[Federal Register Volume 60, Number 13 (Friday, January 20, 1995)]
[Notices]
[Pages 4169-4173]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-1553]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 94N-0173]
International Drug Scheduling; Convention on Psychotropic
Substances; World Health Organization Scheduling Recommendations for
Seven Drug Substances
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, pursuant to 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, on March 14-23,
1995. This notice is issued pursuant to the Controlled Substances Act
(CSA).
DATES: Written comments by February 9, 1995; written requests for a
public meeting and the reasons for such a request by January 30, 1995.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857; 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.
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 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 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 in this document, the Secretary of State has
received a notification from the Secretary-General of the United
Nations. This notification reflects the recommendations from the 29th
WHO Expert Committee for Drug Dependence (ECDD), which met in September
1994. WHO recommends that the substances aminorex, brotizolam, and
mesocarb be added to Schedule IV of the Convention. In addition, WHO
recommends that etryptamine and methcathinone be [[Page 4170]] added to
Schedule I of the Convention and that zipeprol be added to Schedule II.
WHO also recommends that flunitrazepam, presently controlled in
Schedule IV of the Convention, be transferred to Schedule III.
A notice published in the Federal Register of June 20, 1994 (59 FR
31639), announced the WHO review of these seven substances and provided
an opportunity for interested parties to submit information to be
forwarded to WHO. Information submitted in response to that notice was
forwarded to WHO and was considered during the 29th meeting of the WHO
Expert Committee on Drug Dependence in September, 1994.
The full text of the notification from the Secretary-General of the
United Nations is provided below in Section II of this notice. Section
201(d)(2)(B) of the CSA (21 U.S.C. 811(d)(2)(B)) 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 parties to submit information and comments on the proposed
scheduling action.
II. United Nations Notification
Reference:
NAR/CL.10/1994
UNDCP 421/12(1) 1971 CPS
WHO 29th ECDD
CU 94/231
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, pursuant
to article 2, paragraphs 1, 4 and 6, of the Convention on
Psychotropic Substances of 1971, he has received a notification
dated 11 November 1994, from the Director-General of the World
Health Organization (WHO), concerning recommendations for
international control of the following seven substances: aminorex,
brotizolam, etryptamine, flunitrazapam, mesocarb, methcathinone and
zipeprol.
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.
As will be seen from the notification and the attached
assessments and recommendations, WHO recommends that aminorex,
brotizolam and mesocarb be included in Schedule IV of the 1971
Convention; that etryptamine and methcathinone be included in
Schedule I; and that zipeprol be included in Schedule II. WHO also
recommends that flunitrazepam be transferred from Schedule IV to
Schedule III of the Convention.
Pursuant to article 2, paragraph 2, of the Convention, the
notification from WHO will be brought to the attention of the
Commission on Narcotic Drugs at its thirty-eighth session (14-23
March 1995). Any action or decision taken by the Commission with
respect to the notification, pursuant to article 2, paragraph 5 or
6, or the Convention, will be notified to States Parties in due
course.
Article 2, paragraph 5, 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.''
Article 2, paragraph 6 reads:
``If a notification under paragraph 1 relates to a substance
already listed in one of the Schedules, the World Health
Organization shall communicate to the Commission its new findings,
any new assessment of the substance it may make in accordance with
paragraph 4 and any new recommendations on control measures it may
find appropriate in the light of that assessment. The Commission
taking into account the communication from the World Health
Organization as under paragraph 5 and bearing in mind the factors
referred in that paragraph, may decide to transfer the substance
from one Schedule to another or to delete it from the Schedules.''
The Secretary-General would appreciate it if the Government
would submit data on seizures of any of these substances or on the
existence of clandestine laboratories manufacturing them. Such data
would assist the Commission in its consideration of possible
international control of some or all of the substances under review.
In order to further assist the Commission in reaching a
decision, it would be appreciated if any economic, social, legal,
administrative or other factors the Government may consider relevant
to the question of the possible scheduling or rescheduling of these
seven substances could be communicated by 15 January 1995 to the
United Nations International Drug Control Programme, c/o Secretariat
of the Commission on Narcotic Drugs, P.O. Box 500, A-1400 Vienna,
Austria (telefax 239397).
7 December 1994
ANNEX
Note dated 11 November 1994 addressed to the Secretary-General by the
Director-General of the World Health Organization
The Director-General of the World Health Organization presents
his compliments to the Secretary-General of the United Nations and
has the honour to transmit, in accordance with article 2, paragraph
1, 4 and 6 of the Convention on Psychotropic Substances, 1971,
assessments and recommendations of the World Health Organization, as
set forth in the annex hereto, concerning proposed international
control in respect of aminorex, brotizolam, etryptamine,
flunitrazepam, mesocarb, methcathinone, and zipeprol.
The Director-General of the World Health Organization avails
himself of this opportunity to renew to the Secretary-General of the
United Nations the assurance of his highest consideration.
Aminorex
1. Substance identification
Aminorex (INN; CAS 2207-50-3), chemically 2-amino-5-phenyl-2-
oxazoline, is also known as aminoxaphen and aminozafen, and formerly
as Apiquel and Monocil (aminorex fumarate). Aminorex has one
asymmetric carbon atom in the molecule, so that two stereoisomeric
forms and one racemate are possible.
2. Similarity to already known substances and affects on the central
nervous system
Aminorex is chemically similar to 4-methylaminorex, which is
included in Schedule I of the Convention on Psychotropic Substances,
1971. Aminorex produces effects that are characteristic of central
nervous system stimulants such as amfetamine, and was used
clinically for its anorectic effects. Aminorex produces adverse
effects similar to those produced by central nervous system
stimulants. In addition, when used as an anorectic, aminorex was
considered to have been responsible for the occurrence of a
significant incidence of pulmonary hypertension. This led to its
withdrawal from the market in 1968.
3. Dependence potential
In drug discrimination studies, aminorex generalized to
amfetamine and cocaine. Animal self-administration studies indicate
that aminorex has some reinforcing effects. These animal studies
suggest that aminorex has a moderate dependence potential.
4. Actual abuse and/or evidence of likelihood of abuse
Police and forensic reports indicate that aminorex is illicitly
distributed in the United States of America as well as to a limited
degree in Germany. These cases document the distribution of aminorex
as amfetamine or metamfetamine on the street, suggesting that the
population using the drug mainly comprises stimulant abusers. In
spite of the limited level of actual abuse, aminorex is assessed to
have a moderate abuse liability, taking into account the relative
simplicity of its manufacturing in clandestine laboratories.
5. Therapeutic usefulness
Because of serious adverse effects, aminorex is assessed to have
very little, if any, therapeutic usefulness.
6. Recommendation
Based on the available data concerning its pharmacological and
toxicological profile, dependence potential and likelihood of abuse,
the degree of seriousness of the public health and social problems
associated with the abuse of aminorex is assessed to be significant.
On the basis of this and the assessment of its therapeutic
usefulness, it is recommended that aminorex be included in Schedule
IV of the Convention on Psychotropic Substances, 1971.
Brotizolam
1. Substance identification
Brotizolam (INN; CAS 57801-81-7), chemically 2-bromo-4-
(-chloropenyl)-9- [[Page 4171]] methyl-6H-thianol[3,2-f]-s-
triazolol[4,3-a][1,4]diazepine, is also known as Ladormin, Lendorm,
Lendormin, Lindormin, Noctilan, Dormex, and Sintonal.
2. Similarity to already known substances and affects on the central
nervous system
Brotizolam produces pharmacological effects typical of the class
of benzodiazepines. It binds with high affinity to benzodiazepine
receptors. A number of studies have demonstrated the therapeutic
effects of brotizolam as a short-acting hypnotic with a mean
elimination half-life of 4-5 hours.
3. Dependence potential
Animal studies have shown that brotizolam has barbiturate type
subjective effects. It produces alcohol-barbiturate type mild-to-
severe withdrawal syndromes, and has some reinforcing effects. The
few clinical studies available demonstrate the occurrence of rebound
insomnia upon withdrawal of the drug. These findings collectively
indicate that brotizolam has a moderate dependence potential similar
to other benzodiazepine hypnotics.
4. Actual abuse and/or evidence of likelihood of abuse
In spite of its pharmacological similarity to other
benzodiazepine hynotics, and its marketing in 18 countries, actual
abuse of brotizolam has been reported only in Germany and Hong Kong.
In Germany, although there has been some abuse and illicit activity
involving brotizolam, this was not considered serious enough to
subject the drug to the distribution control measures which are
applicable to controlled drugs. In Hong Kong, following its
introduction to the local market in 1988, the abuse of brotizolam
increased rapidly among young people, leading to the application of
stricter regulatory control measures in 1990. The company withdrew
the product from the market in 1992.
Based on the experiences of Germany and Hong Kong with
brotizolam, it is assessed that brotizolam has an appreciable abuse
liability. The problem may be more acute in situations where
prescription requirements for dispensing are not effectively
implemented or are not applicable.
5. Therapeutic usefulness
Brotizolam is marketed as a hypnotic in 18 countries and may be
considered to have a moderate to great therapeutic usefulness.
6. Recommendation
Based on the available data concerning its pharmacological and
toxicological profile, dependence potential and likelihood of abuse,
the degree of seriousness of the public health and social problems
associated with the abuse of brotizolam is assessed to be
significant, in cases where prescription requirements are not
effectively implemented or required, a situation which exists in
many developing countries. On the basis of this and the assessment
of its therapeutic usefulness, it is recommended that brotizolam be
included in Schedule IV of the Convention on Psychotropic
Substances, 1971.
Etryptamine
1. Substance identification
Etryptamine (INN; CAS 2235-90-7), chemically 3-(2-
aminobutyl)indole, is also known as -ethyltryptamine and
Monase. Etryptamine has a single chiral centre, so that two
stereoisomeric forms and one racemate are possible.
2. Similarity to already known substances and affects on the central
nervous system
Chemically, etryptamine is similar to hallucinogenic
tryptamines, some of which are already in Schedule I of the 1971
Convention. Animal studies indicate that etryptamine produces
effects similar to those produced by 3,4,-
methylenedioxymetamfetamine (MDMA), but its hallucinogenic effects
are more pronounced than its stimulant effects. Like amfetamine,
etryptamine increases locomotor activity in rodents. In a study
using the behaviour pattern monitoring method, etryptamine
significantly decreased investigatory behaviour, which is typical of
hallucinogens and MDMA-like substances. The stimulant effects of
etryptamine are slower in onset and more prolonged in duration than
those of amfetamine. In addition, etryptamine inhibits monoamine
oxidase.
In the early 1960s, etryptamine acetate was placed on the United
States market as an anti-depressant. Soon after its release on the
market, it was reported that etryptamine was associated with a high
incidence of agranulocytosis, a potentially fatal condition. More
recently, there were isolated reports of etryptamine being
associated with the deaths of drug abusers in Germany, Spain, and
the United States of America.
3. Dependence potential
Animal drug discrimination studies indicate that etryptamine has
subjective effects resembling MDMA. Self-administration studies
indicate that etryptamine has a moderate dependence potential, which
is lower than that of cocaine.
4. Actual abuse and/or evidence of likelihood of abuse
Information available from various sources indicates that there
has been some abuse of etryptamine in Germany, Spain and the United
States of America. Etryptamine is estimated to have a high abuse
liability.
5. Therapeutic usefulness
In view of its association with serious adverse reactions such
as agranulocytosis, the therapeutic usefulness of etryptamine is
assessed to be very limited, if any.
6. Recommendation
Based on the available data concerning its pharmacological and
toxicological profile, dependence potential and likelihood of abuse,
the degree of seriousness of the public health and social problems
associated with the abuse of etryptamine is assessed to be
especially serious. On the basis of this and the assessment of its
therapeutic usefulness, it is recommended that etryptamine be
included in Schedule I of the Convention on Psychotropic Substances,
1971.
Flunitrazepam
1. Substance identification
Flunitrazepam (INN; CAS 1622-62-4), chemically 5-(-
fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-
one, is also known as Absint, Darkene, Fluninoc, Flunipam, Fluinita,
Flunitrazepan-ratiopharm, Hypnodrom, Hipnosedon, Inervon, Narcozep,
Parnox, Primun, Rohipnol, Rohypnol and Valsers.
2. Similarity to already known substances and affects on the central
nervous system
Flunitrazepam has typical benzodiazepine effects, with a greater
sedative-hypnotic potency than diazepam or chlordiazepoxide.
Flunitrazepam binds with high affinity to central benzodiazepine
receptors. Flunitrazepam is rapidly absorbed after oral
administration. The elimination half-life of flunitrazepam following
a single oral dose ranges between 9 and 25 hours in humans.
Accumulation occurs with chronic administration.
3. Dependence potential
Drug discrimination, drug withdrawal and self-administration
studies indicate that flunitrazepam has a dependence potential
similar to other benzodiazepines. Rebound insomnia, which is
considered a form of withdrawal from sedative-hypnotics, may be
contributing to the tendency of continuing the medication. These
data do not suggest any substantive difference between flunitrazepam
and other benzodiazepine hypnotics.
However, drug preference studies in opiod users have shown that
flunitrazepam and diazepam stand out from other benzodiazepines in
terms of producing a strong positive reinforcing effect in these
subjects.
Based on the above, flunitrazepam is estimated to have a
moderate abuse potential which may be higher than other
benzodiazepines. The rapid onset and longer duration of action,
coupled with the strong sedative-hypnotic effects, may be
contributing to its higher abuse potential.
4. Actual abuse and/or evidence of likelihood of abuse
Information available indicates that the non-medical use or
abuse of flunitrazepam is widespread among drug abusers,
particularly opioid and cocaine abusers. Flunitrazepam is reported
to be the most widely abused benzodiazepine by opioid abusers in
many large cities in Europe, Asia and Oceania. Flunitrazepam abuse
is reported even in the United States of America where the drug is
not marketed for therapeutic use.
Reported reasons for the abuse of flunitrazepam include
potentiation of opioid effects, substitution for the opioid when it
is difficult to obtain, and self-medication for opioid withdrawal.
Oral intake is the most common route of administration of
flunitrazepam but some abusers take the drug by intravenous
injection or by smoking. Health problems associated with the abuse
of flunitrazepam include deaths directly or indirectly related with
the drug use, drug dependence, withdrawal syndrome, paranoia,
amnesia and other psychiatric disorders. [[Page 4172]]
Information on the extent of association of 37 benzodiazepines
with illicit activities during the period 1984-1989, available to
the 27th meeting of the WHO Expert Committee on Drug Dependence in
1980, clearly indicated a higher incidence of association with
illicit activities of both diazepam and flunitrazepam in comparison
with other benzodiazepines. At that time, however, the data were not
evaluated in relation to drug availability. After and adjustment for
the amounts manufactured and for potency, flunitrazepam further
stands out in both seizures and the number of illicit cases
involving the drug, whereas diazepam is no longer outstanding.
Information on drug involvement in illicit activities after
1980, received from governments in response to the WHO questionnaire
in 1994, is limited, and does not allow a comparison among a large
number of benzodiazepines. However, the recent report from Interpol
and the increasing trend in the United States of America, despite
the lack of licit medical supplies in that country, together with
several recent reports showing flunitrazepam as being the main non-
opioid drug abused by opioid abusers in major European cities,
further substantiate its high abuse liability.
5. Therapeutic usefulness
Flunitrazepam is useful for the treatment of insomnia. It is
also indicated as a pre-anaesthetic medication to assist in the
induction and maintenance of anaesthesia. Flunitrazepam has a
therapeutic usefulness similar to other benzodiazepine hypnotics,
within the range from moderate to great.
6. Recommendation
Flunitrazepam has a greater likelihood of abuse than other
benzodiazepines. Although there is some element of self-medication
for opioid withdrawal, the abuse of flunitrazepam by opioid abusers
complicates the clinical picture, leading to multiple drug
dependence. Its abuse is prevalent also among youths and cocaine
abusers. In addition to its oral and intravenous use, abuse by
``snorting'' has recently been reported. As yet, no other
benzodiazepine has been reported as being abused by three different
routes of administration: oral, nasal and intravenous. Flunitrazepam
abuse has been associated with dependence and other behavioural
problems. Illicit activities involving flunitrazepam are increasing
even in the United States of America, where it is available
illegally despite the lack of marketing for therapeutic use.
Based on the available data concerning its pharmacological and
toxicological profile, dependence potential and likelihood of abuse,
and paying particular regard to the above characteristics, the
degree of seriousness of the public health and social problems
associated with the abuse of flunitrazepam is assessed to have
become substantial. On the basis of this and the assessment of its
therapeutic usefulness, it is recommended that flunitrazepam be
rescheduled into Schedule III of the Convention on Psychotropic
Substances, 1971.
Mesocarb
1. Substance identification
Mesocarb (INN; CAS 34262-84-5), is chemically 3-(-
methlylphenethyl)-N-(phenylcarbamoyl)syndone imine, is also known as
Pharbamocarb, Sidnocarb and Sydnocarb. Mesocarb has one asymmetric
carbon atom in the molecule, so that two stereoisomeric forms and
one racemate are possible.
2. Similarity to already known substances and effects on the central
nervous system
Chemically, mesocarb is a sydnone imine having an amfetamine-
like moiety in its molecule. Of the two optical isomers of mesocarb,
only the levorotatory isomer exerts a stimulant effect on the
central nervous system. This effect is significantly weaker than
that of dexamfetamine. Mesocarb produces locomotor stimulation,
anorectic activity, enhancement of conditioned reflexes, and
shortening of the period of action of hypnotic agents. In addition,
there are several pharmacological studies on mesocarb used in
combination with other substances in animals, such as mesocarb-
acetylsalicylic acid combination. Mesocarb has been reported to
increase work capacity and improve cardiovascular function while
maintaining normal oxygen consumption. Adverse reactions are similar
to those of other CNS stimulants. Several studies in humans have
shown that mesocarb increases resistance to environmental stress
such as cold temperature, low gravity, and low oxygen levels in the
air.
3. Dependence potential
Animal studies indicate that mesocarb has discriminative
stimulus effects similar to CNS stimulants such as dexamfetamine and
cocaine, as well as some reinforcing effects in monkeys, suggesting
a low to moderate dependence potential.
4. Actual abuse and/or evidence of likelihood of abuse
There is some evidence to indicate that mesocab is abused in
sports, and its use has been banned by the International Olympic
Committee.
Though reportedly discontinued, information from the
International Narcotics Control Board indicated that large
quantities of a pharmaceutical preparation containing mesocarb and
acetylsalicylic acid were illegally exported to western Africa.
Although epidemiological data are not available, it is believed that
most, if not all, of the exported combination products was abused.
On the basis of available information, mesocarb is assessed to have
an appreciable abuse liability.
5. Therapeutic usefulness
Mesocarb is used in several countries, mainly in eastern Europe,
as a stimulant to counteract acute intoxication by depressants; for
the treatment of hyperactivity and nocturnal enureses in children;
and as an ``energizer'' to enhance resistance to environmental
stress. The therapeutic usefulness of mesocarb is estimated to be
within the range between little and moderate.
6. Recommendation
Although no epidemiological data are available on health
problems associated with the actual abuse of mesocarb, mesocarb is
abused in sports, and illicit activities involving mesocarb have
been reported. Based on this and the available data concerning its
pharmacological and toxicological profile, dependence potential and
likelihood of abuse, the degree of seriousness of the public health
and social problems associated with the abuse of mesocarb is
assessed to be significant. On the basis of this and the assessment
of its therapeutic usefulness, it is recommended that mesocarb be
included in Schedule IV of the Convention on Psychotropic
Substances, 1971.
Methcathinone
1. Substance identification
Methcathinone (CAS 5650-44-2) chemically 2-(methylamino)-1-
phenylpropan-1-one, is also know as ephedrone and metylcathinone. It
has one chiral centre, so that two stereoisomeric forms and one
racemate are possible.
2. Similarity to already known substances and affects on the central
nervous system
Methcathinone is the N-methyl derivative of cathinone, and is
closely related to metamfetamine. Animal studies have shown that
methcathinone produces CNS stimulant effects similar to those
produces by amfetamine, metamfetamine, cathinone and cocaine. Of the
two optical isomers, the levorotatory form is more active.
3. Dependence potential
Drug discrimination and self-administration studies in animal
indicate that methcathinone has a dependence potential similar to
central nervous system stimulants such as amfetamine and cocaine.
Case reports and a study conducted in the United States of America
on methcathinone abusers also suggest that methcathinone has a high
dependence potential similar to that of metamfetamine.
4. Actual abuse and/or evidence of likelihood of abuse
Significant abuse of methcathinone has been reported in Estonia,
Latvia, the Russian Federation, and in some countries of the
Commonwealth of Independent States as well as in the United States
of America. Methcathinone is readily manufactured from ephedrine by
oxidation. Methcathinone is assessed to have a high abuse liability.
5. Therapeutic usefulness
Methcathinone has not been marketed for therapeutic purposes.
Its therapeutic usefulness is assessed to be very limited, if any.
6. Recommendation
Studies from the United States of America and the Russian
Federation have confirmed that methcathinone abuse results in
adverse health effects similar to those associated with the abuse of
metamfetamine, including fatal cases of acute intoxication. Illicit
activities involving methcathinone, including clandestine
manufacturing, are also reported widely.
Based on the available data concerning its pharmacological and
toxicological profile, dependence potential and likelihood of abuse,
and paying particular regard to the above characteristics, the
degree of [[Page 4173]] seriousness of the public health and social
problems associated with the abuse of methcathinone is assessed to
be especially serious. On the basis of this and the assessment of
its therapeutic usefulness, it is recommended that methcathinone be
included in Schedule I of the Convention on Psychotropic Substances,
1971.
Zipeprol
1. Substance identification
Zipeprol (INN; CAS 34758-83-3), chemically -(-
methoxybenzyl--4-(-methoxyphenethyl)-1-piperazineethanol,
is also know as Antituxil-Z, Carm-3024, Chilvax, Delaviral,
Dovavixin, Jactus, Eritos, Mirsol, Ogyline, Rospilene, Respirase,
Respirax, Sanotus, Sentus, Silentos, Sousibim, Talasa, Tusigen,
Tussiflex and Zitoxil. Zipeprol has three asymmetric carbon atoms in
the molecule, so that eight stereoisomeric forms are possible.
2. Similarity to already known substances and affects on the central
nervous system
In laboratory animals, zipeprol has been shown to have an
antitussive activity weaker than codeine and comparable to
dextromethorphan. Its pharmacological properties are different from
those of opioid antitussives, such as codeine, in that zipeprol has
anti-cholinergic activities. It also does not produce respiratory
depression, bile duct constriction or constipation, which are often
associated with narcotic antitussives.
Unlike opioids, zipeprol is essentially devoid of analgesic
activity, but at higher doses, zipeprol acts like a weak opioid
agonist. Zipeprol showed a bi-phasic effect in competing for binding
sites in rat brain homogenates.
3. Dependence potential
In rats, lower doses of zipeprol amplify some opioid withdrawal
manifestations whereas at higher doses it suppresses several
morphine withdrawal symptoms. In the monkey, zipeprol suppresses
morphine abstinence. Zipeprol is assessed to have a moderate
dependence potential.
4. Actual abuse and/or evidence of likelihood of abuse
There have been a number of reports on the abuse of zipeprol
from Brazil, Chile, Italy, Mexico, the Republic of Korea,
Switzerland, and the former Yugoslavia. These reports suggest that
its sedative, hallucinatory and euphorigenic effects, and its
ability to suppress some signs of opioid withdrawal at high doses,
may be the reasons for its abuse. Over-the-counter distribution of
zipeprol preparations may have contributed to its widespread abuse
in some places. Taking this into account, zipeprol is assessed to
have a moderate abuse liability.
Adverse health consequences of zipeprol abuse include seizures,
hallucinations, confusion and amnesia. Dose escalation is not
uncommon and fatal cases from intoxication were reported from
several countries. The tablet form has been used for intravenous
administration.
5. Therapeutic usefulness
A number of clinical studies have demonstrated the therapeutic
efficacy of zipeprol in the treatment of cough. The therapeutic
usefulness of zipeprol is assessed to be within the range between
little to moderate.
6. Recommendation
Although zipeprol is a weak opioid agonist at high doses, its
toxicity, hallucinogenic and other psychotropic effects constitute a
significant element in its abuse. It is therefore appropriate to
consider its control under the Convention on Psychotropic
Substances, 1971.
Based on the available data concerning its pharmacological and
toxicological profile, dependence potential and likelihood of abuse,
the degree of seriousness of the public health and social problems
associated with the abuse of zipeprol is assessed to be substantial.
On the basis of this and the assessment of its therapeutic
usefulness, it is recommended that zipeprol be included in Schedule
II of the Convention on Psychotropic Substances, 1971.
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 CND 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.
Methcathinone, etryptamine and aminorex, are controlled under the
CSA in Schedule I. The proposed international drug scheduling actions,
if adopted by CND, will result in no greater degree of control of these
substances than are currently applied domestically. Flunitrazepam is
controlled domestically in Schedule IV of the CSA; additional controls
may be necessary if the United Nations moves this substance to Schedule
III of the Convention. Brotizolam, mesocarb, and zipeprol are neither
controlled domestically nor currently marketed for medical use in the
United States. In order to comply with obligations under the
Convention, these three substances would have to be controlled under
the CSA if the United Nations endorses the WHO recommendations.
FDA, on behalf of the Secretary of HHS, invites interested persons
to submit comments on the United Nations notifications concerning these
seven drug substances. 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, pursuant to
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 1995.
IV. Submission of Comments and Opportunity for Public Meeting
Interested persons may, on or before February 9, 1995, 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 contribute to the development of the
U.S. position on any of these two substances, 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 30, 1995. 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 17, 1995.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 95-1553 Filed 1-19-95; 8:45 am]
BILLING CODE 4160-01-F
