1981). HHS stated that because of the lack of published self

- administration studies using orexi n ligands, it is difficult to evaluate the above mentioned data from the self

administration studies. Drug Discrimination Study As described in the HHS review, d rug discrimination is an in vivo behavioral method that can be used to model the subjective ef fects of a drug. A good correlation exists between the discriminative effects of drugs of abuse in animals, and their subjective effects in humans (Solinas et al., 2006). A typical drug discrimination study involves training a laboratory animal to press tw o separate levers, one lever following administration of a drug and the opposite lever11

following placebo control ( i.e., saline or appropriate vehicle control ). After repeated training sessions to learn the behavior, and unknown or “test” drug may be given and the animal’s response is observed. The results regarding the animal’s lever selection are used to determine whether the test drug is similar or different from the training drug. According to the HHS review, d rug discrimination studies were conducted in both morphine

- trained and zolpidem trained female rodents . It should be noted that the effects of using an entirely female rodent population is unknown and atypical for the design of drug discrimination studies. Results in the morphine

- trained animals demonstrated that suvorexant did not substitute for morphine. Results from zolpidem

- trained rodents demonstrated that suvorexant produced approximately 45% dru g - appropriate responding , otherwise referred to as a “partial generalization”, (often defined as 20

- 80% drug appropriate responding) . While this result is not easily interpretable, partial generalization has been proposed to occur when the test drug has

so me degree of pharmacological similarity with the training drug (Buccafusco, 2000). As with the self

- administration study, the lack of published data using orexin receptor agonists in drug discrimination studies makes it difficult to evaluat e the present dr ug discrimination data. The dose of training drug, training drug selection, behavioral history and pretreatment time can influence the outcome of drug discrimination studies (Carter and Griffiths, 2009; Marona

Lewicka et al., 2005; Stolerman et al., 2011). Drugs with different mechanisms of action would not be expected to generalize to one another. Previous studies have shown that in rats trained to discriminate μ

- opioid agonists from saline ( e.g. morphine or fentanyl), non - opioid drugs that are active in the CNS do not produce an appreciable amount of drug

- appropriate responding (Colpaert et al., 1976; Colpaert, 1999).12

Despite the similar subjective effects produced by suvorexant and zolpidem (e.g. sedation), the mechanisms of action of suvorexant (a dual orexin antagonist) appears to be highly specific. While the results fr om the drug discrimination studies are predictable given the pharmacological differences between su vorexant, zolpidem and morphine, results from these
tests suggest that there may be similarities between suvorexant and zolpidem , although the degree of similarity is unknown. Human A b use Potential Study As described in the HHS review, a human abuse potential study was performed to assess the abuse potential of suvorexant in human participant’s , demonstrating that suvorexant and zolpidem (Schedule IV) produce similar reinforcing effects and have a similar potential for abuse in recreational drug users. Results showed that suvorexant produced effects that were statistically indisting uishable from zolpidem on the primary outcome measure such as at the moment Drug Liking as assessed via VAS

. Similarly , on the secondary measure of abuse potential such as Drug Liking, Overall Drug Liking, Take Drug Again, Any Drug Effect and High and Goo d Effects , effects of suvorexant are similar to those of zolpidem

. O n the Bowdle VAS (a measure of perceptual and hallucinogenic effects) , the 15 mg dose of zolpidem produced effects that were
not significantly different from any dose of suvorexant tested

. Zolpidem (Schedule IV) produced more dysphoria and adverse effects than suvorexant

. This suggest s that suvorexant may have an increased abuse potential relative to zolpidem (i.e., recreational drug users are more likely to avoid substances that produce “bad” or aversive effects). For example, the maximum dose of zolpidem (30 mg) produced significantly greater VAS ratings of Bad Effects than the low (40 mg) and high (150 mg) dose of suvorexant. Similarly, on the ARCI LSD subscale, the highest dose of zolpidem (30 mg) produced13

statistically greater scores than all doses of suvorexant, suggesting increased levels of bad or dysphoric effects. S uvorexant produced levels of impairment that were similar to the low dose of zolpidem (Schedule IV) on seve ral outcome measures of cognitive and psychomotor assessments (see: Factor 1). Further, the longer half

- life and duration of action of suvorexant (~8

- 11 hours) relative to zolpidem (2.6 hours) may present a greater safety risk. The low dose of zolpidem (1 5 mg) produced levels of impairment that were similar to all doses of suvorexant (40, 80 and 150 mg) on assessments of choice reaction time. In general, on the Hopkins Verbal Learning test, Ste r nberg Short Term Memory, and the outcome measures from the Div ided Attention task, the low dose of zolpidem (15 mg) produced effects that were comparable to suvorexant (40, 80 and 150 mg). While the clinical significance of the se findings is unknown, it appears as though zolpidem and suvorexant produce similar level s of cognitive impairment. As stated in the HHS review, there was no increase in drug effects as the dose of suvorexant incre ased. This is an important observation, as the low dose of suvorexant in the human abuse potential study is the maximum propose d therapeutic dose (40 mg). Th ese data suggest that the maximum therapeutic dose of suvorexant (40 mg) , which was shown to produce cognitive and psychomotor impairment, will have a signific ant liability for abuse. Psychomotor Performance The effects of suvo rexant (10, 50, and 100 mg) on sleep parameters and next day residual effects were examined in healthy young males aged 18

- 45 (n=19) by three tests: 1) the choice reaction time (CRT), 2) the simple reaction time (SRT), and 3) the digit symbol substitution (DSST). Following overnight dosing with suvorexant, psychomotor assessments were performed in the morning to assess residual or “next

- day “effects . Results demonstrated that the mid and14

high dose s of suvorexant (50 and 100 mg) produced effects on next

- day assessments of psychomotor performance and subjective effects. S uvorexant reduced subject

- related assessments of alertness (50 mg) and increased CRT and SRT (100 mg)

. Suvorexant decreased performance in the DSST; however the results were not statistically significant. The results of this study suggest that supra

- therapeutic doses of suvorexant (e.g. 100 mg) produce residual effects on psychomotor performance, and that doses similar to the proposed therapeutic dose may decrease subjective alertness (e.g., pr oduce drowsiness) (Sun et al., 2013). These results may be clinically relevant as the residual effects may be present in the morning following an evening administration (10 hours post

- dose). Drug Interactions Suvorexant is met abolized via the cytochrome P 450 (CYP) system , CYP3A4

. D rugs that influence CYP3A4 have a potential to either reduce or increase suvorexant metabolism thereby altering its exposure and duration of action

. Suvorexant was shown to interact with the CYP3A4 inhibitor ketoconazole, and wou ld be expected to have interactions with CYP3A4 inhibitors or activating agents. Co

- administration of suvorexant with ketoconazole resulted in an approximately 2.78 and 1.23 fold increase in suvorexant blood plasma concentrations (e.g. AUC 0

- ∞ and C max ). Co

- administration of suvorexant with a moderate CY P3A4 inhibitor (diltiazem) resulted in a 2.05 and 1.21 fold increase in suvorexant AUC 0

- ∞ and C max , respectively. Co

- administration of suvorexant with rifampin, a CYP3A4 inducer, resulted in a significan t decrease in suvorexant exposure. In addition to CYP3A4 interactions, in vitro metabolism studies demonstrate that suvorexant has a potential to inhibit i ntestinal p

- glycoprotein (p

- gp) while the results o f15

psychomotor tests demonstrate that suvorexant a nd alcohol administered concomitantly would result in additive impairment.

3: The State of Current Scientific Knowledge Regarding Suvorexant As stated in the HHS review, t he chemical name for suvorexant is: [(7 R )

- 4

- (5

- c hloro

- 1,3

- benzoxazol

- 2

- yl)

- 7

- methyl

- 1,4

- diazepan

- 1

- yl][5

- methyl

- 2

- (2 H

- 1,2,3

- triazol

- 2

- yl)phenyl]methanone and is a white to off

- white powder

. Other chemical names include: 1) Methanone, [(7 R )

- 4

- (5

- chloro

- 2

- benzoxazolyl)hexahydro

- 7

- methyl

- 1 H

- 1,4

- diazepin

- 1

- yl][5

- methyl

- 2

- (2 H

- 1,2,3

- triazol

- 2

- yl)phenyl]

- ; 2) [(7 R )

- 4

- (5

- chlorobenzoxazol

- 2

- yl)

- 7

- methylhexahydro

- 1 H

- 1,4

- diazepin

- 1

- yl][5

- methyl

- 2

- (2 H

- 1,2,3

- triazol

- 2

- yl)phenyl]methanone ; 3) MK

- 4305; and 4) DORA

- 22. The chemical Abstract Services number (CAS #) of suvorexant is: 1030377

- 33

- 3. At 25°C, suvorexant is insoluble in water, soluble in methanol, very slightly soluble in heptane, and soluble in isopropyl acetate. The pH of a saturated aqueous solution of suvorexant was 8.6. Suvorexant has a molecular formu la of C 23 H 23 ClN 6 O 2 and a molecular weight of 45 0.921g. Suvorexant has a distinct chemical structure that is different from that of other sedative hypnotics such as the benzodiazepines (Schedule IV). The HHS review states that t here are several metabolites of suvorexant, although none appear to contribute significantly to its pharmacodynamic effects or abuse potential. Eight metabolites were detected in the plasma of healthy males administered radiolabeled suvorexant, with two of the metabolites present at concentrations great than 10% (M9 and M12). The M9 metabolite , formed by hydroxylation of the triazolobenzyl group of suvorexant, made up 3 6.5% of total circulating drug while M12 represented 12.2% of the total concentrations of circulating drug. M9 is considered the primary circulating metabolite, and has in vitro activity at the OX116

and OX2 receptors that is similar to suvorexant. However , M9 (doses up to 3 mg/kg) did not demonstrate activity in preclinical canine sleep studies

. T he lack of sleep promoting effects of
M9 is likely due to the fact that it is a substrate for p - gp and thus unable to enter the CNS. P

- gp is a major membrane associated transport protein involved in the transport of numerous drugs and substances into (and out of) the brain (de Klerk et al., 2011; Sharom, 2011)

. According to HHS, t he M12 metabolite is a glucuronidated derivative (a common process in drug excretion and metabolism (Liston et al., 2001)) of an oxidation product of suvorexant.
M12 is more polar than suvorexant, more water soluble, and easily excreted from the body, which suggests that M12 is unlikely to be pharmacologically active or be able to penetrate the brain

. Based on the data from the receptor binding study, other minor metabolites e xamined
appear to have less affinity for the orexin receptors relative to suvorexant. Pharmacokinetics and Metabolism The HHS review noted that a fter oral administration of 15

- 40 mg, peak plasma concentrations (i.e., T max ) of suvorexant occurred at approximately 1

- 2 hours (range 0.5

- 6.0 hours), although the study authors noted slight variab ility based on the time of day. For example, the median T max is 1

- 2 hours and 1.5

- 4 hours following morning and evening dosing , respectively . The terminal half

- li f e of suvorexant is approximately 8

- 11 hours after a 40 mg dose. The pharmacokinetic s of suvorexant following multiple dose administrations were similar to those following single dose administrations, with slightly less than dose proportional pharmacokineti cs over 10

- 80 mg as assessed by AUC 0

- ∞ and C max . Steady state exposure was reached after 2

- 3 days of consecutive dosing. Suvorexant’s pharmacokinetic profile such as its long half

- life (8

- 11 hours) may present a significant safety concern in the form of next day, residual effects. F ollowing a normal night’s17

sleep, subjects would be exposed to levels of suvorexant that are efficacious in the promotion and maintenance of sleep. S uvorexant (20 mg) impro ved several sleep parameters relative to pla cebo in Phase 3 efficacy trials

. P atients receiving the maximum therapeutic dose of suvorexant (40 mg) before bedtime would likely have significant plasma levels of drug upon awakening the next day. In addition, the increased half

- life of drugs observed in older individuals suggests that healthy elderly subjects would have even higher plasma levels of drug upon awakening. Following multiple daily dosing, the apparent terminal half

- life of suvorexant w as approximately 2

- fold higher in healthy elderly subjects ( 18.8 hours ) than in young male subjects receiving the same dose. The HHS review stated that suvorexant is m et abolized via the cytochrome P450 enzyme system ( primarily by CYP3A 4 , with a slight con tribution of CYP2C19 ), is unlikely to result in clinically significant inhibition of human CYP1A2, CYP2B6, CYP2C9, CYP2C19 or CYP2D6 isoforms, and should not affect the pharmacological profile of drugs metabolized via these CYP subtypes. The m ajority of su vorexant is metabolized, with no unchanged drug detected in feces and <1% recovered in urine. While 23% of metabolized radiolabeled suvorexant was recovered in urine, the primary route of suvorexant excretion is through feces with studies reporting approxi mately 66% of a radiolabeled dose of suvorexant recovered in fecal matter.

4: History and Current Pattern of Abuse of Suvorexant As stated in the HHS review, suvorexant is not currently marketed or available for sale in any country, therefore there is no known history of pattern of abuse. However, results from the human abuse potential study suggest that suvorexant produces effects that are similar to zolpidem (Schedule IV) and would have a similar pattern of abuse. As of January 16, 2014 , no18

results for suvorexant were identified in either the National Forensic Laboratory Information System (NFLIS 5 ) or System to Retrieve Information on Drug Evidence (STRIDE 6 ).

5: The Scope, Duration, and Significance of Abuse of Suvorexant While the current scope, duration and significance of abuse of suvorexant are unknown due to its non

- marketed status, the results of the human abuse potential study previously described suggest that , upon marketing, the abuse of suvorexant may be similar to zolpidem (Schedule IV). While epidemiological data from similar Schedule IV sedative drugs can provide a limited context for predicting the abuse, scope, duration and significance of abuse of

suvo rexant , caution should be used in the interpretation of these data due to limitations associated with the data reporting systems such as the Drug Abuse Warning Network ( DAWN 7 ) and the Adverse Event Reporting System ( AERS 8 ). At the present time, DAWN and AERS are the best data currently available and may provide a crude represent ation of abuse and misuse. In general, emergency department (ED) visits reported for zolpidem along with those specifically categorized as “misuse/ab use” have increased every year from 2004

- 2010, with a modest decrease reported for 2011. ED visits related to benzodiazepine sedatives including diazepam (Schedule IV) and lorazepam (Schedule IV) showed similar trend (Table 1).

5 NFLIS, a DEA database which compiles information on exhibits analyzed in state and local laboratories. 6 STRIDE, a DEA database which compiles information on exhibits analyzed in DEA laboratories. 7 The Drug Abuse Warning Network (DAWN) is a public health surveillance system that monitors drug

- related emergency department (ED) visits. DAWN was designed to monitor and collect data on drug misuse and abuse. 8 The FDA’s Adverse Event Reporting System (F AERS), (formerly referred to as AERS), is a database that contains information on adverse event and medication error reports submitted to FDA. The FAERS database is designed to support FDA’s post

- marketing surveillance program and is useful for identifying post

- approval safety concerns.19

Table 1. Drug Abuse Warning Network (DAWN) Emergency Department (ED) Visits from 2004
- 2011 * Weighted Annual Estimates Drugs 2004 2005 2006 2007 2008 2009 2010 2011 All ED Visits Zolpidem 22,307 26,552 31,925 40,068 55,328 61,771 64,175 62,626 Diazepam 25,523 28,443 30,819 37,015 44,440 42,676 44,159 41,247 Lorazepam 30,748 36,679 42,181 51,685 67,987 69,384 69,304 74,659 Misuse and Abuse Related ED Visits Zolpidem 13,903 16,659 20,269 21,595 33,715 35,438 39,557 37,225 Diazepam 19,096 22,332 23,368 24,413 33,214 30,214 31,970 29,804 Lorazepam 20,849 25,535 27,972 32,462 44,465 42,602 44,407 50,339 * As stated in the HHS review of suvorexant

Because changes in drug utilization may result in changes in ED visits , HHS calculated abuse ratio s by divi di ng the number of ED visits by the number of pills or tablets sold through retail pharmacies (e.g., extended units). The abuse ratio for each of the sedative

- like drugs examined appeared to be in agreement with the DAWN estimates (Table 2). Table 2. DAWN Ab use - Ratio D ata a Annual, Calculated Abuse
- Ratio* Drugs 2004 2005 2006 2007 2008 2009 Zolpidem 22.2 25.6 28.2 24.9 32.1 31.7 Diazepam 31.5 36.4 35.1 35.2 47.0 42.8 Lorazepam 21.3 25.2 26.5 28.6 36.9 34.4 * Abuse ratio is calculated as the number of abuse and misuse ED department visits per 1,000,000 extended units of drug (pills, tablets, mL).
a As stated in the HHS review of suvorexant
HHS also reviewed misuse/abuse related AERS reports associated with zolpidem and compared with those associated with benzodiazepines namely diazepam and lorazepam. Fewer than 25 AERS reports/year were associated with misuse/abuse of zolpidem from 1993 through 2004. From 2005, these reports increased peaking to over 70 reports in 2007 and then declining from 2009 through 2011 with over 30 reports in 2011. By way of comparison, lorazepam and diazepam also demonstrated an overall increase in misuse / abuse related AERS reports since20

1993, with diazepam producing quantitatively more reports of misuse/abuse than zolpidem and lorazepam in 2010 and 2011. The patterns of AERS reports of delirium/hallucinations associated with zolpidem were similar to its reports involving abuse/misuse. AERS reports of delirium/hallucinations associated with zolpidem increased from 2003

- 2006, with over 100 reports noted in 2007. The number of reports decreased thereafter, with 30 reports in 2011. Zolpidem produced approximately 3 times more reports of delirium/hallucinations than either loraze pam or diazepam. Data from AERS may have limited usefulness primarily because of the manner in which the data is reported 9

. Collectively , the DAWN and AERS data demonstrate the scope, duration and significance of abuse of zolpidem (Schedule IV) and relate d sedative

- like drugs. Suvorexant would be expected to have a similar scope, duration and significance of abuse.

6: What, If Any, Risk There Is To the Public Health According to HHS, suvorexant has a long terminal half

- life of approximately 8

- 11 hours,

w hich may increase the duration of its sedative effects and psychomotor impairment. This extended duration of action of suvorexant increases the risk to the public health relative to zolpidem (Schedule IV) and other short acting sedatives. In Phase 1 studies, psychomotor and cognitive performance assessed after peak plasma levels of suvorexa nt (e.g. ~8

- 11 hours post dose) showed dose

- related impairments. As mentioned in Factor 2, mid

- and high doses of suvorexant (50 and 100 mg) affected the next

- day

9 There is no certainty that a reported event was actually due to a specific product or drug. FDA does not require that a causal relationship between a product and event be proven, and reports do not always contain enough de tail to properly evaluate an event. In addition, a single AERS report may represent more than one event, and because individuals reporting to AERS are often anonymous, this may result in underreporting. Second, the above AERS reports may include duplicate, irrelevant, and poor quality reports. Finally, changes in drug utilization may also affect AERS reporting.21

assessments of psychomotor performance and produced subjective effects. Specifically, 5 0 mg of suvorexant reduced subject

- reported assessments of alertness, while the highest dose (100 mg) decreased subject

- rated assessments of alertness and redu ced CRT and SRT. The 100 mg

s uvorexant also reduced DSST performance, although the se changes were not statistically significant. These results suggest that the supra therapeutic dose of suvorexant (e.g. 100 mg) has residual effects on psychomotor performanc e and subjective alertness (Sun et al., 2013). As shown in the HHS review, results of the human abuse potential study showed that suvorexant produces behavioral impairment, as evidenced by its effects on psychomotor performance and cognitive function. S uvorexant produced deficits that were statistically indistinguishable from 15 mg of zolpidem (Schedule IV) , demonstrating the behavioral impairing effects of suvorexant suggesting that even at therapeutic doses, suvorexant will present a risk to the public health that is at least equivalent to zolpidem (Schedule IV). Results of the CRT task (a meas ure of reaction time and speed) showed that the low dose of zolpidem impaired performance similar to suvorexant (i.e., there was no statistical difference between the treatments). Suvorexant also altered two of three outcome measures on the divided attention task (mean RMS dist ance and number of target hits), while t he highest dose of suvorexant impaired cognitive performance as measured by a decrease on the Sternb erg sho rt term memory task. Suvorexant may also present a serious risk for cataplexy

- like events and narcolepsy based on a substantial body of evidence linking deficiencies in hypocretin/orexin signaling and cataplexy (Baumann and Bassetti, 2005; Nishino a nd Kanbayashi, 2005; Sakurai and Mieda, 2011). The most common adverse events (AEs) associated with zolpidem treatment (up to 10 nights with doses up to 10 mg) included drowsiness, dizziness and diarrhea, reported by 2%, 1% and 1% of patients respectively. AEs reported following longer term treatment (28

- 35 nights)22

included dizziness (5%) and drugged feelings (3%) . In contrast, AEs reported during Phase 3 trials were headache, somnolence and nasopharyngitis experienced by 7.5%, 6.9% and 5.9% of subjects receiving low dose (20 mg daily /6 months) suvorexant and somnolence, headache and nasopharyngitis experienced by 11.7, 7.8 and 7.4% of subjects receiving high dose (40 mg daily /12 months) suvorexant. According to HHS, r esults from Phase 3 studie s lasting up to one year in duration identified additional AEs including hallucinations (auditor y, visual, hypnagogic, etc.), memory and mental impairment , abnormal dreams and nightmares

. These hallucinations may be similar to hallucinations reported follo wing the use of zolpidem (Andrade, 2002; de Haas et al., 2007; Inagaki et al., 2010; Kummer et al., 2012; Markowitz et al., 1997). Due to the stringent screening procedure used in enrolling the study population, the incidence of AEs in the general populati on may be much greater than what is represented in Table 3 , and may present a significant risk to the public health.23

Table 3. Select Adverse Events of Suvorexant from the Combined Phase 3 Study Population.* Low dose (20 mg) a High dose (40 mg) b PLACEBO N % N % N % TOTAL PATIENTS 493 1291 1025 System Oran Class Preferred Term Nervous System Disorders Somnolence 34 6.9 151 11.7 33 3.2 Headache 37 7.5 101 7.8 68 6.6 Memory Impairment 2 0.4 12 0.9 5 0.5 Mental Impairment 0 0 1 0.1 0 0 Psychiatric Disorders Abnormal Dreams 10 2.0 34 2.6 11 1.1 Nightmare 7 1.4 27 2.1 7 0.7 Hallucination, auditory 0 0 1 0.1 0 0 Hallucination, visual 0 0 1 0.1 0 0 Hypnagogic hallucination 1 0.2 4 0.3 0 0 Hypnopompic hallucination 1 0.2 1 0.1 0 0
Infections and Infestations Nasopharyngitis 29 5.9 95 7.4 67 6.5
* Adapted from Integrated Summary of Safety as stated in HHS review of suvorexant

. a Combined data from studies P028 and P029, Appendix 5.3.5.3.3: 18 b Combined data from studies P028, P029 and P009, Appendix 5.3.5.3.3: 15

7. Psychic or Physiological Dependence Liability of Suvorexant As described in the HHS review, results of the human abuse potential study demonstrate that suvorexant has a psychic dependence liability similar to zolpidem (Schedule IV). Self

administration in laboratory animals (Griffiths et al., 1992; Weerts and Griffiths, 1998), epidemiological data documenting its use and abuse (See Factor 6) and the ability to produce Drug Liking in human drug users (i.e., the human abuse potential study) demonstrate the psychic dependence liability of zolpidem. According to HHS review, d iscontinuation studies suggest that suvorexant does not produce physical dependence or withdrawal syndrome, wi th observed effects including the return24

of insomnia symptoms. Furthermore, a lack of tolerance in humans from suvorexant was demonstrated by the sustained efficacy of suvorexant in Phase 3 trials where subjects reported improvement in sleep

- related assess ments that were still present one month after the start of
treatment

. As mentioned in the HHS review, w ithdr awal symptoms were assessed via eDiary u sing the Tyrer Withdra wal Symptom Questionnaire (WSQ) and administered in all three Phase 3 studies. The WSQ was given on the last day of drug treatment to establish baseline values, and then during the dose run out phase in two studies, and during the randomized discontinuation phase of another study. The WSQ has 20 self

- scored items. Withdrawal was defined as the presence of three or more symptoms on any night during the first three nights of the run

- out or discontinuation phase. Based on this definition, <9% of patients in any treatment group experienced wit hdrawal symptoms (Table 4). When comparing patients on suvorexant that switched to placebo to subjects that continued on drug, no clear pattern of withdrawal effects was observed. Table 4. Withdrawal Related Effects After Suvorexant Discontinuation, Combined Phase 3 Population.* NIGHT 1 NIGHT 2 NIGHT 3 TREATMENT/RUN

- OUT PHASE TREATMENT N a n b (%) N a n b (%) N a n b (%) Suvorexant low dose / Suvorexant low dose 157 6 (3.8) 160 5 (3.1) 151 7 (4.6) Suvorexant low dose / Placebo 184 7 (3.8) 186 13 (7.0) 182 9 (4.9) Suvorexant high dose / Suvorexant high dose 398 6 (1.5) 396 16 (4.0) 387 9 (2.3) Suvorexant high dose / Placebo 393 12 (3.1) 383 13 (3.4) 381 8 (2.1) Placebo / Placebo 677 17 (2.5) 681 19 (2.8) 664 18 (2.7) * Adapted from Appendix 2.7.4:183 Summary of Clinical Safety as stated in HHS review of suvorexant

. a Overall sample size b Number of subjects experiencing withdrawal related events25

Similarly, in female rats, abrupt discontinuation of suvorexant showed no signs of withdrawal

. Based on these results, the study authors determined a 30

- day no

- observable

- effect

level (NOEL) of at least 325 mg/kg/day of suvorexant. In the physical dependence study, placebo or 80, 160 or 324 mg/kg suvorexant were administered to four groups of ten r ats per group (n=40) . According to the study authors, the 325 mg/kg suvorexant is the maximum feasible dose level.

8: Whether Suvorexant is an Immediate Precursor of a Substance Already Controlled Under This Article Suvorexant is not an immediate precurs or of any controlled substance.26



### III . Findings for Schedule Placement Pursuant to 21 U.S.C. 812(b)

21 U.S.C. 812(b) requires the evaluation of a substance’s abuse potential, accepted medical use, and safety for use under medical supervision for scheduling under the CSA as a controlled substance. After consideration of the above eight factors determinat ive of control of a substance (21 U.S.C. 811(c)), and a review of the scientific and medical evaluation and scheduling recommendation provided by HHS, DEA finds that suvorexant meets the following criteria for placement in Schedule I V of the CSA pursuant t o 21 U.S.C. 812 (b)(5). 1) Suvorexant has a low potential for abuse relative to the drugs or other substances in Schedule III . There is evidence that suvorexant has a comparable potential for abuse as zolpidem (Schedule IV) , and like zolpidem, suvorexan t has a low potential for abuse relative to the drugs or other substances in Schedule III. Suvorexant was co mpared to zolpidem i n human studies of recreational sedative users to measure its abuse potential relative to that of a sedative

- hypnotic in Schedule IV. The abuse potential of suvorexant (40, 80 and 150 mg) relative to zolpidem (15 and 30 mg) and placebo was evaluated via a VAS, with results demonstrating that the effects of
suvorexant were statistically indistinguishable from zolpidem

. The re sults of the human abuse potential study suggest that suvorexant and zolpidem produce similar reinforcing effects and have a similar potential for abuse. In addition, preclinical studies demonstrated that suvorexant (10, 20, 30 and 60 mg/kg) dose dependent ly redu ced locomotor activity in rats, similar to other sedative drugs including zolpidem (Schedule IV).27

2) Suvorexant has a currently accepted medical use in the United States. Upon approval of the pending new drug application, suvorexant will have a currently accepted medical u se in the treatment of insomnia in the United States. 3) Abuse of suvorexant may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in S chedule III . The available evidence indicates that abuse of suvorexant may lead to limited psychological dependence relative to the drugs or other substances in schedule III. The potential for psychological dependence is similar to that of zolpidem (schedule IV).28 

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