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 2014
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BASIS FOR THE RECOMMENDATION TO PLACE SUVOREXANT IN SCHEDULE 

IV OF THE CONTROLLED SUBSTANCES ACT

I. BACKGROUND

Suvorexant ([(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-

methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone; MK-4305), is a new chemical substance that 

is being developed by Merck for the treatment of insomnia. Suvorexant, 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 orally active, 

selective, dual orexin receptor antagonist. Clinical studies suggest suvorexant at 10 and 40 

milligrams (mg) administered orally produces sedative and sleep promoting effects. Abuse 

liability studies in humans show that suvorexant produces reinforcing effects and has a potential 

for abuse that is similar to that of zolpidem (Schedule IV). Thus, the relative abuse potential of 

suvorexant can be evaluated by comparing with zolpidem (Schedule IV) as the comparator drug.

On June 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 IV 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 IV of the Controlled Substances Act 

(CSA) under 21 U.S.C. 812(b). 
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The Controlled Substances Act (CSA) requires DEA, as delegated by the Attorney 

General1, to determine whether HHS’s scientific and medical evaluation and all other relevant 

data constitute substantial 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 evaluation 

document for suvorexant, DEA considers all other relevant data regarding suvorexant’s actual or 

relative potential for abuse. Since suvorexant is a new chemical entity and has not been 

marketed in the United States or in any other country, information 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, 91st Cong., Sess. 1 

(1970); as reprinted in 1970 U.S.C.C.A.N. 4566, 4601.
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Data from clinical studies investigating the abuse potential of suvorexant suggest that its 

effect is similar to Zolpidem. 

As stated in the HHS review, suvorexant 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, eszopiclone3and zaleplon [Schedule IV]),

suvorexant acts as an antagonist at the OX1 and OX2 receptors. A more detailed 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 histories of recreational sedative use. Similar to zolpidem (Schedule IV), 

suvorexant produced reinforcing subjective effects. Through the use of visual analog scales

(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”. 

Following 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 suvorexant were 

compared to 15 and 30 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 stereoisomer, i.e., an isomer, of zoplicone (schedule IV).
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Liking, Take Drug Again, Any Drug Effect, assessment of subjective drug value, and overall 

familiarity, suvorexant produced effects similar to zolpidem on VAS assessments. Similarly, the 

effects of all doses of suvorexant on VAS assessments of High and Good Effects were 

statistically indistinguishable from that of the 15 mg dose of zolpidem (Schedule IV). Similarly,

the 15 mg dose of zolpidem and suvorexant (40, 80 and 150 mg) produced 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 increased 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 

subscale4(a measure of dysphoric effects and/or anxiety), suggesting increased levels of bad or 

dysphoric effects. 

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 supratherapeutic 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 derived 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 sedation, 4) Amphetamine (A) scale, and 5) Benzedrine group BG scale. The A and the BG scales are 

both indices of amphetamine-like effects.
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Similar levels of impairment on 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). The maximum dose of suvorexant (150 mg) produced a significantly 

greater degree of impairment than any dose of zolpidem on 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, there 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 produce 

cognitive and psychomotor impairment. 

As mentioned in the HHS review, it is important to note that human abuse potential 

studies are believed to have both high predictive and face validity in terms of the likelihood of 

abuse in recreational drug abusers (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 (Schedule 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 (Johnson et al., 

2006), while results for studies involving either methylphenidate or morphine showed that 
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recreational stimulant users indicated that they like the drug and would pay money for it 

(Parasrampuria et al., 2007; Stoops et al., 2010).

Further, studies 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) have a similar abuse potential. These similarities between suvorexant and zolpidem 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 drug’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 Pharmacological Effects

As stated in the HHS review, the 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 

produced through cleavage of a preprohormone. 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 broadly expressed in cortical, thalamic and hypothalamic 
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neuronal circuits. Suvorexant blocks the wakefulness promoting effects of 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 Ki value. In in vitro studies, suvorexant showed

high affinity and selectivity for OX1 and OX2 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 (Ca2+) release. 

Receptor binding studies used a stably transfected Chinese Hamster Ovary cell line

(CHO) that expressed human orexin receptors to determine binding affinity as assessed by the 

ability of suvorexant to displace a reference compound (expressed as a Ki value). Suvorexant 

produced Ki 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 Studies
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As mentioned in the HHS review, locomotor testing is used 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 zolpidem (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%, respectively). 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). Signs and symptoms included transient limb 

buckling, unsteady 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 selfadministration 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, 
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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 receptors 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 laboratory 

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 orexin ligands, it is difficult to evaluate the above mentioned data from the selfadministration studies.

Drug Discrimination Study

As described in the HHS review, drug discrimination is an in vivo behavioral method that 

can be used to model the subjective effects 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 two separate levers, one lever following administration of a drug and the opposite lever 
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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, drug 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% drug-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

some 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 evaluate the present drug 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; MaronaLewicka 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).
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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 from the drug discrimination studies are predictable given the 

pharmacological differences between suvorexant, 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 Abuse 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 

indistinguishable 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 Good 

Effects, effects of suvorexant are similar to those of zolpidem. On 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 suggests 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) produced 
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statistically greater scores than all doses of suvorexant, suggesting increased levels of bad or 

dysphoric effects. 

Suvorexant produced levels of impairment that were similar to the low dose of zolpidem 

(Schedule IV) on several 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 (15 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, 

Sternberg Short Term Memory, and the outcome measures from the Divided 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 these findings is unknown, it appears as though 

zolpidem and suvorexant produce similar levels of cognitive impairment. 

As stated in the HHS review, there was no increase in drug effects as the dose of 

suvorexant increased. This is an important observation, as the low dose of suvorexant in the 

human abuse potential study is the maximum proposed therapeutic dose (40 mg). These data 

suggest that the maximum therapeutic dose of suvorexant (40 mg), which was shown to produce 

cognitive and psychomotor impairment, will have a significant liability for abuse.

Psychomotor Performance

The effects of suvorexant (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 and 
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high doses of suvorexant (50 and 100 mg) produced effects on next-day assessments of 

psychomotor performance and subjective effects. Suvorexant 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., produce 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 metabolized via the cytochrome P450 (CYP) system, CYP3A4. Drugs 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 would 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. 

AUC0-∞ and Cmax). Co-administration of suvorexant with a moderate CYP3A4 inhibitor 

(diltiazem) resulted in a 2.05 and 1.21 fold increase in suvorexant AUC0-∞ and Cmax, 

respectively. Co-administration of suvorexant with rifampin, a CYP3A4 inducer, resulted in a 

significant decrease in suvorexant exposure.

In addition to CYP3A4 interactions, in vitro metabolism studies demonstrate that 

suvorexant has a potential to inhibit intestinal p-glycoprotein (p-gp) while the results of 
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psychomotor tests demonstrate that suvorexant and alcohol administered concomitantly would 

result in additive impairment. 

3: The State of Current Scientific Knowledge Regarding Suvorexant

As stated in the HHS review, the chemical name for suvorexant is: [(7R)-4-(5-chloro-1,3-

benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-

yl)phenyl]methanone and is a white to off-white powder. Other chemical names include: 1) 

Methanone, [(7R)-4-(5-chloro-2-benzoxazolyl)hexahydro-7-methyl-1H-1,4-diazepin-1- yl][5-

methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]-; 2) [(7R)-4-(5-chlorobenzoxazol-2-yl)-7-

methylhexahydro-1H-1,4-diazepin-1-yl][5-methyl-2- (2H-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 formula of C23H23ClN6O2 and a molecular 

weight of 450.921g. 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 there 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 36.5% 

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 OX1 
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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. The 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, the 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 examined 

appear to have less affinity for the orexin receptors relative to suvorexant.

Pharmacokinetics and Metabolism

The HHS review noted that after oral administration of 15-40 mg, peak plasma 

concentrations (i.e., Tmax) of suvorexant occurred at approximately 1-2 hours (range 0.5-6.0 

hours), although the study authors noted slight variability based on the time of day. For example, 

the median Tmax is 1-2 hours and 1.5-4 hours following morning and evening dosing, 

respectively. The terminal half-life of suvorexant is approximately 8-11 hours after a 40 mg 

dose. The pharmacokinetics of suvorexant following multiple dose administrations were similar 

to those following single dose administrations, with slightly less than dose proportional 

pharmacokinetics over 10-80 mg as assessed by AUC0-∞ and Cmax. 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. Following a normal night’s 
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sleep, subjects would be exposed to levels of suvorexant that are efficacious in the promotion 

and maintenance of sleep. Suvorexant (20 mg) improved several sleep parameters relative to 

placebo in Phase 3 efficacy trials. Patients 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 was

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 metabolized via the cytochrome P450 enzyme 

system (primarily by CYP3A4, with a slight contribution 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 majority of suvorexant 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 

approximately 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, no 
18

results for suvorexant were identified in either the National Forensic Laboratory Information 

System (NFLIS5) or System to Retrieve Information on Drug Evidence (STRIDE6). 

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 

suvorexant, 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 (DAWN7)

and the Adverse Event Reporting System (AERS8). At the present time, DAWN and AERS are 

the best data currently available and may provide a crude representation of abuse and misuse.

In general, emergency department (ED) visits reported for zolpidem along with those 

specifically categorized as “misuse/abuse” 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 (FAERS), (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 ratios by dividing 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 Abuse-Ratio Dataa

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 since 
20

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 lorazepam or diazepam. Data from AERS 

may have limited usefulness primarily because of the manner in which the data is reported9.

Collectively, the DAWN and AERS data demonstrate the scope, duration and 

significance of abuse of zolpidem (Schedule IV) and related 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, 

which 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 suvorexant (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 detail 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, 50 mg of 

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

decreased subject-rated assessments of alertness and reduced CRT and SRT. The 100 mg 

suvorexant also reduced DSST performance, although these changes were not statistically 

significant. These results suggest that the supratherapeutic dose of suvorexant (e.g. 100 mg) has

residual effects on psychomotor performance 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. Suvorexant 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 measure 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 distance and number of target hits), while the highest dose of suvorexant impaired 

cognitive performance as measured by a decrease on the Sternberg short 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 and 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 by11.7, 7.8 and 7.4% of subjects receiving high dose (40 mg

daily/12 months) suvorexant. 

According to HHS, results from Phase 3 studies lasting up to one year in duration 

identified additional AEs including hallucinations (auditory, visual, hypnagogic, etc.), memory 

and mental impairment, abnormal dreams and nightmares. These hallucinations may be similar 

to hallucinations reported following 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 population 

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)bPLACEBO

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). Selfadministration 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, discontinuation studies suggest that suvorexant does not 

produce physical dependence or withdrawal syndrome, with observed effects including the return 
24

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 assessments that were still present one month after the start of 

treatment.

As mentioned in the HHS review, withdrawal symptoms were assessed via eDiary using 

the Tyrer Withdrawal 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 withdrawal 

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 events
25

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-effectlevel (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 rats 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 precursor 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 determinative 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 IV of the CSA pursuant to 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, suvorexant has a low potential for abuse relative to the drugs 

or other substances in Schedule III. Suvorexant was compared to zolpidem in 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 results 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 dependently reduced 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 use 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 Schedule 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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