[Federal Register: December 13, 2005 (Volume 70, Number 238)]
[Notices]               
[Page 73775-73779]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr13de05-55]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2005N-0479]

 
International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; Butorphanol; Delta-9-
tetrahydrocannabinol (Dronabinol); Gamma-Hydroxybutyric Acid; Ketamine; 
Khat; Tramadol; Zopiclone; Buprenorphine; Oripavine

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is requesting 
interested persons to submit comments concerning abuse potential, 
actual abuse, medical usefulness, trafficking, and impact of scheduling 
changes on availability for medical use of nine drug substances. These 
comments will be considered in preparing a response from the United 
States to the World Health Organization (WHO) regarding the abuse 
liability and diversion of these drugs. WHO will use this information 
to consider whether to recommend that certain international 
restrictions be placed on these drugs. This notice requesting comments 
is required by the Controlled Substances Act (CSA).

DATES: Submit written or electronic comments by January 12, 2006.

ADDRESSES: Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852. Submit electronic comments to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments
.


FOR FURTHER INFORMATION CONTACT: James R. Hunter, Center for Drug 
Evaluation and Research (HFD-9), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-443-5563, e mail: 
hunterj@cder.FDA.gov.


SUPPLEMENTARY INFORMATION: The United States is a party to the 1971 
Convention on Psychotropic Substances. Article 2 of the Convention on 
Psychotropic Substances provides that if a party to the convention or 
WHO has information about a substance, which in its opinion may require 
international control or change in such control, it shall so notify the 
Secretary General of the United Nations and provide the Secretary 
General of the United Nations with information in support of its 
opinion.
    The CSA (21 U.S.C. 811 et seq.) (Title II of the Comprehensive Drug 
Abuse Prevention and Control Act of 1970) provides that when WHO 
notifies the United States under Article 2 of the Convention on 
Psychotropic Substances that it has information that may justify adding 
a drug or other substances to one of the schedules of the convention, 
transferring a drug or substance from one schedule to another, or 
deleting it from the schedules, the Secretary of State must transmit 
the notice to the Secretary of the Department of Health and Human 
Services (the Secretary of HHS). The Secretary of HHS must then publish 
the notice in the Federal Register and provide opportunity for 
interested persons to submit comments that will be considered by HHS in 
its preparation of the scientific and medical evaluations of the drug 
or substance.

I. WHO Notification

    The Secretary of HHS received the following notices from WHO:
    Ref: C.L.29.2005

WHO Questionnaire for Collection of Information for Review of 
Dependence-Producing Psychoactive Substances

    The WHO presents its compliments and has the pleasure of 
informing Member States and Associate Members that the Thirty-fourth 
Expert Committee on Drug Dependence will meet from March 28 to 31, 
2006 to review the following substances:
    1. Butorphanol (INN)
    2. Dronabinol (INN)\1\
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    \1\Including its stereo-isomers.
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    3. Gamma-hydroxybutyric acid
    4. Ketamine (INN)
    5. Khat (Catha edulis Forsk)
    6. Tramadol (INN)
    7. Zopiclone (INN)
    As a follow-up for the thirty-third meeting of the Expert 
Committee on Drug Dependence, final decisions will be taken for 
buprenorphine (INN) and oripavine (INN).
    One of the essential elements of the established review 
procedure is for the Secretariat to collect relevant information 
from Member States to prepare a Critical Review Report for 
submission to the Expert Committee on Drug Dependence. WHO invites 
Member States to collaborate, as in the past, in this process by 
providing pertinent information mentioned in the attached 
questionnaire concerning substances listed above.
    Further clarification on any of the above items can be obtained 
from Quality Assurance and Safety: Medicines, Department of 
Medicines Policy and Standards, WHO, Geneva, to which replies should 
be sent not later than January 3, 2006.
    WHO takes this opportunity to renew to Member States and 
Associate Members the assurance of its highest consideration.
    GENEVA, October 27, 2005
* * * * *

[[Page 73776]]

    If statistical information requested is not readily available, a 
brief descriptive answer would be appreciated.
    Please attach copies of relevant study reports and other 
background information as appropriate.
* * * * *

1. BUTORPHANOL (INN)

1. LEGITIMATE USE OF THE SUBSTANCE
    1.1 Is the substance currently registered as a medical product? 
(Yes/No)
    If ``yes,'' since when (year of marketing)? 19------
    Please indicate trade name(s), dosage form(s) with strength(s) 
and indication(s):

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              Trade Name                     Dosage Form              Strength(s)             Indication(s)
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                                       .......................  .......................  .......................
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                                       .......................  .......................  .......................
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    1.2 If the answer to 1.1 is ``no,'' is there other legitimate 
use of the substance? (Yes/No)
    If ``yes,'' please describe the purpose of use.
    1.3 If there is legitimate use of the substance, how is the 
substance supplied? (Imported/Manufactured in the country)
2. ABUSE OF THE SUBSTANCE
    2.1 Is the substance abused or misused\2\ in your country? (Yes/
No/No Information)
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    \2\In this questionnaire, ``abuse or misuse'' refers to use of 
the substance other than for medical or scientific purposes.
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    2.2 If ``yes,'' any information on the extent of abuse?
    2.3 Any information on the extent of public health or social 
problems associated with the abuse of the substance (statistics on 
cases of overdose deaths, dependence, etc.)?
3. ILLICIT ACTIVITIES INVOLVING THE SUBSTANCE
    3.1 Any information on the nature and extent of illicit 
activities involving the substance (clandestine manufacture, 
smuggling, diversion, seizure, etc.)?
4. IMPACT OF SCHEDULING
    4.1 If butorphanol is placed under international control, do you 
think that its availability for medical use will be affected? (Yes/
No)
    4.2 If ``yes,'' how do you think the transfer will impact its 
medical availability?

2. DRONABINOL (INN) AND ITS STEREO-ISOMERS

1. LEGITIMATE USE OF THE SUBSTANCE
    1.1 Is the substance currently registered as a medical product? 
(Yes/No)
    If ``yes,'' since when (year of marketing)? 19------
    Please indicate trade name(s), dosage form(s) with strength(s) 
and indication(s):

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              Trade Name                     Dosage Form              Strength(s)             Indication(s)
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                                       .......................  .......................  .......................
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                                       .......................  .......................  .......................
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    1.2 If the answer to 1.1 is ``no,'' is there other legitimate 
use of the substance? (Yes/No)
    If ``yes,'' please describe the purpose of use.
    1.3 If there is legitimate use of the substance, how is the 
substance supplied? (Imported/Manufactured in the country)
2. ABUSE OF THE SUBSTANCE
    2.1 Is the substance abused or misused in your country? (Yes/No/
No information)
    2.2 If ``yes,'' any information on the extent of abuse?
    2.3 Any information on the extent of public health or social 
problems associated with the abuse of the substance (statistics on 
cases of overdose deaths, dependence, etc.)?
3. ILLICIT ACTIVITIES INVOLVING THE SUBSTANCE
    3.1 Any information on the nature and extent of illicit 
activities involving the substance (clandestine manufacture, 
smuggling, diversion, seizure, etc.)?

3. GAMMA-HYDROXYBUTYRIC ACID (GHB)

1. LEGITIMATE USE OF THE SUBSTANCE
    1.1 Is the substance currently registered as a medical product? 
(Yes/No)
    If ``yes,'' since when (year of marketing)? 19------
    Please indicate trade name(s), dosage form(s) with strength(s) 
and indication(s):

----------------------------------------------------------------------------------------------------------------
              Trade Name                     Dosage Form              Strength(s)             Indication(s)
----------------------------------------------------------------------------------------------------------------
                                       .......................  .......................  .......................
----------------------------------------------------------------------------------------------------------------
                                       .......................  .......................  .......................
----------------------------------------------------------------------------------------------------------------

    1.2 If the answer to 1.1 is ``no,'' is there other legitimate 
use of the substance? (Yes/No)
    If ``yes,'' please describe the purpose of use.
    1.3 If there is legitimate use of the substance, how is the 
substance supplied? (Imported/Manufactured in the country)
2. ABUSE OF THE SUBSTANCE
    2.1 Is the substance abused or misused in your country? (Yes/No/
No information)
    2.2 If ``yes,'' any information on the extent of abuse?
    2.3 Any information on the extent of public health or social 
problems associated with the abuse of the substance (statistics on 
cases of overdose deaths, dependence, etc.)?
3. ILLICIT ACTIVITIES INVOLVING THE SUBSTANCE
    3.1 Any information on the nature and extent of illicit 
activities involving the substance (clandestine manufacture, 
smuggling, diversion, seizure, etc.)?
4. IMPACT OF TRANSFER TO SCHEDULE II or III OF THE CONVENTION ON 
PSYCHOTROPIC SUBSTANCES, 1971, ON MEDICAL AVAILABILITY
    4.1 If gamma-hydroxybutyric acid is transferred from Schedule IV 
of the Convention on Psychotropic Substances, 1971, to either 
Schedule II or III of the Convention on Psychotropic Substances, do 
you think that its availability for medical use will be affected? 
(Yes/No)
    4.2 If ``yes,'' how do you think the transfer will impact its 
medical availability?

[[Page 73777]]

4. KETAMINE (INN)

1. LEGITIMATE USE OF THE SUBSTANCE
    1.1 Is the substance currently registered as a medical product? 
(Yes/No)
    If ``yes,'' since when (year of marketing)? 19------
    Please indicate trade name(s), dosage form(s) with strength(s) 
and indication(s):

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              Trade Name                     Dosage Form              Strength(s)             Indication(s)
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                                       .......................  .......................  .......................
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                                       .......................  .......................  .......................
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    1.2 If the answer to 1.1 is ``no,'' is there other legitimate 
use of the substance? (Yes/No)
    If ``yes,'' please describe the purpose of use.
    1.3 If there is legitimate use of the substance, how is the 
substance supplied? (Imported/Manufactured in the country)
2. ABUSE OF THE SUBSTANCE
    2.1 Is the substance abused or misused in your country? (Yes/No/
No information)
    2.2 If ``yes,'' any information on the extent of abuse?
    2.3 Any information on the extent of public health or social 
problems associated with the abuse of the substance (statistics on 
cases of overdose deaths, dependence, etc.)?
3. ILLICIT ACTIVITIES INVOLVING THE SUBSTANCE
    3.1 Any information on the nature and extent of illicit 
activities involving the substance (clandestine manufacture, 
smuggling, diversion, seizure, etc.)?
4. IMPACT OF SCHEDULING
    4.1 If ketamine is placed under international control, do you 
think that its availability for medical use will be affected? (Yes/
No)
    4.2 If ``yes,'' how do you think the transfer will impact its 
medical availability?

5. KHAT (CATHA EDULIS Forsk.)

1. LEGITIMATE USE OF THE SUBSTANCE
    1.1 Is the substance currently registered as a medical product? 
(Yes/No)
    If ``yes,'' since when (year of marketing)? 19------
    Please indicate trade name(s), dosage form(s) with strength(s) 
and indication(s):

----------------------------------------------------------------------------------------------------------------
              Trade Name                     Dosage Form              Strength(s)             Indication(s)
----------------------------------------------------------------------------------------------------------------
                                       .......................  .......................  .......................
----------------------------------------------------------------------------------------------------------------
                                       .......................  .......................  .......................
----------------------------------------------------------------------------------------------------------------

    1.2 If the answer to 1.1 is ``no,'' is there other legitimate 
use of the substance? (Yes/No)
    If ``yes,'' please describe the purpose of use.
    1.3 If there is legitimate use of the substance, how is the 
substance supplied? (Imported/Manufactured in the country)
2. ABUSE OF THE SUBSTANCE
    2.1 Is the substance abused or misused in your country? (Yes/No/
No information)
    2.2 If ``yes,'' any information on the extent of abuse?
    2.3 Any information on the extent of public health or social 
problems associated with the abuse of the substance (statistics on 
cases of overdose deaths, dependence, etc.)?
3. ILLICIT ACTIVITIES INVOLVING THE SUBSTANCE
    3.1 Any information on the nature and extent of illicit 
activities involving the substance (clandestine manufacture, 
smuggling, diversion, seizure, etc.)?
4. IMPACT OF SCHEDULING
    4.1 If khat is placed under international control, do you think 
that its availability for medical use will be affected? (Yes/No)
    4.2 If ``yes,'' how do you think the transfer will impact its 
medical availability?

6. TRAMADOL (INN)

1. LEGITIMATE USE OF THE SUBSTANCE
    1.1 Is the substance currently registered as a medical product? 
(Yes/No)
    If ``yes,'' since when (year of marketing)? 19------
    Please indicate trade name(s), dosage form(s) with strength(s) 
and indication(s):

----------------------------------------------------------------------------------------------------------------
              Trade Name                     Dosage Form              Strength(s)             Indication(s)
----------------------------------------------------------------------------------------------------------------
                                       .......................  .......................  .......................
----------------------------------------------------------------------------------------------------------------
                                       .......................  .......................  .......................
----------------------------------------------------------------------------------------------------------------

    1.2 If the answer to 1.1 is ``no,'' is there other legitimate 
use of the substance? (Yes/No)
    If ``yes,'' please describe the purpose of use.
    1.3 If there is legitimate use of the substance, how is the 
substance supplied? (Imported/Manufactured in the country)
2. ABUSE OF THE SUBSTANCE
    2.1 Is the substance abused or misused in your country? (Yes/No/
No information)
    2.2 If ``yes,'' any information on the extent of abuse?
    2.3 Any information on the extent of public health or social 
problems associated with the abuse of the substance (statistics on 
cases of overdose deaths, dependence, etc.)?
3. ILLICIT ACTIVITIES INVOLVING THE SUBSTANCE
    3.1 Any information on the nature and extent of illicit 
activities involving the substance (clandestine manufacture, 
smuggling, diversion, seizure, etc.)?
4. IMPACT OF SCHEDULING
    4.1 If tramadol is placed under international control, do you 
think that its availability for medical use will be affected? (Yes/
No)
    4.2 If ``yes,'' how do you think the transfer will impact its 
medical availability?

7. ZOPICLONE (INN)

1. LEGITIMATE USE OF THE SUBSTANCE
    1.1 Is the substance currently registered as a medical product? 
(Yes/No)
    If ``yes,'' since when (year of marketing)? 19------
    Please indicate trade name(s), dosage form(s) with strength(s) 
and indication(s):

[[Page 73778]]



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              Trade Name                     Dosage Form              Strength(s)             Indication(s)
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                                       .......................  .......................  .......................
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                                       .......................  .......................  .......................
----------------------------------------------------------------------------------------------------------------

    1.2 If the answer to 1.1 is ``no,'' is there other legitimate 
use of the substance? (Yes/No)
    If ``yes,'' please describe the purpose of use.
    1.3 If there is legitimate use of the substance, how is the 
substance supplied? (Imported/Manufactured in the country)
2. ABUSE OF THE SUBSTANCE
    2.1 Is the substance abused or misused in your country? (Yes/No/
No information)
    2.2 If ``yes,'' any information on the extent of abuse?
    2.3 Any information on the extent of public health or social 
problems associated with the abuse of the substance (statistics on 
cases of overdose deaths, dependence, etc.)?
3. ILLICIT ACTIVITIES INVOLVING THE SUBSTANCE
    3.1 Any information on the nature and extent of illicit 
activities involving the substance (clandestine manufacture, 
smuggling, diversion, seizure, etc.)?
4. IMPACT OF SCHEDULING
    4.1 If zopiclone is placed under international control, do you 
think that its availability for medical use will be affected? (Yes/
No)
    4.2 If ``yes,'' how do you think the transfer will impact its 
medical availability?

8. BUPRENORPHINE (INN)

1. IMPACT OF TRANSFER TO SCHEDULE I OF THE SINGLE CONVENTION ON 
NARCOTIC DRUGS, 1961, ON MEDICAL AVAILABILITY
    1.1 If buprenorphine is transferred from Schedule III of the 
Convention on Psychotropic Substances, 1971, to Schedule I of the 
Single Convention on Narcotic Drugs, 1961, do you think that its 
availability for medical use will be affected? (Yes/No)
    1.2 If ``yes,'' how do you think the transfer will impact its 
medical availability?

II. Background

    Butorphanol is classified as a synthetic opiate partial agonist 
analgesic. It is marketed in the United States for the management of 
pain as an injectable and as a nasal spray solution. It is controlled 
domestically in Schedule IV of the CSA and is not controlled 
internationally under the Psychotropic Convention or the Single 
Convention on Narcotic Drugs.
    Synthetic delta-9-tetrahydrocannabinol (delta-9-THC), or 
dronabinol, is the active component of the drug product Marinol, which 
is marketed in the United States as an antiemetic in the setting of 
cancer chemotherapy and for treatment of AIDS wasting syndrome. Marinol 
is currently controlled in Schedule III of the CSA, and the drug 
substance dronabinol (which is the synthetic equivalent of the natural 
active component of marijuana, delta-9-THC) is controlled in Schedule I 
of the CSA. The drug substance dronabinol, including its isomers, is 
controlled internationally in Schedule II of the Psychotropic 
Convention.
    Gamma-hydroxybutyric acid (GHB) is classified as a central nervous 
system depressant. In 2002, FDA approved a GHB-containing product, 
Xyrem, for the treatment of cataplexy associated with narcolepsy. Xyrem 
was approved under the regulations in 21 CFR part 314, subpart H (21 
CFR 314.520), and the product labeling contained a comprehensive risk 
management program, which includes restricted distribution of the drug 
through a central pharmacy. Xyrem is controlled domestically in 
Schedule III of the CSA, while bulk GHB and all other material 
containing GHB is controlled in Schedule I. In addition, illicit use of 
Xyrem is subject to Schedule I penalties of the CSA. GHB is controlled 
internationally in Schedule IV of the Psychotropic Convention.
    Ketamine is classified as a rapid-acting general anesthetic agent 
used for short diagnostic and surgical procedures that do not require 
skeletal muscle relaxation. It is marketed in the United States as an 
injectable. Ketamine is controlled domestically in Schedule III of the 
CSA. It is not controlled internationally under the Psychotropic 
Convention or the Single Convention on Narcotic Drugs.
    Khat (or qat) refers to the leaves and young shoots of the plant 
Cathia edulis Forsk. The principal psychoactive substances contained in 
khat leaves are cathinone and cathine. Cathinone ([alpha]-
ketoamphetamine) is a monoamine alkaloid that is controlled 
domestically and internationally in Schedule I. The DEA published a 
final rule on January 14, 1993 (58 FR 4316), that results in the 
placement of any material that contains cathinone into Schedule I, 
which includes khat. Cathine, also a monoamine alkaloid, is controlled 
domestically in Schedule IV of the CSA and internationally in Schedule 
III drug under the Convention on Psychotropic Substances. In 1980, WHO 
classified khat as a drug of abuse that can produce mild to moderate 
psychic dependence, however khat is not controlled internationally 
under the Psychotropic Convention or the Single Convention on Narcotic 
Drugs.
    Tramadol is a centrally acting synthetic analgesic. At least two 
complementary mechanisms of action appear applicable: binding of parent 
and metabolite to mu-opioid receptors and inhibition of the reuptake of 
norepinephrine and serotonin. It is marketed in the United States for 
the treatment of moderate to moderately severe pain. Cases of abuse and 
dependence of tramadol have been reported. It is not controlled in the 
United States under the CSA or controlled internationally under the 
Psychotropic Convention or the Single Convention on Narcotic Drugs.
    Zopiclone is classified as a nonbenzodiazepine hypnotic. The pure 
enantiomer (optical isomer) of zopiclone, eszopiclone, is marketed in 
the United States for the treatment of insomnia. The precise mechanism 
of action of eszopiclone as a hypnotic is unknown, but its effect is 
believed to result from its interaction with gamma-aminobutyric acid 
(GABA)-receptor complexes at binding domains located close to or 
allosterically coupled to benzodiazepine receptors. Eszopiclone and 
zopiclone are controlled domestically in Schedule IV of the CSA and are 
not controlled internationally under the Psychotropic Convention or 
Single Convention on Narcotic Drugs.
    Buprenorphine is a semisynthetic opium derivative with partial mu-
opioid receptor agonist activity. In the United States, buprenorphine 
is available as a parenteral product marketed for the relief of 
moderate to severe pain, as a sublingual single-entity tablet, and as a 
sublingual combination tablet with naloxone. The sublingual tablets are 
used for the treatment of opiate addiction. Buprenorphine is controlled 
domestically in Schedule III of the CSA as a narcotic and is controlled 
internationally in Schedule III of the Psychotropic Convention.
    Oripavine is a phenanthrene alkaloid contained in the species of 
the Papaver plant. It is a chemical derivative of thebaine, a 
naturally-occurring substance found in the opium plant. Oripavine is 
controlled domestically in Schedule II of the CSA because it is a 
derivative of thebaine, opium, and other opiates. Oripavine is not 
under international control.

[[Page 73779]]

III. Opportunity to Submit Domestic Information

    As required by section 201(d)(2)(A) of the CSA (21 U.S.C. 
811(d)(2)(A)), FDA, on behalf of HHS, invites interested persons to 
submit comments regarding the nine named drugs. Any comments received 
will be considered by HHS when it prepares a scientific and medical 
evaluation of these drugs. HHS will forward a scientific and medical 
evaluation of these drugs to WHO, through the Secretary of State, for 
WHO's consideration in deciding whether to recommend international 
control/decontrol of any of these drugs. Such control could limit, 
among other things, the manufacture and distribution (import/export) of 
these drugs and could impose certain recordkeeping requirements on 
them.
    HHS will not now make any recommendations to WHO regarding whether 
any of these drugs should be subjected to international controls. 
Instead, HHS will defer such consideration until WHO has made official 
recommendations to the Commission on Narcotic Drugs, which are expected 
to be made in early 2006. Any HHS position regarding international 
control of these drugs will be preceded by another Federal Register 
notice soliciting public comments as required by section 201(d)(2)(B) 
of the CSA.

IV. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding the drugs. The 
abbreviated comment period is necessary to allow sufficient time to 
prepare and submit the domestic information package by the deadline 
imposed by WHO. Two copies of any comments are to be submitted, except 
that individuals may submit one copy. Comments are to be identified 
with the docket number found in brackets in the heading of this 
document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

    Dated: December 5, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-23958 Filed 12-12-05; 8:45 am]

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