Thursday, February 13, 2014

BREAKING AND EXCLUSIVE: DEA Proposes To Classify Suvorexant, MK-4305, As A Schedule IV Controlled Substance. Ouch. [MUST CREDIT]

Immense thanks go out to our commenters -- the one immediately below, especially! [My rather predictive backgrounder, here -- from May of 2013.]

Updated custom graphics shortly, but This notice of proposed rule-making, from today's Federal Register, is a very serious threat to suvorexant. In June 2013, HHS (the Assistant Secretary for Health of the Department of Health and Human Services, actually) suggested that DEA ought to review the candidate for schedule IV inclusion. DEA has done so, and agrees with FDA/HHS. This development materially threatens suvorexant's ability to become a mega-blockbuster for Merck. MK-4305 will very very tightly controlled -- as a matter of dispensing, record-keeping, and in the detailed required findings -- as a basis for prescribing -- by individual practicioners (i.e., doctors), should the rule become final as written today, and suvorexant be labeled as a schedule IV controlled substance under DEA's jurisdiction.

More in a bit -- but more generally, a schedule IV controlled substance must be separately locked away, even inside a secured pharmacy-space (and doctors who are not DEA registered cannot hold samples of the substance in their offices -- and not even then, unless very well-locked away). Think "Nurse Jackie" here. Ugh:

Security. Suvorexant would be subject to schedule III-V security requirements and would need to be handled and stored pursuant to 21 U.S.C. 821, 823, 871(b) and in accordance with 21 CFR 1301.71-1301.93. . . .

Registration. Any person who handles (manufactures, distributes, dispenses, imports, exports, engages in research, or conducts instructional activities with) suvorexant, or who desires to handle suvorexant, would be required to be registered with the DEA to conduct such activities pursuant to 21 U.S.C. 822, 823, 957, and 958 and in accordance with 21 CFR parts 1301 and 1312. Any person who currently handles suvorexant, and is not registered with the DEA, would need to be registered with the DEA. . . .

Without additional ado -- here is the notice of proposed rule-making then, in pertinent part:

. . . .[Federal Register Volume 79, Number 30 (Thursday, February 13, 2014)]. . . .


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), also known as MK-4305, is a new chemical entity developed for the treatment of insomnia. Suvorexant is a novel, first in class, orexin receptor antagonist with a mechanism of action distinct from any marketed drug. It acts via inhibition of the orexin 1 (OX1) and orexin 2 (OX2) receptors. In pharmacological activity studies, suvorexant functioned as an antagonist as demonstrated by its ability to block agonist-induced calcium (Ca\2+\) release.

Proposed Determination to Schedule Suvorexant

Pursuant to 21 U.S.C. 811(a), proceedings to add a drug or substance to those controlled under the CSA may be initiated by request of the Secretary of the HHS. On June 27, 2013, the HHS provided the DEA with a scientific and medical evaluation document prepared by the FDA entitled "Basis for the Recommendation to Place Suvorexant in Schedule IV of the Controlled Substances Act." Pursuant to 21 U.S.C. 811(b), this document contained an eight-factor analysis of the abuse potential of suvorexant as a new drug, along with the HHS' recommendation to control suvorexant under schedule IV of the CSA.

In response, the DEA reviewed the scientific and medical evaluation and scheduling recommendation provided by the HHS, and all other relevant data, and completed its own eight-factor review document pursuant to 21 U.S.C. 811(c). Included below is a brief summary of each factor as analyzed by the HHS and the DEA, and as considered by the DEA in its proposed scheduling action. Please note that both the DEA and HHS analyses are available in their entirety under "Supporting and Related Material" in the public docket for this proposed rule at, under Docket Number "DEA-381." Full analysis of, and citations to, the information referenced in the summary may also be found in the supporting and related material. . . .

The Drug's Actual or Relative Potential for Abuse: Suvorexant is a new chemical entity that has not been marketed in the United States or any other country. As such, there is no information available detailing actual abuse of suvorexant. 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.

As described further below, there is strong evidence that suvorexant produces behavioral effects in humans and in animals that are similar to those produced by zolpidem (schedule IV).

With a mechanism of action that is distinct from any other marketed drug, including those marketed for insomnia (i.e., schedule IV benzodiazepines, and non-benzodiazepine hypnotics such as zolpidem (schedule IV), eszopiclone (schedule IV), and zaleplon (schedule IV)), suvorexant acts as an antagonist at the OX1 and OX2 receptors and produces sedative and sleep promoting effects in humans.

In a human abuse potential study in subjects with histories of recreational sedative use, suvorexant produced reinforcing subjective effects similar to zolpidem (schedule IV). Doses of 40, 80, and 150 mg of suvorexant were compared to 15 and 30 mg doses of zolpidem schedule IV). On the visual analog scale (VAS), suvorexant produced "'at the moment' Drug Liking" and "High and Good," effects statistically indistinguishable from zolpidem (schedule IV). Suvorexant also produced effects similar to zolpidem (schedule IV) in "Overall Drug Liking," "Take Drug Again," "Any Drug Effect," assessments of subjective drug value, and overall familiarity measures.

Additionally, on the Bowdle VAS (a measure of perceptual and hallucinogenic effects) suvorexant produced effects statistically similar to zolpidem (schedule IV). Suvorexant produced less dysphoria and adverse effects than zolpidem (schedule IV), suggesting that suvorexant may have an increased abuse potential relative to zolpidem (schedule IV). 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 (15 mg) of zolpidem (schedule IV). These data suggest that zolpidem (schedule IV) 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. As the dose of suvorexant increased, there was no increase in drug effects. This fact is especially important because the lowest dose of suvorexant examined in the human abuse potential study (40 mg) is the maximum planned therapeutic dose -- suggesting that therapeutic doses of suvorexant (e.g., 40 mg) will have significant abuse liability and produce cognitive and psychomotor impairment.

These data suggest that suvorexant and zolpidem (schedule IV) have a similar abuse potential. The similarities between suvorexant and zolpidem (schedule IV) indicate that there will be significant diversion of these substances from legitimate channels, and significant use contrary to or without medical advice. In addition, as discussed in Factor 3, the long half-life of suvorexant may be a critical factor in the drug's safety profile as suvorexant's duration of action 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.

2. Scientific Evidence of the Drug's Pharmacological Effects, if Known: 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. Orexin A and orexin B are peptide neurotransmitters 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 neuronal circuits. Suvorexant blocks the wakefulness promoting effects of the orexins, facilitating the sleep process. In pharmacological studies, suvorexant functioned as an antagonist as demonstrated by its ability to block agonist-induced calcium (Ca\2+\) release.

In receptor binding studies to determine the binding affinity as assessed by the ability of suvorexant to displace a reference compound (expressed as 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. In in vitro functional studies, suvorexant blocked the effects of orexin receptor agonist in cells expressing OX1 and OX2 receptors. The concentrations of suvorexant inhibiting 50 percent of response (known as IC50) were 49.9 nM at the OX1 receptors and 54.8 nM at OX2 receptors.

Like zolpidem, suvorexant (10, 20, 30 and 60 mg/kg) dose dependently reduced locomotor activity in rats, an expected characteristic of a sedative drug. Although rhesus monkeys trained to self-administer methohexital (schedule IV) did not self-administer suvorexant, the predictive validity of self-administration studies in evaluating the abuse potential of drugs acting via orexin receptors is unknown.

A human abuse potential study was performed to assess the abuse potential of suvorexant in human participants. The study demonstrated 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 statistically indistinguishable from zolpidem (schedule IV) in primary and secondary outcome measures. There was no increase in drug effects as the dose of suvorexant increased. This is an important observation, as the low dose of suvorexant (40 mg) in the human abuse potential study is the maximum proposed therapeutic dose. These data suggest that the maximum therapeutic dose of suvorexant (40 mg) was shown to produce cognitive and psychomotor impairment and will have a significant liability for abuse.

Results from another study measuring the effects of suvorexant (10, 50, and 100 mg) on sleep parameters and next-day residual effects demonstrated that the mid and high doses of suvorexant (50 and 100 mg) produced effects on next-day assessments of psychomotor performance and subjective effects. These results may be clinically relevant as the residual effects may be present in the morning following an evening administration (10 hours post-dose). . . .

/s/ Thomas M. Harrigan, Deputy Administrator

Ouch. Well, it is not yet over, but the fat lady is certainly clearing her throat, here. Yikes. Here is the illustrious Anon. -- in comments:

. . . .Anonymous said...

Did no one see that earlier today the DEA published for comment their proposal that suvorexant be listed as schedule IV controlled substance? How is that not news anywhere, especially here?

February 13, 2014 at 8:42 PM. . . .

Ahem. Thanks to you -- now it is. Here, anyway. Thanks, again!

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