International Drug Scheduling; Convention on Psychotropic Substances; World Health Organization Scheduling Recommendations for Seven Drug Substances

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]

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