[Federal Register Volume 64, Number 6 (Monday, January 11, 1999)]
[Notices]
[Pages 1629-1634]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-448]



[[Page 1629]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 98N-0148]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; World Health 
Organization Scheduling Recommendations for Ephedrine, 
Dihydroetorphine, Remifentanil, and Certain Isomers

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 and to request 
an informal public meeting concerning recommendations by the World 
Health Organization (WHO) to impose international manufacturing and 
distributing restrictions, under international treaties, on certain 
drug substances. The comments received in response to this notice and/
or public meeting will be considered in preparing the U.S. position on 
these proposals for a meeting of the United Nations Commission on 
Narcotic Drugs (CND) in Vienna, Austria, in March 1999. This notice is 
issued under the Controlled Substances Act.

DATES: Written comments by February 10, 1999; written requests for a 
public meeting and the reasons for such a request by January 26, 1999.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit written requests for a public meeting and 
the reasons for such a request to Nicholas P. Reuter (address below).
FOR FURTHER INFORMATION CONTACT: Nicholas P. Reuter, Office of Health 
Affairs (HFY-20), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-443-1382, or 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 
the 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 shall then evaluate the proposal and furnish a 
recommendation to the Secretary of State which shall be binding on the 
representative of the United States in discussions and negotiations 
relating to the proposal.
    As detailed below, the Secretary of State has received two 
notifications from the Secretary-General of the United Nations (the 
Secretary-General) regarding substances to be considered for control 
under the Psychotropic Convention. These notifications reflect the 
recommendations from the 31st WHO Expert Committee for Drug Dependence 
(ECDD), which met in June 1998. In the Federal Register of March 18, 
1998 (63 FR 13258), FDA announced the WHO ECDD review and invited 
interested persons to submit information for WHO's consideration.
     The full text of the notifications 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.
    The United States is also a party to the 1961 Single Convention on 
Narcotic Drugs. The Secretary of State has received a notification form 
the Secretary-General regarding substances to be considered for control 
under this convention. The CSA does not require HHS to publish a 
summary of such information in the Federal Register. Nevertheless, in 
an effort to provide interested and affected persons an opportunity to 
submit comments regarding the WHO recommendations for narcotic drugs, 
the notification regarding these substances is also included in this 
Federal Register notice. The comments will be shared with other 
relevant agencies to assist the Secretary of State in formulating the 
U.S. position on the control of these substances. The HHS 
recommendations are not binding on the representative of the United 
States in discussions and negotiations relating to the proposal 
regarding control of substances under the Single Convention.

 II. United Nations Notifications

     The formal United Nations notifications which identify the drug 
substances and explain the basis for the recommendations are reproduced 
below.

A. Notification on l-ephedrine, and d,l ephedrine

Reference: NAR/CL.18/1998 CU 98/215
     TLAB/CSSS/303/98
    UNDCP 42nd CND
    WHO/ECDD 31 (1971C)
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 of 1971, has notified the 
Secretary-General by note dated 30 September 1998 that it is of the 
opinion that (1RS2S)-2-methylamino-1-phenylpropan-1-ol (also known 
as l-ephedrine) and the racemate (1RS2SR)-2-methylamino-1-
phenylpropan-1-ol (also known as d,l-ephedrine) should be included 
in Schedule IV of that Convention.
    In accordance with the provisions of article 2, paragraphs 1 and 
4, of the Convention, the Secretary-General hereby transmits the 
text of the notification as annex I to the present note.
    The World Health Organization, in connection with the 
notification has also submitted advance excerpts from the report of 
the thirty-first meeting of the WHO Expert Committee on Drug 
Dependence (23-26 June 1998), which reviewed the substance with a 
view, inter alia, to possible international control. The excerpts 
from that report concerning the substance recommended for scheduling 
are hereby transmitted as annex II.
    In accordance with the provisions of article 2, paragraph 2 of 
the Convention, the notification from the World Health Organization 
will be brought to the attention of the Commission on Narcotic Drugs 
at its next session in March 1999. Any action or decision taken by 
the Commission with respect to this notification, pursuant to 
article 2, paragraph 5, of the Convention, will be notified to 
States Parties in due course. Article 2, paragraph 5, reads as 
follows:
    ``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 form the World 
Health Organization or from other appropriate sources.''
    In order to assist the Commission in reaching a decision, it 
would be appreciated if an economic, social, legal, administrative 
or other factors the Government may consider relevant to the 
possible scheduling of l-ephedrine and the racemate could be

[[Page 1630]]

communicated at the latest by 4 January 1999 to the Executive 
Director of the Office for Drug Control and Crime Prevention, c/o 
Commission and Secretariat Services Section, P.O. Box 500, A-1400 
Vienna, Austria, fax: +43-1-26060-5885.
11 November 1998
NAR/CL.18/1998
Annex I

 Annex I

Note dated 30 September 1998 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 transmit, in accordance with 
Article 2, paragraphs 1 and 4 of the Convention on Psychotropic 
Substances, 1971, assessments and recommendation of the World Health 
Organization concerning the proposed inclusion of ephedrine (l-
ephedrine and its racemate) in Schedule IV of the said Convention, 
as set forth in Annex hereto.
     The World Health Organization avails itself of this opportunity 
to present to the United Nations the assurance of its highest 
consideration.
11 November 1998
NAR/CL.18/1998
Annex II

Annex II

Ephedrine

1. Substance identification

    Ephedrine (2-methylamino-1-phenylpropan-1-ol) exists in fours 
stereoisomeric forms and two corresponding racemic mixtures. They 
are designated traditionally l-ephedrine, d-ephedrine and l-
pseudoephedrine and d-pseudoephedrine. l-Ephedrine, also designated 
as (-)-ephedrine, is chemically (1R,2S)-2-methylamino-1-
phenylpropan-1-ol. Racemic ephedrine also designated as d,l-
ephedrine or ()-ephedrine, is chemically (1RS,2SR)-2-
methylamino-1-phenylpropan-1-ol.

2. Similarity to known substances and effects on the central nervous 
system

    Ephedrine is chemically and pharmacologically similar to 
amphetamines. It is also similar to cathine which is (+)-
norpseudoephedrine. Ephedrine is both an - and -
adrenergic agonist and enhances the release of norepinephrine from 
sympathetic neurons. In general, ephedrine is viewed as being a less 
potent central nervous system stimulating agent but a more effective 
bronchodilator. Ephedrine increases motor activity and mental 
alertness, and diminishes the sense of fatigue. Ephedrine decreases 
appetite and promotes weight loss.

3. Dependence Potential

    In humans with histories of substance abuse, l-ephedrine, d-
amphetamine (INN: dexamfetamine), d-methamphetamine (INN: 
metamfetamine), phenmetrazine, and methylphenidate injected 
subcutaneously produced similar increases in respiratory rate and 
blood pressure and similar types of subjective changes, including 
euphoria. The agents differed in relative potency. In general, 
amphetamine-like stimulants differed only in relative potencies when 
given orally. l-Ephedrine was five times less potent than 
amphetamine in producing amphetamine-like subjective and 
physiological effects in substance abusers, but was more potent than 
amfepramone (diethylpropion).
    In monkeys trained to self-administer cocaine, l-ephedrine 
maintained responding rates greater than saline in substitution 
tests. In rats trained to discriminate cocaine from placebo, l-
ephedrine generalized to cocaine - though at a slightly lower rate 
than d-amphetamine. Ephedrine generalized to cocaine and d-
amphetamine in other drug discrimination studies in rats. In 
amphetamine-trained monkeys, an oral dose of 10 mg racemic ephedrine 
was discriminated as amphetamine. In monkeys trained to self-
administer cocaine, l- and racemic ephedrine had definite 
reinforcing effects. d-Ephedrine was both less efficacious and 
potent than the l-isomer in its ability to generalize to 
amphetamine.

4. Actual abuse and/or evidence of likelihood of abuse

    Of the 50 countries which have returned the questionnaire to 
WHO, ephedrine was available for medical use in 46 countries. Of the 
46 countries, the following 12 countries have indicated present or 
past ephedrine abuse or illicit traffic in ephedrine presumably 
associated with its abuse: Belgium, Burkina Faso, China, Costa Rica, 
Germany, Finland, France, Ireland, Sudan, Slovakia, Thailand and 
USA. Although quantitative information is difficult to obtain, the 
extent of ephedrine abuse was significant enough for some 
governments to implement various regulatory controls. The current 
problem of abuse seems to be particularly serious in certain African 
countries. When abuse exists, it seems to involve ephedrine single 
entity products. In addition, in the USA, combination products 
containing ephedrine in herbal preparations have been abused.
    The problem of ephedrine diversion was reported in the material 
provided by the International Narcotics Control Board, which 
indicated that few countries served as major supplier of ephedrine 
to other countries. Often, there is a large gap between the amount 
required for legitimate use and the amount imported into these 
countries reflecting diversion for abuse. Some ephedrine, traded in 
dosage forms, is used as a precursor to synthesize methamphetamine.

5. Therapeutic usefulness

    Ephedrine is used widely as a bronchodilator in the symptomatic 
treatment of reversible bronchospasm which may occur in association 
with asthma, bronchitis, emphysema, and other obstructive pulmonary 
diseases. Hypotension and shock have been treated with parenteral 
ephedrine through its actions producing cardiac stimulation and 
vasoconstriction. Less common indications include obesity, motion 
sickness and enuresis.
    The commonality of ephedrine use as a medicine is indicated by 
the fact that 92% of the countries which responded to the WHO 
questionnaire (46/50) indicated therapeutic use of ephedrine. This 
figure suggests that ephedrine is used therapeutically in many 
countries in the world. Some of these countries have indicated a 
large number of pharmaceutical products containing ephedrine on the 
market, often as combination products.

6. Recommendation

    On the basis of the available information concerning its 
pharmacological profile, dependence potential and actual abuse, the 
public health and social problems associated with the abuse of 
ephedrine are assessed to be significant. The current problem 
appears to be particularly serious in certain African countries. On 
this basis, it is recommended that l-ephedrine and the racemate be 
placed in Schedule IV of the Convention on Psychotropic Substances, 
1971. The d-isomer, which is significantly less potent than the l-
isomer, need not be controlled. In making this recommendation, it is 
noted that ephedrine combination products would be eligible for 
exemption according to the 1971 Convention.
    It is further noted that there are overlapping jurisdictions 
concerning the 1971 Convention and the 1988 UN Convention Against 
Illicit Traffic in Narcotic Drugs and Psychotropic Substances, which 
may make full effective international regulations of ephedrine 
difficult. The interrelationship and interpretation of these 
conventions needs clarification by appropriate international bodies, 
including the International Narcotics Control Board and the World 
Health Organization. In addition, it is recommended that these 
bodies develop ways to alert Member States which export 
pharmaceutical formulations of ephedrine, that these preparations 
have the potential for abuse and use as a precursor.

B. Notification Regarding the Proposal of the Government of Spain

Reference: NAR/CL.17/1998 CU 98/214
     TLAB/CSSS/302/98
    UNDCP 42nd CND
    WHO/ECDD 31 (1971C)
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 refer to his note NAR/CL.4/1997 of 28 May 1997, by 
which he transmitted a notification received from the Government of 
Spain pursuant to article 2, paragraph 1 of the Convention on 
Psychotropic Substances, 1971. In its notification the Government of 
Spain informed the Secretary-General that it was of the opinion that 
Schedules I and II of the 1971 Convention should be amended to 
include: (a) isomers, except were expressly excluded, of substances 
listed in those Schedules, whenever the existence of such isomers is 
possible; (b) esters and ethers of substance in those Schedules, 
except where included in another Schedule, whenever the existence of 
such esters or ethers is possible; (c) salts of those esters, ethers 
and isomers, under the conditions stated above, whenever the 
formation of such salts is possible; and (d) a substance resulting 
from modification of the chemical structure of a substance already 
in Schedule I or II and which produces pharmacological effects 
similar to those produces by the original substances.

[[Page 1631]]

    The Secretary-General also transmitted a copy of that 
notification to the World Health Organization (WHO), in accordance 
with the provision of article 2, paragraph 2 of the Convention, for 
consideration by the thirty-first meeting of the WHO Expert 
Committee on Drug Dependence in 1988.
    In accordance with the provision of article 2, paragraph 4, of 
the Convention, the World Health Organization has transmitted to the 
Secretary-General, by a noted dated 30 September 1988, its 
assessment and recommendation in response to the proposal made by 
the Government of Spain. Those recommendations read as follows:
    (i) WHO does not recommend to amend Schedule I and Schedule II 
of the 1971 Convention, to extend international controls 
collectively to esters, ethers, and analogues of controlled 
substances;
    (ii) with regard to isomers, WHO recommends that a phrase could 
be added for substances in Schedule I of the 1971 Convention. That 
phrase would read as follows: ``The stereoisomers, unless 
specifically excepted, of substance in this Schedule, whenever the 
existence of such stereoisomers is possible within the specific 
chemical designation'', and
    (iii) with regard to stereoisomers of the substances in Schedule 
II, III and IV of the 1971 Convention, WHO recommends that 
interpretation guidelines should be developed by the International 
Narcotic Control Board in collaboration with the World Health 
Organization, in order to eliminate the confusion arising from 
inconsistencies in the present nomenclature of the Schedules in the 
1971 Convention.
    In accordance with the provisions of article 2, paragraphs 1 and 
4, of the Convention, the Secretary-General hereby transmits the 
text of the notification as annex I to the present note.
    The World Health Organization, in connection with the 
notification has also submitted advance excerpts from the report of 
the thirty-first meeting of the WHO Expert Committee on Drug 
Dependence (23-26 June 1998), which examined the proposal of the 
Government of Spain. The excerpts from that report are hereby 
transmitted as annex II.
    In accordance with the provision of article 2, paragraph 2 of 
the Convention, the notifications from the Government of Spain and 
from the World Health Organization will be brought to the attention 
of the Commission on Narcotic Drugs at its next session in March 
1999. Any action or decision taken by the Commission with respect to 
this notification, pursuant to article 2, paragraph 5, of the 
Convention, will be notified to States Parties in due course. 
Article 2, paragraph 5, reads as follows:
    ``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 form the World 
Health Organization or from other appropriate sources.''
    In order to assist the Commission in reaching a decision, it 
would be appreciated if an economic, social, legal, administrative 
or other factors the Government may consider relevant to the 
recommendations made by the World Health Organization in response to 
the proposal made by the Government of Spain could be communicated a 
the latest by 4 January 1999 to the Executive Director of the Office 
for Drug Control and Crime Prevention, c/o Commission and 
Secretariat Services Section, P.O. Box 500, A-1400 Vienna, Austria, 
fax: +43-1-26060-5885.
11 November 1998
NAR/CL.17/1998
Annex I

 Annex I

Note dated 30 September 1998 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 transmit, in accordance with 
Article 2, paragraphs 1 and 4 of the Convention on Psychotropic 
Substances, 1971, assessments and recommendation of the World Health 
Organization, as set forth in Annex hereto, in response to the Note 
Verbale of 15 May 1997 concerning the proposal by the Government of 
Spain.
     The World Health Organization avails itself of this opportunity 
to present to the United Nations the assurance of its highest 
consideration.
11 November 1998
NAR/CL.17/1998
Annex II

Annex II

Proposal of the Government of Spain

1. Outline of the Proposal

    In 1997, the Spanish Government submitted a proposal to the 
Secretary General of the United Nations to amend the 1971 Convention 
on Psychotropic Substances by adding to Schedules I and II, the 
chemical compositions of the isomers, esters and ethers of the 
psychotropic substances already in these schedules, as well as any 
modified chemical compounds producing effects similar to those 
produced by the original substances (hereinafter referred to as 
``analogues''). The Spanish proposal also recommends the inclusion 
of the salts of the substances. However, the question of salts is 
not addressed in the following section since the salts of the 
substances listed in these Schedules are already under international 
control. An in-depth analysis of potential advantages and 
disadvantages of this proposal has led to the following conclusions.

2. Assessment and recommendation

    With regard to the scheduling of analogues or ``any modified 
chemical compounds producing effects similar to those produced by 
the original substances'', extending controls collectively to these 
groups of substances which are related to, but potential 
pharmacologically different from, the substances in the two 
Schedules may contradict the scheduling procedure stipulated in 
Article 2 of the 1971 Convention on Psychotropic Substances which 
requires WHO to evaluate individual problems, such as disagreements 
among Parties concerning the precise scope of substances under 
control. The same questions may arise concerning the scheduling of 
esters and ethers. In addition, the advantages in terms of extended 
scope of control would be rather limited. Though difficult to 
evaluation, controlling analogues, esters and ethers is likely to 
have a negative impact on legitimate industrial and research 
activities involving these substances.
    For these reasons, it is not recommend to amend Schedules I and 
II of the 1971 Convention to extend international controls 
collectively to esters, ethers and analogues of controlled 
substances. It has been noted, however, that criminal activities 
involving analogues of controlled substances can be controlled at 
the national level, without extending unnecessary administrative and 
regulatory controls to these substances used for legitimate 
industrial and research purposes. In one country, this was achieved 
by applying only criminal controls to certain specified acts 
involving analogues. Governments having similar problems with 
analogues should consider the desirability of adopting similar 
selective control measures, an option which is not available under 
the 1971 Convention once analogues have been scheduled.
    In some countries, introducing national controls for new 
analogues synthesized by clandestine laboratories is very difficult. 
Ideally, a combination of national and international controls should 
be developed concurrently. There is a need to expedite the critical 
review of substance brought to the attention of WHO by governments.
    With regard to isomers, a useful clarification could be provided 
by introducing a modified qualifying phrase in the proposal of the 
Spanish Government into Schedule I. The revised phrase to be added 
to Schedule I would read as follows (addition underlined):
    The stereoisomers, unless specifically excepted, of psychotropic 
substance in this Schedule, whenever the existence of such 
stereoisomers is possible within the specific chemical designation 
in this Schedule.
    This renders the proposal chemically precise and consistent with 
the current interpretation of the Schedule. Hence the proposal could 
provide an explicit clarification of the scope of controlled isomers 
including racemates.
    With regard to stereoisomers of the substances in Schedules II, 
III and IV, the confusion arising from the inconsistencies in the 
present nomenclature of the Schedules should be clarified by means 
of interpretation guidelines to be developed by an appropriate 
international body, such as the International Narcotics Control 
Board, in collaboration with WHO.

C. Notification on Dihydroetorphine and Remifentanil

Reference: NAR/CL.16/1998 CU 98/213
     TLAB/CSSS/301/98
    UNDCP 42nd CND
    WHO/ECDD 31 (1961C)
    The Secretary-General of the United Nations presents his 
compliments to the

[[Page 1632]]

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 3, paragraphs 1 and paragraph 3 (iii), of 
the Single Convention on Narcotic Drugs, 1961, and of that 
Convention as amended by the 1971 Protocol, has notified the 
Secretary-General by note dated 30 September 1998 that it is of the 
opinion that 7,8-dihydro-7--[1-(R)-hydroxy-1-methylbutyl]-
6,14-endo-ethanotetrahydrooripavine (also known as dihydroetorphine) 
and that 1-(2-methoxycarbonylethyl)-4-(phenylpropionylamino)-
piperidine-4-carboxylic acid methyl ester (also known as 
remifentanil) should be included in Schedule I of the Convention.
    In accordance with the provisions of article 3, paragraph 2, of 
the Convention, the Secretary-General hereby transmits the text of 
the notification as annex I to the present note.
    The World Health Organization, in connection with the 
notification has also submitted advance excerpts from the report of 
the thirty-first meeting of the WHO Expert Committee on Drug 
Dependence (23-26 June 1998), which reviewed these substances with a 
view, inter alia, to possible international control. The excerpts 
from that report concerning the two substances recommend for 
scheduling, are hereby transmitted as annex II.
    In accordance with the provisions of article 3, paragraph 2 of 
the Convention, the notification from the World Health Organization 
will be brought to the attention of the Commission on Narcotic Drugs 
at its next session in March 1999 in accordance with article 3, 
paragraph (iii), of the Convention.
    Article 3, paragraph 3 (iii), reads as follows:
    ``If the World Health Organization finds that the substance is 
liable to similar abuse and productive of similar ill effects as the 
drugs in Schedule I or Schedule II or is convertible into a drug, it 
shall communicate that finding to the Commission which may, in 
accordance with the recommendation of the World Health Organization, 
decide that the substance shall be added to Schedule I or Schedule 
II.''
    Any action or decision taken by the Commission with respect to 
this notification, pursuant to article 3, paragraph 3 (iii), of the 
Convention, will be notified to Governments in due course.
11 November 1998
NAR/CL.16/1998
Annex I

 Annex I

Note dated 30 September 1998 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 transmit, in accordance with 
Article 3, paragraphs 1 and 3 (iii) of the Single Convention on 
Narcotic Drugs, 1961, as amended by the 1972 Protocol Amending the 
Single Convention on Narcotic Drugs, 1961, assessments and 
recommendation of the World Health Organization, as set forth in the 
annex hereto, concerning the proposed inclusion of dihydroetorphine 
and remifentanil in Schedule I of the said Convention.
     The World Health Organization avails itself of this opportunity 
to present to the United Nations the assurance of its highest 
consideration.
11 November 1998
    NAR/CL.16/1998
    Annex II

Annex II

Dihydroetorphine

1. Substance identification

Dihydroetorphine (CAS 14357-76-7) is chemically 7,8-dihydro-7-
-[1-(R)-hydroxy-1-methylbutyl]-6,14-endo-
ethanotetrahydrooripavine.

2. Similarity to known substances and effects on the central nervous 
system

Dihydroetorphine is chemically similar to etorphine, which is in 
Schedule I of the Single Convention on Narcotic Drugs, 1961. 
Pharmacologically, animal studies indicate that dihydroetorphine is 
a highly potent analgesic, with an analgesic efficacy of 6,000 and 
11,000 times as potent as morphine in mice and rabbits, 
respectively. In mice and rabbits, the peak analgesic effect was 
attained 15 minutes after subcutaneous injection of 
dihydroetorphine, and the duration of analgesic effect lasted 60-90 
minutes, which was shorter than that of morphine (120-150 minutes). 
Radioligand binding assay indicated that dihydroetorphine is a 
selective mu-type opioid-receptor agonist.

3. Dependence Potential

Animal studies indicated that dihydroetorphine possessed a strong 
psychological dependence potential, 5,000-10,000 times more potent 
than morphine in self-administration tests in rats, 500 and 100 
times more potent than morphine and heroin in self-administration 
studies in monkeys, 8,000 and 1,000 times more potent than morphine 
and heroin in drug discrimination studies in rats, respectively. 
However, animal studies showed that the physical dependence-
producing properties of dihydroetorphine were relatively low. The 
withdrawal syndromes caused by dihydroetorphine in mice jumping 
tests were weaker than morphine. In monkey withdrawal precipitation 
tests and abrupt withdrawal tests, withdrawal syndromes of 
dihydroetorphine were significantly weaker than those of morphine.

4. Actual abuse and/or evidence of likelihood of abuse

Abuse of dihydroetorphine began soon after it was marketed in China 
in 1992. Although indicated as an analgesic, it was also used as an 
opiate withdrawal syndrome suppressing agent. Its abuse spread very 
quickly in the country. Epidemiological studies have shown that 
there were two reasons for starting to abuse dihydroetorphine - 
iatrogenic and social. One group of abusers began to use the drug 
for medical purposes but increased the doses because tolerance 
developed quickly, and the potent dependence-producing properties of 
dihydroetorphine played a dominant role in compelling the patient to 
start abusing the drug. Opiate abusers were another group of people 
who took the drug as a substitute for heroin because of its stronger 
psychological dependence-producing properties, cheaper price, and 
less strict control than heroin.

5. Therapeutic usefulness

Dihydroetorphine was registered in China in December 1992 for the 
relief of acute severe pain. However, it is not useful as a drug for 
substitution treatment of opioid withdrawal because of short 
duration of action.

6. Recommendation

Dihydroetorphine is a potent mu-type opioid-receptor agonist. Based 
on its pharmacological properties and dependence potential 
demonstrated in animal studies, as well as its actual abuse observed 
in China, it is estimated that dihydroetorphine is liable to similar 
abuse and productive of similar ill effects as the drugs in Schedule 
I of the Single Convention on Narcotic Drugs, 1961. It is therefore 
recommended that dihydroetorphine be placed in Schedule I of this 
Convention.
Remifentanil (INN)

1. Substance Identification

Remifentanil (CAS-132875-61-7), chemically 1-(2-
methoxycarbonylethyl)-4-(phenylpropionylamino)-piperidine-4-
carboxylic acid methyl ester, is also known as GI 87084X. 
Remifentanil hydrochloride (CAS-132539-07-2) is also known as GI 
87084B. There are no chiral carbon atoms in the molecule; so no 
stereoisomers or racemates are possible.

2. Similarity to known substances and effects on the central nervous 
system

Remifentanil is classified as a relatively selective mu-type opioid-
receptor agonist with a profile similar to fentanyl, alfentanil and 
sufentanil, but with an ultra-short duration of action. Comparison 
of potency in in vitro binding assays specific for the mu-type 
opioid receptor has demonstrated similar potencies of remifentanil 
and fentanyl. Remifentanil's analgesic potency was found as similar 
to fentanyl, alfentanil and sufentanil in rats, mice and dogs.
In clinical pharmacology studies, remifentanil exhibited properties 
(including adverse effects) that were similar to other fentanyl 
analogues. The most serious adverse effects were attributable to its 
mu-type opioid-receptor agonist properties and included 
hyptotension, bradycardia, muscle rigidity and respiratory 
depression.

3. Dependence potential

Withdrawal signs developed in rats following cessation of 
remifentanil administration. Remifentanil substituted for morphine 
in morphine-dependent withdrawn monkeys. Remifentanil was found 
reinforcing in self-administration studies in monkeys.
In opiate-experienced nondependent human subjects, the very rapid 
subjective peak effects of remifentanil were not significantly 
different from those of fentanyl. In another study involving healthy 
subjects, euphoria occurred at about the same incidence for 
remifentanil as for fentanyl and alfentanil.

[[Page 1633]]

4. Actual abuse and/or evidence of likelihood of abuse

One case of remifentanil abuse and overdose by intra-nasal 
administration occurred during the clinical study of the drug. 
Remifentanil had been administered over a period of several weeks, 
leading to an overdose resulting in loss of consciousness, 
tachycardia, depressed respiration and seizures. Following emergency 
room treatment, the patient recovered.

5. Therapeutic usefulness

Remifentanil is used as an analgesic during induction and 
maintenance of general anesthesia, in postoperative anesthesia, and 
in monitored anesthesia care. Remifentanil has been approved for 
marketing in 17 countries.

6. Recommendation

Remifentanil is a short-acting mu-type opioid-receptor agonist. 
Based on its pharmacological properties and dependence potential, it 
is estimated that remifentanil is liable to similar abuse and 
productive of similar ill effects as the drugs in Schedule I of the 
Single Convention on Narcotic Drugs, 1961. It is therefore 
recommended that remifentanil be placed in Schedule I of this 
Convention.

 III. Discussion

     Although WHO has made specific scheduling recommendations for each 
of the drug substances, 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) reject the recommendations entirely.

A. Ephedrine

    Ephedrine has been recommended for control in Schedule IV of the 
Psychotropic Convention. If ephedrine is controlled in Schedule IV, the 
United States, as a signatory to the Convention would have to determine 
what additional domestic controls, if any, may be needed to fulfill its 
obligations.
    The Convention requires licenses for manufacturers, distributors, 
and those entities in the retail trade. In addition, Article 9 of the 
Convention states that ``[t]he Parties shall require that substances in 
Schedules II, III and IV be supplied or dispensed for use by 
individuals pursuant to medical prescription only, except when 
individuals may lawfully obtain, use, dispense or administer such 
substances in the duly authorized exercise of therapeutic or scientific 
functions.'' On the other hand, the WHO notification on ephedrine 
states that ``in making this recommendation, it is noted that ephedrine 
combination products would be eligible for exemption according to the 
1971 Convention.'' The Psychotropic Convention does not mention 
``combinations'' but the term ``preparations'' is defined under Article 
1 as ``(i) any solution or mixture, in whatever physical state 
containing one or more psychotropic substances, or (ii) one or more 
psychotropic substances in dosage form.'' Under Article 3, paragraphs 2 
and 3, a party may exempt a preparation from certain controls under the 
Convention, including the prescription requirement, if the preparation 
is compounded in such a way that it presents no, or a negligible, risk 
of abuse.
    Ephedrine is available in the United States as an ingredient in 
over-the-counter (OTC) bronchodilator products and in certain OTC 
hemorrhoid treatment products. Importantly, ephedrine has been 
designated as a listed chemical under the CSA (21 U.S.C. 802(34)) and 
is subject to regulations under 21 CFR 1309, 1310, and 1313 , which are 
enforced by the Drug Enforcement Administration. Accordingly, 
distribution of ephedrine single-entity products and certain 
transactions involving ephedrine combination products are subject to 
the recordkeeping, reporting, registration, and import/export 
notification provisions of the CSA. These controls must be examined to 
determine whether they enable the United States to fulfil its 
obligations for ephedrine, should it be controlled under Schedule IV of 
the Psychotropic Convention. Finally, it should be noted that under 
Article 2, paragraph 7(d), of the Psychotropic Convention, a party may 
notify the United Nations that, due to exceptional circumstances, it 
will elect not to apply all of the provisions required by the 
Convention.

B. Spanish Proposal on Isomers of Schedule I Substances

    WHO has also recommended adding a phrase to Schedule I that would 
``clarify'' that stereoisomers of psychotropic substances in Schedule I 
of the Convention would be considered as Schedule I substances. 
According to WHO, this is ``chemically precise and consistent with the 
current interpretations of the Convention * * * [and] could provide an 
explicit clarification of the scope of controlled isomers including 
racemates.''
    It should be noted that WHO is recommending a change in the wording 
of the list of substances controlled in Schedule I. A similar change 
was approved by the Commission on Narcotic Drugs in 1977 which modified 
the Schedules to state, ``[a]lso under international control are the 
salts of the substances listed in these Schedules, whenever the 
existence of such salts is possible.'' Adding such a statement about 
stereoisomers, as WHO has recommended, should not have a significant 
impact on the scope of control of psychotropic substances. 
Domestically, under the CSA, stereoisomers are automatically subject to 
control when a substance is added to Schedule I.

 C. Dihydroetorphine and Remifentanil

    Dihydroetorphine is a hydrogenated derivative of etorphine and a 
potent -opioid-receptor agonist used as a short-acting 
analgesic in China. It is not marketed in the United States, but it is 
considered a Schedule II narcotic substance under the CSA because it is 
a thebaine derivative. Remifentanil is a selective -opioid-
receptor agonist of the fentanyl group. Remifentanil is approved in the 
Unites States as an anesthetic and is controlled domestically as a 
narcotic in schedule II of the CSA. As such, no additional controls 
will be necessary to fulfil U.S. obligations if remifentanil is 
controlled under Schedule I of the Single Convention.
    FDA, on behalf of the Secretary of HHS, invites interested persons 
to submit comments on the United Nations notifications concerning these 
drug substances and WHO's recommendations on stereoisomers pursuant to 
the proposal from the Government of Spain. FDA, in cooperation with the 
National Institute on Drug Abuse, will consider the comments on behalf 
of HHS in evaluating the WHO scheduling recommendations. Then, under 
section 811(d)(2)(B) of the CSA, HHS will recommend to the Secretary of 
State what position the United States should take when voting on the 
recommendations at the CND meeting in March 1999. Comments regarding 
the WHO recommendations for control of substances under the Single 
Convention will also be forwarded to the relevant agencies for 
consideration in developing the U.S. position regarding narcotic 
substances at the CND meeting.

IV. Submission of Comments and Opportunity for Public Meeting

    Interested persons may, on or before February 10, 1999, submit to 
the Dockets Management Branch (address above) written comments 
regarding this notice. FDA does not presently plan to hold a public 
meeting. If any person believes that, in addition to its written 
comments, a public meeting would

[[Page 1634]]

contribute to the development of the U.S. position on the substances to 
be considered for control under the Psychotropic Convention, a request 
for a public meeting and the reasons for such a request should be sent 
to Nicholas P. Reuter (address above) on or before January 26, 1999. 
The short time period for the submission of comments and requests for a 
public meeting is needed to assure that HHS may, in a timely fashion, 
carry out the required action and be responsive to the United Nations. 
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 (address above) between 9 a.m. and 4 p.m., 
Monday through Friday.

    Dated: January 4, 1999.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 99-448 Filed 1-8-99; 8:45 am]
BILLING CODE 4160-01-F