Federal Register / Vol. 87, No. 105 / Wednesday, June 1, 2022 / Rules and Regulations 32991 

8R.J. Reynolds Tobacco Co., No. 6:20–cv–00176 

(E.D. Tex. February 10, 2022) (order postponing 

effective date), Doc. No. 94. 

9R.J. Reynolds Tobacco Co., No. 6:20–cv–00176 

(E.D. Tex. May 10, 2022) (order postponing effective 

date), Doc. No. 96. 

additional 90 days.8 On May 10, 2022, 

the court issued another order to 

postpone the effective date of the final 

rule by an additional 90 days.9 The 

court ordered that the new effective date 

of the final rule is July 8, 2023. Pursuant 

to the court order, any obligation to 

comply with a deadline tied to the 

effective date is similarly postponed, 

and those obligations and deadlines are 

now tied to the postponed effective 

date. 

To the extent that 5 U.S.C. 553 applies 

to this action, the Agency’s 

implementation of this action without 

opportunity for public comment, 

effective immediately upon publication 

today in the Federal Register, is based 

on the good cause exception in 5 U.S.C. 

553(b)(B). Seeking public comment is 

impracticable, unnecessary, and 

contrary to the public interest. The 90- 

day postponement of the effective date, 

until July 8, 2023, is required by court 

order in accordance with the court’s 

authority to postpone a rule’s effective 

date pending judicial review (5 U.S.C. 

705). Seeking prior public comment on 

this postponement would have been 

impracticable, as well as contrary to the 

public interest in the orderly issuance 

and implementation of regulations. 

Dated: May 24, 2022. 

Lauren K. Roth, 

Associate Commissioner for Policy. 

[FR Doc. 2022–11568 Filed 5–31–22; 8:45 am] 

BILLING CODE 4164–01–P 

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. 

• 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 http:// 

www.regulations.gov 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 Regulations.gov. If you have 

received a Comment Tracking Number, 

your comment has been successfully 

submitted and there is no need to 

resubmit the same comment. 

• 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. 

• 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 http://

www.regulations.gov. 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 


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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. 

2https://www.accessdata.fda.gov/drugsatfda_

docs/label/2022/215904s000lbl.pdf. Date accessed 

March 28, 2022. 

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 http://www.regulations.gov 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 

http://www.regulations.gov 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

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 (3a-hydroxy-3b-methyl5a-pregnan-20-one) is a new molecular 

entity (NME) with CNS activity. 

Ganaxolone is a neuroactive positive 

allosteric modulator of gammaaminobutyric 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 doseescalation 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

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 http://www.regulations.gov, 

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 


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3NFLIS 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. 

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. 

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 

(D1 and D2), serotonin (1a, 2a, and 2c), 

cannabinoid (CB1 and CB2), 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 selfadministration 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, activeand 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 euphoriarelated 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, euphoriarelated 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 selfadministration studies conducted in 

animals, ganaxolone produced 

rewarding effects, but its selfadministration 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 


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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 3ahydroxy-3b-methyl-5a-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 3b-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,Ndimethylacetamide. 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 abuserelated 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 selfadministration 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. 


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Federal Register / Vol. 87, No. 105 / Wednesday, June 1, 2022 / Rules and Regulations 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, cyclindependent, 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 euphoriarelated 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 


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32996 Federal Register / Vol. 87, No. 105 / Wednesday, June 1, 2022 / Rules and Regulations 

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 

■ 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. 

■ 2. In § 1308.15: 

■ a. Redesignate paragraphs (e)(4) 

through (6) as paragraphs (e)(5) through 

(7); and 

■ b. Add new paragraph (e)(4). 

The addition reads as follows: 

§ 1308.15 Schedule V. 

* * * * * 

(e) * * * 

(4) Ganaxolone (3a-hydroxy-3b-methyl-5a-pregnan-20-one) ........................................................................................................... 2401 

* * * * * 

Anne Milgram, 

Administrator. 

[FR Doc. 2022–11735 Filed 5–31–22; 8:45 am] 

BILLING CODE 4410–09–P 

DEPARTMENT OF JUSTICE 

Drug Enforcement Administration 

21 CFR Part 1308 

[Docket No. DEA–495] 

Schedules of Controlled Substances: 

Placement of N-Ethylhexedrone, alphaPyrrolidinohexanophenone, 4-Methylalpha-ethylaminopentiophenone, 4′- 

Methyl-alphapyrrolidinohexiophenone, alphaPyrrolidinoheptaphenone, and 4′- 

Chloro-alphapyrrolidinovalerophenone in Schedule 

I 

AGENCY: Drug Enforcement 

Administration, Department of Justice. 

ACTION: Final rule. 

SUMMARY: By this rule, the Drug 

Enforcement Administration 

permanently places six synthetic 

cathinones, as identified in this rule, in 

schedule I of the Controlled Substances 

Act. These six substances are currently 

listed in schedule I pursuant to a 

temporary scheduling order. As a result 

of this rule, the regulatory controls and 

administrative, civil, and criminal 

sanctions applicable to schedule I 

controlled substances on persons who 

handle (manufacture, distribute, reverse 

distribute, import, export, engage in 

research, conduct instructional 

activities or chemical analysis, or 

possess) or propose to handle these six 

specified controlled substances will 

continue to apply. 

DATES: Effective June 1, 2022. 

FOR FURTHER INFORMATION CONTACT: 

Terrence L. Boos, Drug and Chemical 

Evaluation Section, Diversion Control 

Division, Drug Enforcement 

Administration; Telephone: (571) 362– 

8207. 

SUPPLEMENTARY INFORMATION: In this 

rule, the Drug Enforcement 

Administration (DEA) is permanently 


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