Rule2022-11735
Schedules of Controlled Substances: Placement of Ganaxolone in Schedule V
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
June 1, 2022
Effective
June 1, 2022
Issuing agencies
Justice DepartmentDrug Enforcement Administration
Abstract
On March 18, 2022, the United States Food and Drug Administration approved a new drug application for ZTALMY, an oral suspension of ganaxolone, for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients two years of age and older. The Department of Health and Human Services provided the Drug Enforcement Administration with a scheduling recommendation to place ganaxolone and its salts in schedule V of the Controlled Substances Act. In accordance with the Controlled Substances Act, as amended by the Improving Regulatory Transparency for New Medical Therapies Act, Drug Enforcement Administration is hereby issuing an interim final rule placing ganaxolone, including its salts in schedule V of the Controlled Substances Act.
Full Text
<html>
<head>
<title>Federal Register, Volume 87 Issue 105 (Wednesday, June 1, 2022)</title>
</head>
<body><pre>
[Federal Register Volume 87, Number 105 (Wednesday, June 1, 2022)]
[Rules and Regulations]
[Pages 32991-32996]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2022-11735]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF JUSTICE
Drug Enforcement Administration
21 CFR Part 1308
[Docket No. DEA-990]
Schedules of Controlled Substances: Placement of Ganaxolone in
Schedule V
AGENCY: Drug Enforcement Administration, Department of Justice.
ACTION: Interim final rule; request for comments.
-----------------------------------------------------------------------
SUMMARY: On March 18, 2022, the United States Food and Drug
Administration approved a new drug application for ZTALMY, an oral
suspension of ganaxolone, for the treatment of seizures associated with
cyclin-dependent kinase-like 5 deficiency disorder in patients two
years of age and older. The Department of Health and Human Services
provided the Drug Enforcement Administration with a scheduling
recommendation to place ganaxolone and its salts in schedule V of the
Controlled Substances Act. In accordance with the Controlled Substances
Act, as amended by the Improving Regulatory Transparency for New
Medical Therapies Act, Drug Enforcement Administration is hereby
issuing an interim final rule placing ganaxolone, including its salts
in schedule V of the Controlled Substances Act.
DATES: This rule is effective June 1, 2022. Comments must be submitted
electronically or postmarked on or before July 1, 2022. Interested
persons may file written comments on this rulemaking in accordance with
21 U.S.C. 811(j)(3) and 21 CFR 1308.43(g). Commenters should be aware
that the electronic Federal Docket Management System will not accept
comments after 11:59 p.m. Eastern Time on the last day of the comment
period.
Interested persons may file a request for a hearing or waiver of a
hearing in accordance with 21 U.S.C. 811(j)(3) and 21 CFR 1308.44.
Requests for a hearing and waivers of an opportunity for a hearing or
to participate in a hearing must be received on or before July 1, 2022.
ADDRESSES: To ensure proper handling of comments, please reference
``Docket No. DEA-990'' on all correspondence, including any
attachments.
<bullet> Electronic comments: The Drug Enforcement Administration
(DEA) encourages that all comments be submitted electronically through
the Federal eRulemaking Portal, which provides the ability to type
short comments directly into the comment field on the web page or
attach a file for lengthier comments. Please go to <a href="http://www.regulations.gov">http://www.regulations.gov</a> and follow the online instructions at that site for
submitting comments. Upon completion of your submission, you will
receive a Comment Tracking Number for your comment. Submitted comments
are not instantaneously available for public view on <a href="http://Regulations.gov">Regulations.gov</a>.
If you have received a Comment Tracking Number, your comment has been
successfully submitted and there is no need to resubmit the same
comment.
<bullet> Paper comments: Paper comments that duplicate electronic
submissions are not necessary and are discouraged. Should you wish to
mail a paper comment in lieu of an electronic comment, it should be
sent via regular or express mail to: Drug Enforcement Administration,
Attn: DEA Federal Register Representative/DPW, 8701 Morrissette Drive,
Springfield, VA 22152.
<bullet> Hearing requests: All requests for a hearing and waivers
of participation, together with a written statement of position on the
matters of fact and law asserted in the hearing, must be sent to: Drug
Enforcement Administration, Attn: Hearing Clerk/OALJ, 8701 Morrissette
Drive, Springfield, Virginia 22152. All requests for hearing and
waivers of participation should also be sent to: (1) Drug Enforcement
Administration, Attn: Administrator, 8701 Morrissette Drive,
Springfield, Virginia 22152; and (2) Drug Enforcement Administration,
Attn: DEA Federal Register Representative/DPW, 8701 Morrissette Drive,
Springfield, Virginia 22152.
FOR FURTHER INFORMATION CONTACT: Terrence L. Boos, Drug & Chemical
Evaluation Section, Diversion Control Division, Drug Enforcement
Administration; Telephone: (571) 362-3249.
SUPPLEMENTARY INFORMATION:
Posting of Public Comments
Please note, all comments received in response to this docket are
considered part of the public record. The Drug Enforcement
Administration (DEA) will make comments available, unless reasonable
cause is given, for public inspection online at <a href="http://www.regulations.gov">http://www.regulations.gov</a>. Such information includes personal identifying
information (such as your name, address, etc.) voluntarily submitted by
the commenter. The Freedom of Information Act applies to all comments
received. If you want to submit personal identifying information (such
as your name, address, etc.) as part of your comment, but do not want
DEA to make it publicly available, you must include the phrase
``PERSONAL IDENTIFYING INFORMATION'' in the first paragraph of your
comment. You must also place all of the personal identifying
information you do not want made publicly available in the first
paragraph of your comment and identify what information you want
redacted.
If you want to submit confidential business information as part of
your comment, but do not want DEA to make it publicly available, you
must include the phrase ``CONFIDENTIAL BUSINESS INFORMATION'' in the
first paragraph of your comment. You must also prominently identify the
confidential business information to be redacted within the comment.
DEA will generally make available in publicly redacted form
comments
[[Page 32992]]
containing personal identifying information and confidential business
information identified, as directed above. If a comment has so much
confidential business information or personal identifying information
that DEA cannot effectively redact it, DEA may not make available
publicly all or part of that comment. Comments posted to <a href="http://www.regulations.gov">http://www.regulations.gov</a> may include any personal identifying information
(such as name, address, and phone number) included in the text of your
electronic submission that is not identified as confidential as
directed above.
An electronic copy of this document and supplemental information to
this interim final rule (IFR) are available at <a href="http://www.regulations.gov">http://www.regulations.gov</a> for easy reference.
Request for Hearing or Appearance; Waiver
Pursuant to 21 U.S.C. 811(a), this action is a formal rulemaking
``on the record after opportunity for a hearing.'' Such proceedings are
conducted pursuant to the provisions of the Administrative Procedure
Act (APA), 5 U.S.C. 551-559. 21 CFR 1308.41-1308.45; 21 CFR part 1316,
subpart D. Interested persons may file requests for a hearing or
notices of intent to participate in a hearing in conformity with the
requirements of 21 CFR 1308.44(a) or (b), and such requests must
include a statement of the person's interests in the proceeding and the
objections or issues, if any, concerning which the person desires to be
heard. 21 CFR 1316.47(a). Any interested person may file a waiver of an
opportunity for a hearing or to participate in a hearing together with
a written statement regarding the interested person's position on the
matters of fact and law involved in any hearing as set forth in 21 CFR
1308.44(c).
All requests for hearings and waivers of participation, together
with a written statement of position on the matters of fact and law
involved in such hearing, must be sent to DEA using the address
information provided above.
Background and Legal Authority
Under the Controlled Substances Act (CSA), as amended in 2015 by
the Improving Regulatory Transparency for New Medical Therapies Act
(section 2(b) of Publ. L. 114-89), DEA is required to commence an
expedited scheduling action with respect to certain new drugs approved
by the Food and Drug Administration (FDA). As provided in 21 U.S.C.
811(j), this expedited scheduling is required where both of the
following conditions apply: (1) The Secretary of the Department of
Health and Human Services (HHS) has advised DEA that a New Drug
Application (NDA) has been submitted for a drug that has a stimulant,
depressant, or hallucinogenic effect on the central nervous system
(CNS), and that it appears that such drug has an abuse potential; and
(2) the Secretary of HHS recommends that DEA control the drug in
schedule II, III, IV, or V pursuant to 21 U.S.C. 811(a) and (b). In
these circumstances, DEA is required to issue an interim final rule
(IFR) controlling the drug within 90 days.
Subsection (j)(2) states that the 90-day timeframe starts the later
of (1) the date DEA receives HHS' scientific and medical evaluation/
scheduling recommendation, or (2) the date DEA receives notice of the
NDA approval by HHS. Subsection (j)(3) specifies that the rulemaking
shall become immediately effective as an IFR without requiring DEA to
demonstrate good cause therefore. Thus, the purpose of subsection (j)
is to speed the process by which DEA schedules newly approved drugs
that are currently either in schedule I or not controlled (but which
have sufficient abuse potential to warrant control) so that such drugs
may be marketed without undue delay following FDA approval.\1\
---------------------------------------------------------------------------
\1\ Given the parameters of subsection (j), in DEA's view, it
would not apply to a reformulation of a drug containing a substance
currently in schedules II through V for which an NDA has recently
been approved.
---------------------------------------------------------------------------
Subsection (j)(3) further provides that the IFR shall give
interested persons the opportunity to comment and to request a hearing.
After the conclusion of such proceedings, DEA must issue a final rule
in accordance with the scheduling criteria of 21 U.S.C. 811(b) through
(d) and 812(b).
Ganaxolone (3[alpha]-hydroxy-3[beta]-methyl-5[alpha]-pregnan-20-
one) is a new molecular entity (NME) with CNS activity. Ganaxolone is a
neuroactive positive allosteric modulator of gamma-aminobutyric acid
type-A (GABA-A) receptors and an inhibitory neurosteroidal substance
that shares structural features and a pharmacological mechanism of
action with progesterone and schedule IV depressants alfaxalone and
brexanolone.
On July 20, 2021, Marinus Pharmaceuticals, Inc. (Sponsor) submitted
an NDA for ganaxolone to FDA. On March 18, 2022, DEA received
notification that FDA, on the same date, approved the NDA for ZTALMY
(ganaxolone oral suspension), under section 505(c) of the Federal Food,
Drug, and Cosmetic Act (FDCA), for the treatment of seizures associated
with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD)
in patients two years of age and older. Pursuant to its FDA-approved
prescription drug labeling, ZTALMY is to be administered orally three
times daily (TID) with food on a titration schedule through a dose-
escalation protocol over the first 3 weeks of drug administration.
Patients weighing 28 kg or less receive a final dose of 21 mg/kg TID
(63 mg/kg/day) and patients weighing more than 28 kg receive a final
dose of 600 mg TID (1800 mg/day).\2\
---------------------------------------------------------------------------
\2\ <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215904s000lbl.pdf">https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215904s000lbl.pdf</a>. Date accessed March 28, 2022.
---------------------------------------------------------------------------
Determination To Schedule Ganaxolone
On March 14, 2022, DEA received from HHS a scientific and medical
evaluation entitled ``Basis for the Recommendation to Control
Ganaxolone and its Salts in Schedule V of the Controlled Substances
Act'' and a scheduling recommendation. Pursuant to 21 U.S.C. 811(b) and
(c), this document contained an eight-factor analysis of the abuse
potential, legitimate medical use, and dependence liability of
ganaxolone, along with HHS's recommendation to control ganaxolone and
its salts under schedule V of the CSA.
In response, DEA reviewed the scientific and medical evaluation and
scheduling recommendation provided by HHS, along with all other
relevant data, and completed its own eight-factor review pursuant to 21
U.S.C. 811(c). DEA concluded that ganaxolone meets the 21 U.S.C.
812(b)(5) criteria for placement in schedule V of the CSA.
Pursuant to subsection 811(j), and based on HHS' scheduling
recommendation, the approval of the NDA by HHS/FDA, and DEA's
determination, DEA is issuing this IFR to schedule ganaxolone as a
schedule V controlled substance under the CSA.
Included below is a brief summary of each factor as analyzed by HHS
and DEA, and as considered by DEA in its scheduling action. Please note
that both DEA and HHS analyses are available in their entirety under
``Supporting Documents'' in the public docket for this IFR at <a href="http://www.regulations.gov">http://www.regulations.gov</a>, under Docket Number ``DEA-990.'' Full analysis of,
and citations to, the information referenced in the summary may also be
found in the supporting and related material.
1. Its Actual or Relative Potential for Abuse
Ganaxolone is an NME that has not been marketed in the United
States or
[[Page 32993]]
any country. Thus, evidence regarding its diversion, illicit
manufacturing, or deliberate ingestion is currently lacking. DEA notes
that there are no reports of law enforcement encounters of ganaxolone
in the National Forensic Laboratory Information System (NFLIS)
database,\3\ which collects drug cases submitted to and analyzed by
state and local forensic laboratories. Ganaxolone has sedative effects
and is likely to have abuse potential, although less than that of
schedule IV sedatives such as lorazepam. Thus, it is reasonable to
assume that ganaxolone may be diverted from legitimate channels, used
contrary to or without medical advice, and capable of creating hazards
to the users and to the safety of the community. In preclinical and
clinical studies, ganaxolone produced effects that are less than that
of schedule IV sedative drugs such as methohexital and lorazepam.
Ganaxolone produced positive subjective responses and euphoria-related
adverse events (AEs) that were significantly greater than placebo, but
statistically less than that of lorazepam (schedule IV) in healthy
humans, nondependent with a history of recreational use of CNS
depressants; thus, it is likely to be abused for its sedative effects
contrary to medical advice.
---------------------------------------------------------------------------
\3\ NFLIS is a comprehensive information system that includes
data from forensic laboratories that handle more than 96% of an
estimated 1.0 million distinct annual State and local drug analysis
cases. NFLIS includes drug chemistry results from completed analyses
only. While NFLIS data is not direct evidence of abuse, it can lead
to an inference that a drug has been diverted and abused. See 76 FR
77330, 77332, Dec. 12, 2011. NFLIS data were queried on January 18,
2022.
---------------------------------------------------------------------------
2. Scientific Evidence of Its Pharmacological Effects, if Known
Ganaxolone shares a pharmacological profile with other inhibitory
neurosteroids such as alfaxalone and brexanolone, both schedule IV
drugs. Ganaxolone acts on GABA-A receptors to enhance the effects of
GABA, a major inhibitory neurotransmitter in the CNS. Data from in
vitro binding studies showed that ganaxolone had significant affinity
(greater than 96 percent) for the GABA-chloride channels. Ganaxolone
did not show significant affinity (less than 50 percent) for 47 other
receptor sites, ion channels, steroid sites, and enzymes. The sites
tested included abuse-related sites such as dopamine (D<INF>1</INF> and
D<INF>2</INF>), serotonin (1a, 2a, and 2c), cannabinoid (CB<INF>1</INF>
and CB<INF>2</INF>), opioid (mu, kappa, delta), glutamate (NMDA/AMPA,
phencyclidine, glycine, kainite), and monoamine transporters (dopamine,
serotonin, or norepinephrine). Functional activity studies showed that
ganaxolone potentiated GABA-evoked chloride currents in Xenopus oocytes
expressing human GABA-A receptor subunits.
In animal studies, orally-administered ganaxolone's effect on
general behavioral profile showed that it did not produce behavioral
activity that differed significantly from the saline-treated group.
However, ganaxolone elicited time-dependent (6-hour post treatment)
behavior changes such as abnormal gait, grasping loss, abnormal
righting reflex, and low carriage indicative of the sedative and muscle
relaxation properties of the drug. Ganaxolone's effect on motor
coordination was evaluated in three rotarod studies in rats. The
studies showed that ganaxolone produced a dose-dependent increase in
the number of rats that failed to maintain themselves on the rotarod,
indicative of its interference on motor coordination. Ganaxolone
produced a dose-dependent decrease in locomotor activity and loss of
righting reflex.
In a drug discrimination study using rats trained to discriminate
midazolam (schedule IV) and saline, oral doses of ganaxolone (10 and 30
mg/kg) produced full generalization to midazolam stimuli. Ganaxolone's
reinforcing properties were assessed by determining whether self-
administration behavior was maintained when the drug was substituted
for heroin. Data from this study showed that ganaxolone self-
administration was much less than that of methohexital (schedule IV)
and heroin (schedule I) and was numerically similar to saline. However,
ganaxolone at 0.10 mg/kg/injection dose produced self-administration
that was statistically significantly greater than saline.
A randomized, double-blind, active- and placebo-controlled, cross-
over study was conducted to determine the abuse potential for
ganaxolone in healthy, nondependent, recreational CNS depressant users.
Oral doses of ganaxolone were compared to an oral dose of lorazepam
(schedule IV, served as the positive control). The lower and middle
doses of ganaxolone (400 mg and 800 mg, respectively) produced
responses within or just outside the acceptable placebo range and were
statistically similar to placebo. However, the highest dose of
ganaxolone (2000 mg) produced a drug liking score that was
significantly different from placebo. The three doses of ganaxolone
tested produced drug liking scores that were significantly lower than
that of lorazepam. In addition, all three oral doses of ganaxolone
(400, 800, and 2000 mg) produced responses on all other positive
subjective measures (bipolar visual analog scale for Overall Drug
Liking, High, Good Effects, and Take Drug Again) that were
statistically less than those produced by 6 mg oral dose of lorazepam.
In 23 Phase 1 clinical safety studies that were conducted using
healthy individuals, eight of the studies showed that ganaxolone
produced euphoria-related AEs at all doses tested. Of the eight
studies, three were repeat-dose studies and five were acute-dose
studies. From the three repeat-dose studies, 24 of 64 subjects who
received ganaxolone reported euphoria-related AEs at any dose tested,
compared to 0 of 17 subjects who received placebo. Of the five acute-
dose studies, euphoria-related AEs were reported by 8 of the 101
subjects who received ganaxolone at any dose tested, compared to 1 of
12 subjects who received placebo. Most of the euphoria-related AEs
following ganaxolone administration were mild in severity. In Phase 2/3
clinical studies conducted with ganaxolone in either epilepsy patients
or post-traumatic stress disorder patients, the degree of euphoria-
related AEs could not be determined because all subjects in these
studies were concurrently taking antiepileptic drugs (epilepsy
patients) or benzodiazepines (post-traumatic stress disorder patients).
Because many antiepileptic drugs and benzodiazepines are known to
produce euphoria and sedation, and are often controlled in schedule IV
of the CSA, their use in human subjects confounds interpreting any
ganaxolone euphoria-related AEs that may be reported during these
clinical studies. However, in one of the three clinical studies
conducted in patients with migraine, euphoria was reported in 3 of the
163 subjects who received a single 750 mg oral dose of ganaxolone (1.8
percent, 2 moderate, 1 severe), compared to 1 of 164 subjects who
received placebo (0.6 percent, 1 mild).
In summary, ganaxolone produced incidence of euphoria-related AEs
supportive of its abuse potential. In animal studies, ganaxolone
produced interoceptive cues that were similar to those of midazolam, a
schedule IV depressant, and these data are consistent with the fact
that both drugs share a common mechanism of action involving positive
allosteric modulation of the GABA-A receptors. In self-administration
studies conducted in animals, ganaxolone produced rewarding effects,
but its self-administration was lower than methohexital (schedule IV)
and heroin (schedule I) injections. As mentioned by HHS, in clinical
studies, ganaxolone produced an 8.8 percent incidence of
[[Page 32994]]
euphoria-like AEs, including euphoria, thinking abnormal, feeling
drunk, and depersonalization, across acute doses of 300 to 1,500 mg/day
and repeat doses of 400 to 2,250 mg/day, as compared to that of placebo
(2.3 percent) in healthy individuals.
3. The State of Current Scientific Knowledge Regarding the Drug or
Other Substance
Ganaxolone, chemically known as 3[alpha]-hydroxy-3[beta]-methyl-
5[alpha]-pregnan-20-one, is an NME. It is a structural derivative of
allopregnanolone (also known as brexanolone, schedule IV). Ganaxolone
is structurally different from brexanolone by the presence of an extra
methyl group at the 3[beta]-position. It is insoluble in water,
slightly soluble in methanol, ethanol, isopropanol, ethyl acetate, and
toluene (5 to 25 mg/mL at 20 degrees Celsius), and soluble in N,N-
dimethylacetamide. Ganaxolone is a drug product formulated as a 50 mg/
mL white to off-white immediate release oral suspension in water and is
administered by mouth TID with food. Ganaxolone is absorbed with a time
to peak plasma concentration of 2.0 to 3.0 hours following oral
administration. It undergoes first pass metabolism following oral
administration with 10 percent bioavailability. It is approximately 99
percent protein bound in serum and has a terminal half-life at steady
state of about 8-10 hours.
As discussed in the background section, ganaxolone has an accepted
medical use in the United States.
4. Its History and Current Pattern of Abuse
There is no information on the history and current pattern of abuse
for ganaxolone, since it has not been marketed, legally or illegally,
in the United States or any other country. There is no evidence of
diversion of ganaxolone that has been distributed for research, such as
for clinical trials. Data from preclinical and clinical studies
indicate that the abuse potential of ganaxolone is less than that of
schedule IV CNS depressants such as methohexital and lorazepam.
Consistent with the fact that ganaxolone is an NME, the NFLIS database
had no records of encounters by law enforcement.
In summary, pharmacological data on ganaxolone show that it
produces abuse-related AEs and has an abuse potential less than that of
schedule IV CNS depressants.
5. The Scope, Duration, and Significance of Abuse
Data from preclinical and clinical studies showed that ganaxolone
has an abuse potential that is less than that of schedule IV
depressants. Thus, ganaxolone has a low potential for abuse relative to
substances in schedule IV. A search by DEA of the NFLIS database found
no evidence of law enforcement encounters of ganaxolone in the United
States. Because ganaxolone is a positive allosteric modulator of GABA-A
receptors and has abuse potential, upon availability of ganaxolone in
the market, it is likely to be abused.
6. What, if any, Risk There Is to the Public Health
Ganaxolone's abuse potential, although less than that of schedule
IV depressants, is an indication of its public health risk. As such,
upon availability for marketing, it is likely to pose risk to public
health comparable to drugs in schedule V. According to information
mentioned in the prescription product label for ZTALMY (ganaxolone),
concomitant use of opioids, antidepressants, or other CNS depressants
such as alcohol may potentiate incidence of somnolence and sedation in
patients receiving ganaxolone. The abuse of ganaxolone may present
risks to the public health at a level similar to those associated with
the abuse of CNS depressants.
7. Its Psychic or Physiological Dependence Liability
Ganaxolone's psychic and physiological dependence liability was
assessed using data from a rat physical dependence study and human
data. A physical dependence study was not conducted in clinical studies
because abrupt discontinuation of an antiepileptic drug in epileptic
patients presents serious safety concerns. As described by HHS, data
from a physiologic dependence study conducted in rats demonstrated that
chronic administration of ganaxolone produced a decrease in body weight
and changes in behavior that included ataxia, rearing, escape attempts
from the cage, increased body tone, increased locomotor activity,
increased reaction to sound, explosive movements, and piloerection.
Decreases in body weight, food and water intake, and increased body
temperature were observed upon discontinuation of ganaxolone. During
ganaxolone discontinuation, 5 of 10 rats showed behaviors that included
increased locomotor activity, increased reaction to sound, hunched
posture, and piloerection. Further, since ganaxolone produced positive
subjective responses and euphoria-related AEs in human subjects, it is
likely that it may produce psychic dependence.
In summary, data from animal studies demonstrate that chronic
administration of ganaxolone produces signs or symptoms of withdrawal
upon discontinuation. Ganaxolone produces physical dependence.
8. Whether the Substance Is an Immediate Precursor of a Substance
Already Controlled Under the CSA
Ganaxolone is not an immediate precursor of any controlled
substance, as defined by 21 U.S.C. 802(23).
Conclusion: After considering the scientific and medical evaluation
and scheduling recommendation provided by HHS, and its own eight-factor
analysis, DEA has determined that these facts and all relevant data
constitute substantial evidence of potential for abuse of ganaxolone.
As such, DEA hereby schedules ganaxolone as a controlled substance
under the CSA.
Determination of Appropriate Schedule
The CSA lists the findings required to place a drug or other
substance in any particular schedule (I, II, III, IV, or V). 21 U.S.C.
812(b). After consideration of the analysis and recommendation of the
Assistant Secretary for Health of HHS and review of all available data,
the Administrator of DEA (Administrator), pursuant to 21 U.S.C.
812(b)(5), finds that:
(1) Ganaxolone has a low potential for abuse relative to the drugs
or other substances in schedule IV.
Ganaxolone, a neuroactive steroid, is a positive allosteric
modulator of GABA-A receptors and produces sedation in general
behavioral studies including rotarod and locomotion studies. In a drug
discrimination study in animals, ganaxolone generalized to midazolam
(schedule IV), demonstrating it has GABA-A receptor agonist properties.
In a self-administration study in animals, ganaxolone self-
administration was significantly different from saline, but was less
than that of methohexital (schedule IV) and heroin (schedule I).
Ganaxolone produced positive subjective responses and euphoria-related
AEs less than that of lorazepam (schedule IV), but greater than that of
placebo in a human abuse potential study. Furthermore, data from
pharmacokinetic clinical studies show that ganaxolone produced
incidence of euphoria in 8.8 percent of healthy individuals as compared
to 2.3 percent incidence following placebo. Therefore, ganaxolone has
some potential for abuse, but it is low relative to lorazepam,
methohexital and other substances in schedule IV.
[[Page 32995]]
(2) Ganaxolone has a currently accepted medical use in treatment in
the United States.
FDA recently approved the NDA for ZTALMY (ganaxolone) as an oral
adjunctive therapy for the treatment of an epilepsy condition, cyclin-
dependent, kinase-like 5 deficiency disorder, in patients aged two
years and older. Thus, ganaxolone has a currently accepted medical use
in treatment in the United States.
(3) Abuse of ganaxolone may lead to limited physical dependence or
psychological dependence relative to the drugs or other substances in
schedule IV.
Ganaxolone shares a similar pharmacology profile with brexanolone
(schedule IV). Data from a rat physical dependence study demonstrated
that discontinuation of chronic administration of ganaxolone produced
withdrawal syndrome. Thus, abuse of ganaxolone may lead to limited
physical dependence. Further, because ganaxolone produced positive
subjective responses and euphoria-related AEs, it may produce psychic
dependence. However, there were fewer reports of euphoria-related AEs
associated with ganaxolone than lorazepam (schedule IV). Ganaxolone may
lead to limited physical or psychological dependence relative to other
substances in schedule IV.
Based on these findings, the Administrator concludes that
ganaxolone warrants control in schedule V of the CSA. 21 U.S.C.
812(b)(5).
Requirements for Handling Ganaxolone
Ganaxolone is subject to the CSA's schedule V regulatory controls
and administrative, civil, and criminal sanctions applicable to the
manufacture, distribution, reverse distribution, dispensing, importing,
exporting, research, and conduct of instructional activities and
chemical analysis with, and possession involving schedule V substances,
including the following:
1. Registration. Any person who handles (manufactures, distributes,
reverse distributes, dispenses, imports, exports, engages in research,
or conducts instructional activities or chemical analysis with, or
possesses), or who desires to handle, ganaxolone must be registered
with 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 or intends to handle ganaxolone and is not
registered with DEA must submit an application for registration and may
not continue to handle ganaxolone unless DEA has approved that
application, pursuant to 21 U.S.C. 822, 823, 957, and 958, and in
accordance with 21 CFR parts 1301 and 1312. These registration
requirements, however, are not applicable to patients (end users) who
possess ganaxolone pursuant to a lawful prescription.
2. Disposal of stocks. Any person unwilling or unable to obtain a
schedule V registration to handle ganaxolone, but who subsequently does
not desire or is not able to maintain such registration must surrender
all quantities of currently held ganaxolone, or may transfer all
quantities of currently held ganaxolone to a person registered with
DEA. Ganaxolone is required to be disposed of in accordance with 21 CFR
part 1317, in addition to all other applicable Federal, state, local,
and tribal laws.
3. Security. Ganaxolone is subject to schedule III-V security
requirements for DEA registrants, and it must be handled and stored in
accordance with 21 CFR 1301.71-1301.77. Non-practitioners handling
ganaxolone must also comply with the employee screening requirements of
21 CFR 1301.90-1301.93. These requirements, however, are not applicable
to patients (end users) who possess ganaxolone pursuant to a lawful
prescription.
4. Labeling and Packaging. All labels, labeling, and packaging for
commercial containers of ganaxolone must comply with 21 U.S.C. 825 and
958(e), and be in accordance with 21 CFR part 1302.
5. Inventory. Every DEA registrant who possesses any quantity of
ganaxolone must take an inventory of ganaxolone on hand, pursuant to 21
U.S.C. 827 and 958, and in accordance with 21 CFR 1304.03, 1304.04, and
1304.11(a) and (d).
Any person who registers with DEA to handle ganaxolone must take an
initial inventory of all stocks of controlled substances (including
ganaxolone) on hand on the date the registrant first engages in the
handling of controlled substances, pursuant to 21 U.S.C. 827 and
958(e), and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11(a)
and (b).
After the initial inventory, every DEA registrant must take an
inventory of all stocks of controlled substances (including ganaxolone)
on hand every two years, pursuant to 21 U.S.C. 827 and 958(e), and in
accordance with 21 CFR 1304.03, 1304.04, and 1304.11. These
requirements, however, are not applicable to patients (end users) who
possess ganaxolone pursuant to a lawful prescription.
6. Records and Reports. DEA registrants must maintain records and
submit reports for ganaxolone, pursuant to 21 U.S.C. 827, 832(a), and
958(e), and in accordance with 21 CFR 1301.74(b) and (c) and parts
1304, 1312, and 1317.
7. Prescriptions. All prescriptions for ganaxolone, or products
containing ganaxolone, must comply with 21 U.S.C. 829, and be issued in
accordance with 21 CFR parts 1306 and 1311, subpart C.
8. Manufacturing and Distributing. In addition to the general
requirements of the CSA and DEA regulations that are applicable to
manufacturers and distributors of schedule V controlled substances,
such registrants should be advised that (consistent with the foregoing
considerations) any manufacturing or distribution of ganaxolone may
only be for the legitimate purposes consistent with the drug's
labeling, or for research activities authorized by the FDCA, as
applicable, and the CSA.
9. Importation and Exportation. All importation and exportation of
ganaxolone must comply with 21 U.S.C. 952, 953, 957, and 958, and be in
accordance with 21 CFR part 1312.
10. Liability. Any activity involving ganaxolone not authorized by,
or in violation of, the CSA or its implementing regulations, is
unlawful, and may subject the person to administrative, civil, and/or
criminal sanctions.
Regulatory Analyses
Administrative Procedure Act
Section 553 of the APA (5 U.S.C. 553) generally requires notice and
comment for rulemakings. However, 21 U.S.C. 811(j) provides that in
cases where a certain new drug is (1) approved by HHS, under section
505(c) of the FDCA and (2) HHS recommends control in CSA schedule II-V,
DEA shall issue an IFR scheduling the drug within 90 days. As stated in
the legal authority section, the 90-day time frame is the later of: (1)
The date DEA receives HHS's scientific and medical evaluation/
scheduling recommendation, or (2) the date DEA receives notice of the
NDA approval by HHS. Additionally, subsection (j) specifies that the
rulemaking shall become immediately effective as an IFR without
requiring DEA to demonstrate good cause.
Executive Orders 12866 (Regulatory Planning and Review) and 13563
(Improving Regulation and Regulatory Review)
In accordance with 21 U.S.C. 811(a) and (j), this scheduling action
is subject to formal rulemaking procedures performed ``on the record
after opportunity for a hearing,'' which are
[[Page 32996]]
conducted pursuant to the provisions of 5 U.S.C. 556 and 557. The CSA
sets forth the procedures and criteria for scheduling a drug or other
substance. Such actions are exempt from review by the Office of
Management and Budget (OMB) pursuant to section 3(d)(1) of Executive
Order (E.O.) 12866 and the principles reaffirmed in E.O. 13563.
Executive Order 12988, Civil Justice Reform
This regulation meets the applicable standards set forth in
sections 3(a) and 3(b)(2) of E.O. 12988 to eliminate drafting errors
and ambiguity, minimize litigation, provide a clear legal standard for
affected conduct, and promote simplification and burden reduction.
Executive Order 13132, Federalism
This rulemaking does not have federalism implications warranting
the application of E.O. 13132. The rule does not have substantial
direct effects on the States, on the relationship between the national
government and the States, or on the distribution of power and
responsibilities among the various levels of government.
Executive Order 13175, Consultation and Coordination With Indian Tribal
Governments
This rule does not have tribal implications warranting the
application of E.O. 13175. It does not have substantial direct effects
on one or more Indian tribes, on the relationship between the Federal
government and Indian tribes, or on the distribution of power and
responsibilities between the Federal government and Indian tribes.
Regulatory Flexibility Act
The Regulatory Flexibility Act (RFA) (5 U.S.C. 601-612) applies to
rules that are subject to notice and comment under section 553(b) of
the APA. As noted in the above discussion regarding the applicability
of the APA, DEA is not required to publish a general notice of proposed
rulemaking. Consequently, the RFA does not apply to this IFR.
Unfunded Mandates Reform Act of 1995
In accordance with the Unfunded Mandates Reform Act (UMRA) of 1995,
2 U.S.C. 1501 et seq., DEA has determined that this action would not
result in any Federal mandate that may result ``in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any 1 year.'' Therefore, neither a Small Government
Agency Plan nor any other action is required under UMRA of 1995.
Paperwork Reduction Act of 1995
This action does not impose a new collection of information
requirement under the Paperwork Reduction Act of 1995. 44 U.S.C. 3501-
3521. This action would not impose recordkeeping or reporting
requirements on State or local governments, individuals, businesses, or
organizations. An agency may not conduct or sponsor, and a person is
not required to respond to, a collection of information unless it
displays a currently valid OMB control number.
Congressional Review Act
This rule is not a major rule as defined by the Congressional
Review Act (CRA), 5 U.S.C. 804. However, pursuant to the CRA, DEA is
submitting a copy of this IFR to both Houses of Congress and to the
Comptroller General.
List of Subjects in 21 CFR Part 1308
Administrative practice and procedure, Drug traffic control,
Reporting and recordkeeping requirements.
For the reasons set out above, DEA amends 21 CFR part 1308 as
follows:
PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES
0
1. The authority citation for 21 CFR part 1308 continues to read as
follows:
Authority: 21 U.S.C. 811, 812, 871(b), 956(b) unless otherwise
noted.
0
2. In Sec. 1308.15:
0
a. Redesignate paragraphs (e)(4) through (6) as paragraphs (e)(5)
through (7); and
0
b. Add new paragraph (e)(4).
The addition reads as follows:
Sec. 1308.15 Schedule V.
* * * * *
(e) * * *
(4) Ganaxolone (3[alpha]-hydroxy-3[beta]-methyl-5[alpha]- 2401
pregnan-20-one)........................................
* * * * *
Anne Milgram,
Administrator.
[FR Doc. 2022-11735 Filed 5-31-22; 8:45 am]
BILLING CODE 4410-09-P
</pre></body>
</html>Indexed from Federal Register on June 1, 2022.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.