Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use; Proposed Amendment of Monograph for OTC Bronchodilator Drug Products

Proposed Rules

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310 and 341

[Docket No. 95N-0205]

RIN 0905-AA06

Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug

Products for Over-the-Counter Human Use; Proposed Amendment of

Monograph for OTC Bronchodilator Drug Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend

the final monograph for over-the-counter (OTC) bronchodilator drug

products to remove the ingredients ephedrine, ephedrine hydrochloride,

ephedrine sulfate, and racephedrine hydrochloride and to classify these

ingredients as not generally recognized as safe and effective for OTC

use. This action is being taken in response to a request from the U.S.

Department of Justice, Drug Enforcement Administration (DEA) to

restrict OTC availability of ephedrine because of its illicit use as

the primary precursor utilized in the synthesis of the controlled

substances methamphetamine and methcathinone. This action is also based

on new information that shows that the misuse and abuse of OTC

ephedrine drug products has the potential for causing harm and on

comments made by FDA's Pulmonary-Allergy Drugs Advisory Committee and

the Nonprescription Drugs Advisory Committee on November 14, 1994. This

proposal is part of the ongoing review of OTC drug products conducted

by FDA.

DATES: Written comments or objections by August 28, 1995; written

comments on the agency's economic impact determination by August 28,

1995. FDA is proposing that any final rule that may issue based on this

proposal become effective 30 days after its date of publication in the

Federal Register.

ADDRESSES: Submit written comments or objections to the Dockets

Management Branch (HFA-305), Food and Drug Administration, rm. 1-23,

12420 Parklawn Dr., Rockville, MD 20857.

on the agency's economic impact determination by August 28,

1995. FDA is proposing that any final rule that may issue based on this

proposal become effective 30 days after its date of publication in the

Federal Register.

ADDRESSES: Submit written comments or objections to the Dockets

Management Branch (HFA-305), Food and Drug Administration, rm. 1-23,

12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug

Evaluation and Research (HFD-810), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-594-5000.

SUPPLEMENTARY INFORMATION:

I. Background-

In the Federal Register of September 9, l976 (41 FR 38312), FDA

published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance

notice of proposed rulemaking to establish a monograph for OTC cold,

cough, allergy, bronchodilator, and antiasthmatic drug products,

together with the recommendations of the Advisory Review Panel on OTC

Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products

(the Panel), which was the advisory review panel responsible for

evaluating data on the active ingredients in this drug class. The Panel

recommended that ephedrine preparations be Category I (generally

recognized as safe and effective) for OTC bronchodilator use (41 FR

38312 at 38370 and 38371, September 9, 1976). The agency concurred with

the Panel in the bronchodilator tentative final monograph (47 FR 47520

at 47527, October 26, 1982) and included ephedrine preparations in the

final monograph for OTC bronchodilator drug products (51 FR 35326 at

35339, October 2, 1986).

II. Recent Developments

nized as safe and effective) for OTC bronchodilator use (41 FR

38312 at 38370 and 38371, September 9, 1976). The agency concurred with

the Panel in the bronchodilator tentative final monograph (47 FR 47520

at 47527, October 26, 1982) and included ephedrine preparations in the

final monograph for OTC bronchodilator drug products (51 FR 35326 at

35339, October 2, 1986).

II. Recent Developments

Since publication of the final monograph for OTC bronchodilator

drug products, the agency's views about OTC ephedrine-containing

bronchodilator drug products have changed for several reasons: (1) A

large-scale diversion of OTC ephedrine-containing drug products to

illicit use in the manufacture of the controlled substances

methamphetamine and methcathinone, (2) new information that ephedrine

may be unsafe for OTC use and has the potential for causing harm as a

result of misuse and abuse, due to widespread and easy availability as

an OTC drug, and (3) the consensus of FDA's Pulmonary-Allergy Drugs

Advisory Committee and the Nonprescription Drugs Advisory Committee

(the Committee) on November 14, 1994, that the use of oral ephedrine

drug products as an OTC bronchodilator to relieve the symptoms of

asthma can no longer be justified when the drug's potential for illicit

use and misuse is considered.

III. Illicit Use of OTC Ephedrine Drug Products

FDA has received correspondence and inquiries from consumers, U.S.

Senators, DEA, and others (Ref. 1) concerning the need for additional

controls on the distribution of OTC ephedrine-containing drug products.

The ``Domestic Chemical Diversion Control Act of 1993, Pub. L. 103-

200'' was signed into law on December 17, 1993, to control the

diversion of certain chemicals (e.g., ephedrine) used in the illicit

production of controlled substances such as methcathinone and

methamphetamine

s (Ref. 1) concerning the need for additional

controls on the distribution of OTC ephedrine-containing drug products.

The ``Domestic Chemical Diversion Control Act of 1993, Pub. L. 103-

200'' was signed into law on December 17, 1993, to control the

diversion of certain chemicals (e.g., ephedrine) used in the illicit

production of controlled substances such as methcathinone and

methamphetamine. The law became effective on April 16, 1994, and

removed the exemption from the definition of a ``regulated

transaction'' that had existed for single entity ephedrine drug

products legally marketed under the Federal Food, Drug, and Cosmetic

Act (the act). Thus, drugs that were previously marketed lawfully under

the act are no longer exempt from chemical precursor controls. The new

law was intended to close this loophole and help eliminate the

availability of ephedrine as a raw material source in the clandestine

synthesis of methamphetamine and methcathinone.-

In the Federal Register of October 11, 1994 (59 FR 51365), DEA

issued a final rule eliminating the threshold for ephedrine and

subjecting all transactions involving bulk ephedrine and single entity

ephedrine drug products to the applicable provisions of the Controlled

Substances Act (21 U.S.C. 801). The final rule eliminated the threshold

(an amount of a listed chemical that determines if a transaction such

as receipt or sale of the chemical is a regulated transaction under

part 1310 (21 CFR part 1310)) for single entity ephedrine drug

products. The final rule established that all transactions involving

ephedrine, regardless of size, are subject to recordkeeping and

reporting requirements set forth in part 1310 and the notification

provisions of part 1310 (21 CFR part 1313). However, the final rule did

not apply to combination drug products containing ephedrine.

At the Committee meeting on November 14, 1994, the Committees

discussed OTC bronchodilator drug products. DEA had submitted a comment

(Ref

e, regardless of size, are subject to recordkeeping and

reporting requirements set forth in part 1310 and the notification

provisions of part 1310 (21 CFR part 1313). However, the final rule did

not apply to combination drug products containing ephedrine.

At the Committee meeting on November 14, 1994, the Committees

discussed OTC bronchodilator drug products. DEA had submitted a comment

(Ref. 2) to the Committee expressing its concern that, although the

recent legislation and proposed regulations (59 FR 12562, March 17,

1994) (now final regulations (59 FR 51365)) adequately address the

ability to control single ingredient ephedrine products, DEA is aware

that laboratories may turn to combination drug products containing

ephedrine and guaifenesin that would be exempt from the final rule.

The comment stated that the illicit use of OTC ephedrine drug

products is contributing to a serious public health problem that is an

extremely critical

issue requiring further action at the Federal level. The comment added

that the OTC marketing status and broad distribution of these products

is hindering efforts to prevent this illicit use of ephedrine and urged

the Committees to restrict the OTC availability of this ingredient.

The agency has also received comments from county, State, and

Federal Government organizations; pharmacists' associations; and

consumers who object to the continued marketing of OTC ephedrine drug

products because some manufacturers are promoting these products for

misuse as stimulant, weight control, and muscle enhancement products

(Ref. 3). The comments contended that this promotion has resulted in

extensive and extremely dangerous misuse and abuse of such products,

particularly in teenaged children.

IV. Misuse and Abuse of OTC Ephedrine Drug Products-

arketing of OTC ephedrine drug

products because some manufacturers are promoting these products for

misuse as stimulant, weight control, and muscle enhancement products

(Ref. 3). The comments contended that this promotion has resulted in

extensive and extremely dangerous misuse and abuse of such products,

particularly in teenaged children.

IV. Misuse and Abuse of OTC Ephedrine Drug Products-

The agency has received a number of reports (Ref. 4) of young

people abusing OTC ephedrine drug products. In one case, nine junior

high school students took three to eight ephedrine 25 milligram (mg)

tablets for added energy and experienced rapid heart beats. One female

who took eight tablets had 200 heart beats per minute 2 hours after

taking the tablets. The student was able to purchase the ephedrine

tablets from a product display at a local convenience store without

being questioned about the reason for its use. Another report (Ref. 5)

indicated that three 15-year-old girls had consumed 24 to 33 tablets of

ephedrine-containing OTC drugs for ``kicks.''

The agency is aware of numerous other reports involving young

people who have overdosed by using OTC ephedrine products promoted as a

stimulant or for weight control, or by using such products for

recreational purposes in high doses and on a regular basis. One report

(Ref. 5) involved a 17-year-old male who died after ingesting a toxic

or lethal amount of ephedrine. The youth apparently took the ephedrine

to increase alertness, strength, and physical stamina. In another case

(Ref. 4), a 21-year-old female developed respiratory problems (trouble

breathing) after taking three to four 25 mg ephedrine tablets,

purchased OTC, every other hour (and then every hour) over an 8-hour

period and consuming alcoholic beverages. Hospitalization resulted from

this recreational use of ephedrine.

In another case (Ref

ase alertness, strength, and physical stamina. In another case

(Ref. 4), a 21-year-old female developed respiratory problems (trouble

breathing) after taking three to four 25 mg ephedrine tablets,

purchased OTC, every other hour (and then every hour) over an 8-hour

period and consuming alcoholic beverages. Hospitalization resulted from

this recreational use of ephedrine.

In another case (Ref. 4), a 22-year-old female took OTC ephedrine

tablets because her friends had told her they would act as ``uppers.''

The woman's job required her to work long hours, and she felt she

needed a chemical pick-up to get through the day. She presented to a

hospital emergency room with headache, nausea, anxiety, and blood

pressure of 170/110 millimeters mercury. She was treated, with no

permanent adverse effects.

FDA's Spontaneous Reporting System also contains a number of

reports of ephedrine misuse and abuse (Ref. 4), some of which have

resulted in death due to an overdose of ephedrine. In one case, a 52-

year-old male took 10 to 15 ephedrine tablets (believed to be 50 mg)

over the previous 24 hours. In another case, a 24-year-old male who

died of an overdose had a blood level of ephedrine over 30 times the

usual therapeutic range. In another overdose case, the reporting

pharmacist commented that ``ephedrine is becoming a drug for abuse--

would recommend to withdraw OTC status.'' In another case, the

reporting hospital pharmacist noted that the ephedrine overdose (in a

19-year-old female) was the second incident observed this year for

these ephedrine/caffeine products sold at convenience markets and ``not

FDA regulated.''

Interested consumers and state regulatory officials (e.g., health

departments, boards of pharmacy) have expressed concern about OTC

ephedrine drug products being sold under brand names that reflect a use

other than as a bronchodilator (e.g., use as a stimulant or for weight

control); about products being readily available at convenience stores,

truck stops, gas stations, and mini-mart

ted.''

Interested consumers and state regulatory officials (e.g., health

departments, boards of pharmacy) have expressed concern about OTC

ephedrine drug products being sold under brand names that reflect a use

other than as a bronchodilator (e.g., use as a stimulant or for weight

control); about products being readily available at convenience stores,

truck stops, gas stations, and mini-marts with little, or no,

restriction on their sale; and about products being purchased and used

by children and adolescents, on an ever increasing basis, with a

continuing increase in the number of reported adverse events.

One director of an addictions program informed FDA (Ref. 6) that

his locality (in Indiana) is experiencing a surge of adverse responses

or reactions to the use of OTC ephedrine being abused for its stimulant

effect. He reported that a number of people abusing ephedrine have

demonstrated stimulant dependence characterized by compulsion,

obsession, or preoccupation, and that ephedrine abuse has induced or

worsened mental disorders such as depressive anxiety and different

thought disorders. He stated that people are obtaining the drug OTC as

ephedrine (not in combination with other drugs) under different brand

names, some of which are advertised as an ``energizer.'' He mentioned

that the age group abusing ephedrine ranges from teenagers to people

who are in their 40's.

A nurse reported her daughter's adverse experience with an OTC

ephedrine product (Ref. 4) and mentioned that within the last year the

child's pediatrician had treated several adolescents who had overdosed

on ephedrine. The nurse added that many emergency room physicians are

seeing behavior similar to schizophrenia occurring in young adults as a

result of ephedrine obtained OTC. The nurse questioned why this drug

was readily purchasable by unsuspecting teenagers

ne product (Ref. 4) and mentioned that within the last year the

child's pediatrician had treated several adolescents who had overdosed

on ephedrine. The nurse added that many emergency room physicians are

seeing behavior similar to schizophrenia occurring in young adults as a

result of ephedrine obtained OTC. The nurse questioned why this drug

was readily purchasable by unsuspecting teenagers.

The agency concludes that these reports show that OTC ephedrine

drug products are marketed in ways that are misleading, that promote

misuse and abuse, and that can be dangerous. The agency believes that

these reports represent only a small percentage of the actual number of

adverse events that have occurred and that ephedrine misuse and abuse

are a widespread problem in the United States.

According to one source (Ref. 7), at least 14 states have placed

additional controls and restrictions on ephedrine to address the abuse

problem. These controls include, in at least five states (Florida,

Idaho, New Mexico, Oregon, and Washington), switching the products to

prescription only status. In Michigan, possession of more than 4 grams

of ephedrine requires a prescription. Six states (Arizona, Missouri,

Nevada, Ohio, Oklahoma, and Wisconsin) have scheduled ephedrine as a

controlled substance. The agency is aware that Kentucky, Massachusetts,

and Virginia have introduced bills to tighten ephedrine controls and

that other states are also considering similar actions.

The agency concludes that the misuse and abuse of OTC ephedrine

drug products have the potential for causing harm as shown by the many

reports submitted to the agency. FDA has determined that action is

needed to eliminate this misuse/abuse potential. FDA's proposed action,

when finalized, will eliminate the need for future action by individual

states.

V. Advisory Committee Comments

actions.

The agency concludes that the misuse and abuse of OTC ephedrine

drug products have the potential for causing harm as shown by the many

reports submitted to the agency. FDA has determined that action is

needed to eliminate this misuse/abuse potential. FDA's proposed action,

when finalized, will eliminate the need for future action by individual

states.

V. Advisory Committee Comments

At a meeting of FDA's Pulmonary-Allergy Drugs Advisory Committee

and Nonprescription Drugs Advisory Committee (the Committee) held on

November 14, 1994, the Committee members heard presentations from

private citizens and state officials concerning the misuse and abuse of

OTC ephedrine drug products (Ref. 8). The Committee members expressed

concern about the reports of abuse and illicit diversion of ephedrine.

One Committee member mentioned that removal of ephedrine from the OTC

marketplace by FDA or DEA regulatory action would cause no harm and,

indeed, would do some amount of good. Although the Committee did not

hear from manufacturers of OTC ephedrine drug products and was not

asked the specific question whether these products should be removed

from the OTC market, there was a consensus that the benefit of OTC

ephedrine does not justify its continued use as an OTC bronchodilator

active ingredient when the potential for illicit use and misuse is

considered (Ref. 9).

FDA received comments from manufacturers in response to the notice

for the Committee meeting (59 FR 34847, July 7, 1994). Two

manufacturers opposed the marketing of any OTC bronchodilator drug

product (Ref. 10). One manufacturer submitted a ``Profile of Asthma

Sufferers and Users of Nonprescription Epinephrine (Mist) and Ephedrine

Combination (Tablets)'' in support of its position these drug products

remain available OTC (Ref. 11). Another manufacturer supported the

continued marketing of legitimate OTC ephedrine-containing

bronchodilator drug products (Ref. 12)

ronchodilator drug

product (Ref. 10). One manufacturer submitted a ``Profile of Asthma

Sufferers and Users of Nonprescription Epinephrine (Mist) and Ephedrine

Combination (Tablets)'' in support of its position these drug products

remain available OTC (Ref. 11). Another manufacturer supported the

continued marketing of legitimate OTC ephedrine-containing

bronchodilator drug products (Ref. 12). This manufacturer briefly

discussed the abuse potential for single ingredient ephedrine-

containing products, particularly those that are deliberately labeled

to imply nonmonographed usage. The manufacturer stated that the extent

of any abuse is unclear and potentially exaggerated by a small number

of highly publicized abuse instances. The comment noted that a number

of states have enacted legislation to discourage abuse, in response to

this situation. The comment mentioned that most states have generally

made provisions to ensure continued OTC availability of legitimate

combination asthma products, such as its product containing ephedrine

sulfate and guaifenesin, an expectorant.-

The agency has considered the manufacturers' views in developing

this proposal. As discussed above, the agency believes that the misuse/

abuse problem is widespread and much broader than one manufacturer

suggested. Continued OTC availability of combination products

containing ephedrine and guaifenesin would not alleviate this problem.

Large quantities of guaifenesin are generally safe, and the combination

product would not stop people from taking large amounts for the effects

of the ephedrine. Further, DEA has informed FDA that it is aware that

ephedrine can readily be isolated from such combinations for illicit

manufacture (Ref. 13). Accordingly, FDA concludes that the best

resolution for this misuse/abuse problem is for ephedrine, singly or in

combination products, not to be available OTC.

VI. References-

205, Dockets Management Branch.---

(9)-Transcript of a Joint Meeting of the Pulmonary-Allergy Drugs

Advisory Committee and the Nonprescription Drugs Advisory Committee,

November 14, 1994, pp. 235, 236, 258, 259, 264, 265, 270, 271, and

272, in OTC Vol. 04BPEA, Docket No. 95N-0205, Dockets Management

Branch.

(10) Comments No. C8, APE1, and C11, Docket No. 94N-0232,

Dockets Management Branch.

(11) Comment No. LET144, Docket No. 94N-0232, Dockets Management

Branch.

(12) Comment No. C18, Docket No. 94N-0232, Dockets Management

Branch.

(13) Memorandum of a telephone conversation between D. Snyder,

DEA, and G. Rachanow, FDA, dated April 20, 1994, in OTC Vol. 04BPEA,

Docket No. 95N-0205, Dockets Management Branch.

VII. Summary of the Agency's Proposed Change

The agency is proposing that ephedrine, ephedrine hydrochloride,

ephedrine sulfate, and racephedrine hydrochloride should no longer be

included in the final monograph for OTC bronchodilator drug products

based on their extensive use in illicit drug manufacture and their

potential for causing harm as a result of misuse and abuse due to their

widespread and easy availability as an OTC drug. This proposed

amendment removes the ingredients ephedrine, ephedrine hydrochloride,

ephedrine sulfate, and racephedrine hydrochloride from the final

monograph for OTC bronchodilator drug products (21 CFR part 341). It

does not affect the monograph status of epinephrine-containing drug

products when used in a hand-held rubber bulb nebulizer. Such products

will remain in the final monograph for OTC bronchodilator drug

products.

This proposal would remove all oral systemically acting

bronchodilator drug products from the OTC market. Thus, the agency is

proposing to amend Sec. 341.16 of the final monograph for OTC

bronchodilator drug products to remove Sec. Sec. 341.16(a), (b), (c),

and (f) for ephedrine ingredients and to redesignate Sec. 341.16(d),

emain in the final monograph for OTC bronchodilator drug

products.

This proposal would remove all oral systemically acting

bronchodilator drug products from the OTC market. Thus, the agency is

proposing to amend Sec. 341.16 of the final monograph for OTC

bronchodilator drug products to remove Sec. Sec. 341.16(a), (b), (c),

and (f) for ephedrine ingredients and to redesignate Sec. 341.16(d),

(e), and (g) as Sec. 341.16(a), (b), and (c), respectively. Also, the

agency is proposing to amend Sec. 341.76(c) to remove paragraph (5), to

revise the heading for paragraph (6), and to redesignate paragraphs

(6)(i), (6)(ii), and (6)(iii) as paragraphs (5)(i), (5)(ii), and

(5)(iii), respectively. In addition, the agency is proposing to amend

Sec. 341.76(d) to remove paragraph (1), to redesignate paragraph (2) as

paragraph (1), to revise the heading in new paragraph (1), and to

reserve paragraph (2). The agency is also proposing to amend

Sec. 341.90 by removing paragraph (a) that pertains to ephedrine and

redesignating paragraphs (b) through (q) as paragraphs (a) through (p),

respectively. Furthermore, the agency is proposing to amend the list of

ingredients that are not generally recognized as safe and effective for

specified uses in Sec. 310.545 (21 CFR 310.545) by adding new

paragraphs (a)(6)(iv)(D) and (d)(27) for ephedrine preparations.

VIII. Analysis of Impacts-

FDA has examined the impacts of the proposed rule under Executive

Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). The agency believes that

this proposed rule is consistent with the regulatory philosophy and

principles identified in the Executive Order

available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). The agency believes that

this proposed rule is consistent with the regulatory philosophy and

principles identified in the Executive Order. In addition, the proposed

rule is not a significant regulatory action as defined by the Executive

Order and, thus, is not subject to review under the Executive Order.

The Regulatory Flexibility Act requires agencies to analyze

regulatory

options that would minimize any significant impact of a rule on small

entities. This rule would eventually stop the marketing of OTC

bronchodilator drug products containing ephedrine, ephedrine

hydrochloride, ephedrine sulfate, or racephedrine hydrochloride. The

agency has determined that legitimate drug manufacturers have little or

no interest in single ingredient OTC ephedrine drug products. However,

some manufacturers may have an interest in combination drug products

containing ephedrine.

The agency acknowledges that this proposed rule, if finalized,

would have an impact on consumers who legitimately use OTC

bronchodilator drug products containing ephedrine to relieve their

bronchial asthma. They will no longer be able to purchase these

products without a doctor's prescription. However, all OTC

bronchodilator drug products must bear a label warning that states ``Do

not use this product unless a diagnosis of asthma has been made by a

doctor.'' Therefore, it is presumed that legitimate users of these

products have seen a doctor and are under a doctor's occasional care

for the treatment of their asthma. These consumers will be able to

obtain an ephedrine drug product upon a doctor's prescription if the

doctor determines that ephedrine is the drug that should be used to

treat the condition

nosis of asthma has been made by a

doctor.'' Therefore, it is presumed that legitimate users of these

products have seen a doctor and are under a doctor's occasional care

for the treatment of their asthma. These consumers will be able to

obtain an ephedrine drug product upon a doctor's prescription if the

doctor determines that ephedrine is the drug that should be used to

treat the condition. These consumers will also be able to purchase OTC

epinephrine for inhalation to treat their bronchial asthma without a

doctor's prescription. At its November 14, 1994, meeting, the Committee

recommended that epinephrine for inhalation remain available OTC for

self-treatment of asthma under certain conditions. The agency has

weighed the consequences of this proposed rule as it might adversely

impact some legitimate users of these OTC ephedrine drug products.

However, these consumers will have access to another drug without a

prescription and could continue to obtain ephedrine products on a

doctor's prescription. The agency has determined that as a result of

the widespread misuse and abuse of OTC ephedrine drug products,

especially by many young people and people up to in their 40's, that it

is in the best interest of all consumers (especially parents) to remove

from the OTC market ingredients that are used extensively in the

manufacture of illicit drugs and that have widespread misuse and abuse

with the potential to cause harm. Further, the agency is not aware of a

widespread marketing of legitimate OTC bronchodilator drug products

containing ephedrine, although several manufacturers could be adversely

affected by this proposed rule. Accordingly, the agency certifies that

the proposed rule will not have a significant economic impact on a

substantial number of small entities. Therefore, under the Regulatory

Flexibility Act, no further analysis is required

idespread marketing of legitimate OTC bronchodilator drug products

containing ephedrine, although several manufacturers could be adversely

affected by this proposed rule. Accordingly, the agency certifies that

the proposed rule will not have a significant economic impact on a

substantial number of small entities. Therefore, under the Regulatory

Flexibility Act, no further analysis is required.

The agency invites public comment regarding any substantial or

significant economic impact that this rulemaking would have on OTC

bronchodilator drug products that contain ephedrine, ephedrine

hydrochloride, ephedrine sulfate, or racephedrine hydrochloride.

Comments regarding the impact of this rulemaking on these drug products

should be accompanied by appropriate documentation. A period of 30 days

from the date of publication of this proposed rulemaking in the Federal

Register will be provided for development and submission of comments on

this subject. Because of the existing serious public health problem

identified by DEA and a number of states, and the many reports of

misuse and abuse of OTC ephedrine drug products that FDA has received,

the Commissioner has determined that there is good cause for a

shortened comment period. FDA will evaluate any comments and supporting

data that are received and will reassess the economic impact of this

rulemaking in the preamble to the final rule.

IX. Environmental Impact

and a number of states, and the many reports of

misuse and abuse of OTC ephedrine drug products that FDA has received,

the Commissioner has determined that there is good cause for a

shortened comment period. FDA will evaluate any comments and supporting

data that are received and will reassess the economic impact of this

rulemaking in the preamble to the final rule.

IX. Environmental Impact

The agency has determined that under 21 CFR 25.24(c)(6) that this

action is of a type that does not individually or cumulatively have a

significant effect on the human environment. Therefore, neither an

environmental assessment nor an environmental impact statement is

required.

Interested persons may, on or before August 28, 1995, submit to the

Dockets Management Branch (address above) written comments or

objections regarding this proposal. Written comments on the agency's

economic impact determination may be submitted on or before August 28,

1995. Three copies of all comments or objections are to be submitted,

except that individuals may submit one copy. Comments and objections

are to be identified with the docket number found in brackets in the

heading of this document and may be accompanied by a supporting

memorandum or brief. Comments and objections may be seen in the office

above between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects

21 CFR Part 310

Administrative practice and procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping requirements.

21 CFR Part 341

Labeling, Over-the-counter drugs.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, it is

proposed that 21 CFR parts 310 and 341 be amended as follows:

PART 310--NEW DRUGS

R Part 310

Administrative practice and procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping requirements.

21 CFR Part 341

Labeling, Over-the-counter drugs.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, it is

proposed that 21 CFR parts 310 and 341 be amended as follows:

PART 310--NEW DRUGS

1. The authority citation for 21 CFR part 310 continues to read as

follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-

516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,

360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301,

302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C.

216, 241, 242(a), 262, 263b-263n).

2. Section 310.545 is amended by adding new paragraphs

(a)(6)(iv)(D) and (d)(27) and by revising paragraph (d) introductory

text to read as follows:

Sec. 310.545 Drug products containing certain active ingredients

offered over-the-counter (OTC) for certain uses.

(a) * * *

(6) * * *

(iv) Bronchodilator drug products. * * *

(D) Approved as of August 28, 1995.

Ephedrine

Ephedrine hydrochloride

Ephedrine sulfate

Racephedrine hydrochloride

* * * * *

(d) Any OTC drug product that is not in compliance with this

section is subject to regulatory action if initially introduced or

initially delivered for introduction into interstate commerce after the

dates specified in paragraphs (d)(1) through (d)(27) of this section.

* * * * *

(27) August 28, 1995, for products subject to paragraph

ide

Ephedrine sulfate

Racephedrine hydrochloride

* * * * *

(d) Any OTC drug product that is not in compliance with this

section is subject to regulatory action if initially introduced or

initially delivered for introduction into interstate commerce after the

dates specified in paragraphs (d)(1) through (d)(27) of this section.

* * * * *

(27) August 28, 1995, for products subject to paragraph

(a)(6)(iv)(D) of this section.

PART 341--COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC

DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

3. The authority citation for 21 CFR part 341 continues to read as

follows:

Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the

Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360, 371).

Sec. 341.16 [Amended]

4. Section 341.16 Bronchodilator active ingredients is amended by

removing paragraphs (a), (b), (c), and (f) and by redesignating

paragraphs (d), (e), and (g) as paragraphs (a), (b), and (c),

respectively.

5. Section 341.76 is amended by removing paragraph (c)(5);

redesignating paragraph (c)(6) as paragraph (c)(5); and revising the

heading for newly redesignated paragraph (c)(5); by removing paragraph

(d)(1); by redesignating paragraph (d)(2) as paragraph (d)(1); by

reserving paragraph (d)(2); and by revising the heading in newly

redesignated paragraph (d)(1) to read as follows:

Sec. 341.76 Labeling of bronchodilator drug products.

* * * * *

(c) * * *

(5) For products containing epinephrine, epinephrine bitartrate, or

racepinephrine hydrochloride identified in Sec. 341.16(a), (b), and

(c). * * *

* * * * *

(d) * * *

(1) For products containing epinephrine, epinephrine bitartrate, or

racepinephrine hydrochloride identified in Sec. 341.16(a), (b), and

d as follows:

Sec. 341.76 Labeling of bronchodilator drug products.

* * * * *

(c) * * *

(5) For products containing epinephrine, epinephrine bitartrate, or

racepinephrine hydrochloride identified in Sec. 341.16(a), (b), and

(c). * * *

* * * * *

(d) * * *

(1) For products containing epinephrine, epinephrine bitartrate, or

racepinephrine hydrochloride identified in Sec. 341.16(a), (b), and

(c). * * *

(2) [Reserved]

* * * * *

Sec. 341.90 [Amended]

7. Section 341.90 Professional labeling is amended by removing

paragraph (a) and redesignating paragraphs (b) through (q) as

paragraphs (a) through (p), respectively.

Dated: July 5, 1995.

William K. Hubbard,

Acting Deputy Commissioner for Policy.

[FR Doc. 95-18448 Filed 7-26-95; 8:45 am]

BILLING CODE 4160-01-F