[Federal Register Volume 67, Number 68 (Tuesday, April 9, 2002)]
[Notices]
[Pages 17074-17076]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-8493]



[[Page 17074]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 02N-0101]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; Amfepramone 
(diethylpropion); Amineptine; Buprenorphine; Delta-9-
tetrahydrocannabinol (dronabinol); Tramadol

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 five 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 May 9, 2002.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-09305), 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, 301-827-1999, 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 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.4.2002
    WHO QUESTIONNAIRE FOR COLLECTION OF INFORMATION FOR REVIEW OF 
DEPENDENCE-PRODUCING PSYCHOACTIVE SUBSTANCES
    The Director-General of the World Health Organization presents 
her compliments and has the pleasure of informing Member States that 
the Thirty-third Expert Committee on Drug Dependence (ECDD) will 
meet from 17 to 20 September 2002 to review the following 
substances:
    1. Amfepramone (International Nonproprietary Name (INN))\1\
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    \1\ If the reply to the questionnaire provides sufficient 
information for a critical review.
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    2. Amineptine (INN)
    3. Buprenorphine (INN)
    4. Delta-9-tetrahydrocannabinol\2\
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    \2\ Including dronabinol (INN).
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    5. Tramadol (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 document for 
submission to the Expert Committee on Drug Dependence. The World 
Health Organization invites Member States to collaborate, as in the 
past, in this process by providing pertinent information mentioned 
in the attached questionnaire concerning the substances listed 
above.
    Further clarification on any of the above items can be obtained 
from Quality Assurance and Safety: Medicines (QSM), Essential Drugs 
and Medicines Policy (EDM), WHO, Geneva, to which replies should be 
sent not later than 17 May 2002.
    GENEVA, 7 February 2002

1. AMFEPRAMONE (INN)

1. LEGITIMATE USE OF THE SUBSTANCE
    1.1 Is the substance currently registered as a medical product? 
(Yes/No)
    Please indicate trade name(s), dosage form(s) with strength(s) 
and indication(s):
    1.2 Is there other legitimate use of the substance? (No/Yes, it 
is used for ______.)
    1.3 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, is the abuse increasing? (Yes/No/No information)
    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 A HIGHER SCHEDULE
    4.1 If amfepramone is transferred to Schedule III of the 
Convention on Psychotropic Substances, do you think that its 
availability for medical use will be reduced? (Yes/No/No opinion)
    4.2 If yes, would the reduction adversely affect the provision 
of medical care? (Yes/No/No opinion)
    Please elaborate:

2. AMINEPTINE (INN)

1. LEGITIMATE USE OF THE SUBSTANCE
    1.1 Is the substance currently registered as a medical product? 
(Yes/No)
    Please indicate trade name(s), dosage form(s) with strength(s) 
and indication(s):
    1.2 Is there other legitimate use of the substance? (No/Yes, it 
is used for ______.)
    1.3 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 amineptine is placed under international control, do you 
think that its availability for medical use will be reduced? (Yes/
No/No opinion)
    4.2 If yes, would the reduction adversely affect the provision 
of medical care? (Yes/No/No opinion)
    Please elaborate:

3. BUPRENORPHINE (INN)

1. LEGITIMATE USE OF THE SUBSTANCE
    1.1 Is the substance currently registered as a medical product? 
(Yes/No)
    Please indicate trade name(s), dosage form(s) with strength(s) 
and indication(s):
    1.2 Is there other legitimate use of the substance? (No/Yes, it 
is used for ______.)
    1.3 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)

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    2.2 If yes, is the abuse increasing? (Yes/No/No information)
    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 I/II OF THE SINGLE CONVENTION ON 
NARCOTIC DRUGS, 1961, ON MEDICAL AVAILABILITY
    4.1 If buprenorphine is transferred from Schedule III of the 
Convention on Psychotropic Substances to either Schedule I or II of 
the Single Convention on Narcotic Drugs, do you think that its 
availability for medical use will be reduced? (Yes/No/No opinion)
    4.2 If yes, would the reduction adversely affect the provision 
of medical care? (Yes/No/No opinion)
    Please elaborate:

4. DELTA-9-TETRAHYDROCANNABINOL\3\
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    \3\ Including dronabinol (INN)
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1. LEGITIMATE USE OF THE SUBSTANCE
    1.1 Is the substance currently registered as a medical product? 
(Yes/No)
    Please indicate trade name(s), dosage form(s) with strength(s) 
and 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)
    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.)?

5. TRAMADOL (INN)

1. LEGITIMATE USE OF THE SUBSTANCE
    1.1 Is the substance currently registered as a medical product? 
(Yes/No)
    Please indicate trade name(s), dosage form(s) with strength(s) 
and indication(s):
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 reduced? (Yes/
No/No opinion)
    4.2 If yes, would the reduction adversely affect the provision 
of medical care? (Yes/No/No opinion)
    Please elaborate:

II. Background

    Amfepramone, also known in the United States as diethylpropion, is 
classified as an anorexiant with pharmacological effects similar to the 
amphetamines. It is marketed in the United States for short term (8 to 
12 weeks) use, in conjunction with a regimen of weight reduction based 
on caloric restriction, in patients with obesity and who have not 
responded to an appropriate weight reducing regimen (diet or exercise) 
alone. It is controlled domestically in Schedule IV of the CSA and 
internationally in Schedule IV of the Psychotropic Convention.
    Amineptine is classified as a tricyclic antidepressant. It is not 
marketed in the United States. It has been marketed in other countries 
for the treatment of major depressive disorders and has also been 
studied for its potential use in the treatment of amphetamine 
withdrawal. In 1999, amineptine products were voluntarily removed from 
the market in France and Portugal due to risks of misuse and addiction. 
It is not controlled in the United States under the CSA or 
internationally under the Psychotropic Convention or the Single 
Convention on Narcotic Drugs.
    Buprenorphine is a semisynthetic opium derivative with partial mu-
opioid receptor agonist activity. In the United States buprenorphine is 
currently only available as a parenteral product and is marketed for 
the relief of moderate to severe pain. Buprenorphine is also marketed 
for the treatment of pain in several other countries in both sublingual 
and parenteral dosage forms. A high-dose formulation of buprenorphine 
is also marketed in other countries for use in the treatment of opiate 
dependence. It is currently controlled domestically in Schedule V of 
the CSA as a narcotic and is controlled internationally in Schedule III 
of the Psychotropic Convention. In the Federal Register of March 21, 
2002 (67 FR 13114), the Drug Enforcement Administration published a 
proposed rule to increase the regulatory controls placed on 
buprenorphine by rescheduling buprenorphine from a Schedule V narcotic 
to a Schedule III narcotic.
    Delta-9-tetrahydrocannabinol (delta-9-THC), the active component of 
marijuana, is currently controlled in Schedule I of the CSA. Synthetic 
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. Dronabinol in sesame oil and encapsulated in an FDA-approved 
product is controlled in Schedule III of the CSA. Marinol is the only 
product that meets this definition. Dronabinol (which is the synthetic 
equivalent of the natural active component of marijuana, delta-9-THC) 
in any other form is controlled in Schedule I of the CSA. The drug 
substance dronabinol is controlled internationally in Schedule II of 
the Psychotropic Convention.
    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 weak 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.

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 the Department of Health and Human 
Services (DHHS), invites interested persons to submit comments 
regarding the five named drugs. Any comments received will be 
considered by DHHS when it prepares a scientific and medical evaluation 
of these drugs. DHHS 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.
    DHHS will not now make any recommendations to WHO regarding whether 
any of these drugs should be subjected to international controls. 
Instead, DHHS will defer such consideration until WHO has made official 
recommendations to the Commission on Narcotic Drugs, which

[[Page 17076]]

are expected to be made in late 2002. Any DHHS 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 Dockets Management Branch 
(address above) written or electronic comments regarding the drugs by 
May 9, 2002. This 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 Dockets 
Management Branch between 9 a.m. and 4 p.m., Monday through Friday.

    Dated: March 29, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-8493 Filed 4-8-02; 8:45 am]
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