[Federal Register Volume 70, Number 238 (Tuesday, December 13, 2005)]
[Notices]
[Pages 73775-73779]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-23958]
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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://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:
[email protected].
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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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):
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Trade Name Dosage Form Strength(s) Indication(s)
----------------------------------------------------------------------------------------------------------------
....................... ....................... .......................
----------------------------------------------------------------------------------------------------------------
....................... ....................... .......................
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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 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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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)
----------------------------------------------------------------------------------------------------------------
....................... ....................... .......................
----------------------------------------------------------------------------------------------------------------
....................... ....................... .......................
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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 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):
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Trade Name Dosage Form Strength(s) Indication(s)
----------------------------------------------------------------------------------------------------------------
....................... ....................... .......................
----------------------------------------------------------------------------------------------------------------
....................... ....................... .......................
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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 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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....................... ....................... .......................
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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]
BILLING CODE 4160-01-S