[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]
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