[Federal Register Volume 68, Number 22 (Monday, February 3, 2003)]
[Notices]
[Pages 5295-5296]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-2456]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 03N-0015]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; World Health 
Organization Scheduling Recommendation for Amineptine (7-[(10,11-
dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)amino]heptanoic acid)

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is providing interested 
persons with the opportunity to submit written comments concerning a 
recommendation by the World Health Organization (WHO) to impose 
international manufacturing and distribution restrictions, under 
international treaties, on a drug substance. The comments received in 
response to this notice will be considered in preparing the U.S. 
position on this proposal for a meeting of the United Nations 
Commission on Narcotic Drugs (CND) in Vienna, Austria, April 8 to 17, 
2003. This notice is issued under the Controlled Substances Act.

DATES: Submit written or electronic comments by March 1, 2003.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. To ensure expeditious review of written comments, 
send a copy by facsimile or e-mail to: James R. Hunter (see following 
address).

FOR FURTHER INFORMATION CONTACT: James R. Hunter, Controlled Substances 
Staff (HFD-9) Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-2098, FAX: 301-443-9222, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    The United States is a party to the 1971 Convention on Psychotropic 
Substances (the Convention). Section 201(d)(2)(B) of the Controlled 
Substances Act (the CSA) (21 U.S.C. 811(d)(2)(B)) provides that when 
the United States is notified under Article 2 of the Convention that 
CND proposes to decide whether to add a drug or other substance to one 
of the schedules of the Convention, transfer a drug or substance from 
one schedule to another, or delete it from the schedules, the Secretary 
of State must transmit notice of such information to the Secretary of 
Health and Human Services (HHS). The Secretary of HHS must then publish 
a summary of such information in the Federal Register and provide 
opportunity for interested persons to submit comments. The Secretary of 
HHS must then evaluate the proposal and furnish a recommendation to the 
Secretary of State that shall be binding on the representative of the 
United States in discussions and negotiations relating to the proposal.
    As detailed in the following paragraphs, the Secretary of State has 
received notification from the Secretary-General of the United Nations 
(the Secretary-General) regarding a substance to be considered for 
control under the Convention. This notification reflects the 
recommendation from the 33d WHO Expert Committee for Drug Dependence 
(ECDD), which met September 14 to 16, 2002. In the Federal Register of 
April 9, 2002 (67 FR 17074), FDA announced the WHO ECDD review and 
invited interested persons to submit information for WHO's 
consideration.
    The full text of the notification from the Secretary-General is 
provided in section II of this document. Section 201(d)(2)(B) of the 
CSA requires the Secretary of HHS, after receiving a notification 
proposing scheduling, to publish a notice in the Federal Register to 
provide the opportunity for interested persons to submit information 
and comments on the proposed scheduling action.

II. United Nations Notification

    The formal United Nations notification that identifies the drug 
substance and explains the basis for the recommendation is reproduced 
below.
    Notification on amineptine: Reference: NAR/CL.12/2002 CS18/02 CU 
2002/262.
    The Secretary-General of the United Nations presents his 
compliments to the Secretary of State of the United States of 
America and has the honour to inform the Government that the World 
Health Organization (WHO), pursuant to article 2, paragraphs 1 and 4 
of the Convention on Psychotropic Substances, 1971, has notified him 
that it is of the opinion that amineptine should be placed in 
Schedule II of that Convention.
    Article 2, paragraphs 1 and 4, of the Convention read:``
    1. If a Party or the World Health Organization has information 
relating to a substance not yet under international control which in 
its opinion may require the addition of that substance to any of the 
Schedules of this Convention, it shall notify the Secretary-General 
and furnish him with the information in support of that 
notification. The foregoing procedure shall also apply when a Party 
or the World Health Organization has information justifying the 
transfer of a substance from one Schedule to another among those 
Schedules, or the deletion of a substance from the Schedules.''
    ``4. If the World Health Organization finds: (a) That the 
substance has the capacity to produce (i)(1) a state of dependence, 
and (2) central nervous system stimulation or depression, resulting 
in hallucinations or disturbances in motor function or thinking or 
behaviour or perception or mood, or (ii) similar abuse and similar 
ill effects as a substance in Schedule I, II, III or IV, and (b) 
That there is sufficient evidence that the substance is being or is 
likely to be abused so as to constitute a public health and social 
problem warranting the placing of the substance under international 
control, the World Health Organization shall communicate to the 
Commission an assessment of the substance, including the extent or 
likelihood of abuse, the degree of seriousness of the public health 
and social problem and the degree of usefulness of the substance in 
medical therapy, together with recommendations on control measures, 
if any, that would be appropriate in the light of its assessment.''
    In accordance with the provisions of article 2, paragraph 2, of 
the 1971 Convention, the Secretary-General hereby transmits the text 
of that notification as an annex to the present note. The 
notification together with the assessments and recommendations from 
WHO as well as any data received from governments on that substance, 
will also be brought to the attention of the Commission

[[Page 5296]]

on Narcotic Drugs at its forty-sixth session in April 2003.
    Any decision taken by the Commission with respect to that 
notification, pursuant to article 2, paragraph 5 of the Convention, 
will be notified to States Parties in due course.
    Article 2, paragraph 5, of the Convention reads:
    ``The Commission, taking into account the communication from the 
World Health Organization, whose assessments shall be determinative 
as to medical and scientific matters, and bearing in mind the 
economic, social, legal, administrative and other factors it may 
consider relevant, may add the substance to Schedule I, II, III or 
IV. The Commission may seek further information from the World 
Health Organization or from other appropriate sources.''
    The Secretary-General would appreciate it if the Government 
would submit data on seizures of amineptine or on the existence of 
clandestine laboratories manufacturing it, as well as any economic, 
social, administrative or other factors the Government may consider 
relevant to the question of the possible scheduling of amineptine by 
the Commission.
    The Secretary-General would also appreciate it if the requested 
information could be communicated by 30 January 2003 to the 
Secretary, Commission on Narcotic Drugs, P.O. Box 500, A-1400 
Vienna, Austria, fax: +43-1-26060-5885.
    20 December 2002
    NAR/CL.12/2002

Annex--Note Addressed to the United Nations by the World Health 
Organization

    The World Health Organization presents its compliments to the 
United Nations and has the honour to submit, in accordance with 
article 2, paragraphs 1 and 4 of the Convention on Psychotropic 
Substances, 1971, assessments and recommendations of the World 
Health Organization, as set forth in the annex hereto, concerning 
the proposed placement of amineptine in Schedule II of the 1971 
Convention.
    The World Health Organization avails itself of this opportunity 
to present to the United Nations the assurance of its highest 
consideration.

AMINEPTINE (INN)

    Substance identification
    Amineptine (7-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-
yl)amino]heptanoic acid) is available as either the free base (CAS 
57574-09-1) or as the hydrochloride salt (CAS 30272-08-3). There are 
no chiral carbon atoms; therefore, no stereoisomers or racemates are 
possible.
    Similarity to known substances and effects on the central 
nervous system
    Amineptine is a synthetic, atypical tricyclic antidepressant 
with central nervous system stimulating effects. It is an indirect 
dopamine agonist, selectively inhibiting dopamine uptake and 
inducing dopamine release, with additional stimulation of the 
adrenergic system. Its antidepressant effects are similar to other 
tricyclic antidepressant drugs but it has a more rapid action, is 
better tolerated and has little cardiovascular, analgesic or 
anorectic effects. It produces a similar spectrum of pharmacological 
effects to psychomotor stimulants in Schedule II of the 1971 
Convention on Psychotropic Substances.
    Dependence potential
    There have been few animal studies regarding the dependence or 
abuse potential of amineptine. However, some clinical studies 
indicated that amineptine has both dependence and abuse potential, 
particularly in patients with a previous history of substance abuse. 
Clinical observations of significant abuse and dependence are 
reported in patients treated with amineptine in France. Its 
dependence potential appeared to be associated with its psychomotor 
stimulant effect. Withdrawal has been clinically manifested by 
anxiety, insomnia, psychomotor agitation or bulimia. Instances of 
dependence have been reported in Europe and Asia.
    Actual abuse and/or evidence of likelihood of abuse
    Amineptine abuse has mainly been reported in Europe and Asia. It 
has been withdrawn from the market in France, where the drug was 
developed a few decades ago, for reasons of considerable 
hepatotoxicity and abuse. Despite this measure, medical use in 
developing countries, as well as abuse still continues. The abuse-
related adverse drug reaction reports for amineptine collected by 
the international drug monitoring programme indicate a larger number 
of case reports of abuse and dependence than anorectic stimulants 
currently placed in Schedule IV of the 1971 Convention on 
Psychotropic Substances, such as amfepramone. Response of 
governments to the WHO questionnaire also indicated limited 
diversion and abuse of the drug. Some reported hospital admissions 
due to adverse consequences of amineptine abuse.
    Therapeutic usefulness
    The therapeutic usefulness of amineptine is low because of 
hepatotoxicity, secondary features such as acne eruption and anxiety 
and the availability of safer antidepressants. Of the 103 countries 
that responded to the WHO questionnaire, only 17 indicated 
amineptine use.

III. Discussion

    Although WHO has made specific scheduling recommendations for 
amineptine, the CND is not obliged to follow the WHO recommendations. 
Options available to the CND for substances considered for control 
under the Psychotropic Convention include: (1) Acceptance of the WHO 
recommendations; (2) acceptance of the recommendations to control, but 
control the drug substance in a schedule other than that recommended; 
or (3) rejection of the recommendations entirely. Amineptine is not 
approved for marketing in the United States and is not a controlled 
substance in the United States. Therefore, current controls in the 
United States on amineptine do not appear to meet the requirements of 
the recommended Schedule II of the Psychotropic Convention.

IV. Comments

    Interested persons may, submit to the Dockets Management Branch 
(see ADDRESSES) written comments regarding this notice. 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 (see ADDRESSES) between 9 a.m. and 4 p.m., Monday 
through Friday.

    Dated: January 28, 2003.
Margaret M. Dotzel,
Assistant Commissioner for Policy.
[FR Doc. 03-2456 Filed 1-31-03; 8:45 am]
BILLING CODE 4160-01-S