Status of Certain Additional Over-the-Counter Drug Category II and III Active Ingredients

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. 98N-0636]

RIN 0910-AA01

Status of Certain Additional Over-the-Counter Drug Category II

and III Active Ingredients

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule

stating that certain ingredients in over-the-counter (OTC) drug

products are not generally recognized as safe and effective or are

misbranded. FDA is issuing this final rule after considering the

reports and recommendations of various OTC drug advisory review panels

and public comments on proposed agency regulations, which were issued

in the form of a tentative final monograph (proposed rule). Based on

the absence of any submissions on these ingredients to the panels, as

well as the failure of interested parties to submit new data or

information to FDA under the proposed regulations, the agency has

determined that the presence of these ingredients in an OTC drug

product would result in that drug product not being generally

recognized as safe and effective for its intended use or would result

in misbranding. This final rule is part of the ongoing review of OTC

drug products conducted by FDA.

EFFECTIVE DATE: February 22, 1999.

FOR FURTHER INFORMATION CONTACT: Gerald M. Rachanow, Center for Drug

Evaluation and Research (HFD-560), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-827-2307.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of November 7, 1990 (55 FR 46914), FDA

published under Sec. 330.10(a)(7)(ii) (21 CFR 330.10(a)(7)(ii)) a final

rule on the status of certain OTC drug Category II and III active

ingredients. That final rule declared as not generally recognized as

safe and effective certain active ingredients that had been proposed as

nonmonograph (Category II or Category III) under the agency's OTC drug

review. The periods for submission of comments and new data following

the publication of a notice of proposed rulemaking (NPRM) had closed

and no significant comments or new data had been submitted to upgrade

the status of these ingredients. In each instance, a final rule for the

class of ingredients involved had not been published to date.

In the Federal Register of May 10, 1993 (58 FR 27636), FDA

published a final rule establishing that certain additional active

ingredients in OTC drug products are not generally recognized as safe

and effective or are misbranded. That final rule included active

ingredients from a number of OTC drug rulemakings that were not covered

by the November 7, 1990, final rule (see Table I of the May 10, 1993,

final rule (58 FR 27636 at 27639 to 27641) for a list of OTC drug

rulemakings and active ingredients covered by that final rule). The

final rule included a number of active ingredients found in OTC

internal analgesic and orally administered menstrual drug products.

Those ingredients are listed in Sec. 310.545(a)(23) and (a)(24) (21 CFR

310.545(a)(23) and (a)(24)), respectively.

The ingredients listed in these sections do not include ephedrine,

ephedrine salts (ephedrine hydrochloride, ephedrine sulfate,

racephedrine hydrochloride), atropine, or atropine salts (atropine

sulfate). The agency is aware of several combination drug products

marketed for OTC internal analgesic or menstrual use that include

ephedrine sulfate and atropine sulfate among their ingredients, in

addition to aspirin or acetaminophen (Ref. 1). No submissions of data

supporting the use of ephedrine or atropine singly or in combination

were made to the advisory review panels that reviewed these classes of

OTC drug products. No information was provided following publication of

the tentative final monographs for OTC orally administered menstrual

drug products or internal analgesic, antipyretic, and antirheumatic

drug products on November 16, 1988 (53 FR 46194 and 46204,

respectively). A final rule has not been published to date for either

of these classes of OTC drug products.

FDA is not aware of any information that supports the use of

ephedrine or atropine as active ingredients in OTC orally administered

menstrual or internal analgesic, antipyretic, and antirheumatic drug

products. Accordingly, these active ingredients will not be included in

the relevant final monographs because they have not been shown to be

generally recognized as safe and effective for their intended use(s).

These ingredients should be eliminated from OTC drug products 180 days

after the date of publication in the Federal Register of this final

rule, regardless of whether further testing is undertaken to justify

future use.

Publication of a final rule under this proceeding does not preclude

a manufacturer's testing an ingredient. New, relevant data can be

submitted to the agency at a later date as the subject of a new drug

application (NDA) that may provide for prescription or OTC marketing

status (see part 314 (21 CFR part 314)). As an alternative, where there

are adequate data establishing general recognition of safety and

effectiveness, such data may be submitted in an appropriate citizen

petition to amend a monograph (see Sec. 10.30 (21 CFR 10.30)).

II. The Agency's Final Conclusions on Certain OTC Drug Category II

and III Ingredients

The agency notes that no comments or data have been submitted to

the OTC drug review to support any ephedrine or atropine ingredient as

being generally recognized as safe and effective for any OTC uses in

orally administered menstrual or internal analgesic, antipyretic, and

antirheumatic drug products. The agency has determined that these

ingredients should be deemed not generally recognized as safe and

effective for OTC use before a final monograph for each respective drug

category is established. Accordingly, any drug product containing any

of these ingredients and labeled for OTC

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oral menstrual or internal analgesic, antipyretic, and antirheumatic

use will be considered nonmonograph and misbranded under section 502 of

the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 352) and

a new drug under section 201(p) of the act (21 U.S.C. 321(p)) for which

an approved application under section 505 of the act (21 U.S.C. 355)

and part 314 of the regulations is required for marketing. As an

alternative, where there are adequate data establishing general

recognition of safety and effectiveness, such data may be submitted in

a citizen petition to amend the appropriate monograph to include any of

these ingredients in OTC drug products (see Sec. 10.30). Any OTC drug

product containing any of these ingredients and labeled for the uses

discussed in this document that is initially introduced or initially

delivered for introduction into interstate commerce after the effective

date of this final rule and that is not the subject of an approved

application will be in violation of sections 502 and 505 of the act

and, therefore, subject to regulatory action. Further, any OTC drug

product subject to the final rule that is repackaged or relabeled after

the effective date of the rule would be required to be in compliance

with the rule regardless of the date the product was initially

introduced or initially delivered for introduction into interstate

commerce. Manufacturers are encouraged to comply voluntarily with the

rule at the earliest possible date.

III. Reference

(1) American Pharmaceutical Association, Handbook of

Nonprescription Drugs, 10th ed., pp. 646, 648, and 667, 1993.

IV. Analysis of Impacts

FDA has examined the impacts of the final rule under Executive

Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).

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). Under the Regulatory

Flexibility Act, if a rule has a significant impact on a substantial

number of small entities, an agency must analyze regulatory options

that would minimize any significant impact of the rule on small

entities.

Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et

seq.) requires that agencies prepare a written statement and economic

analysis before proposing any rule that may result in an expenditure in

any 1 year by State, local, and tribal governments, in the aggregate,

or by the private sector, of $100 million (adjusted annually for

inflation).

The agency believes that this final rule is consistent with the

principles set out in the Executive Order and in these two statutes.

The purpose of this final rule is to act on the nonmonograph status of

certain ingredients in advance of finalization of other monograph

conditions in order to expedite completion of the OTC drug review.

There are a limited number of products currently marketed that will be

affected by this rule. The agency is aware of at least three products,

although there may be more. These products are marketed by three

different manufacturers, all of which are considered small entities,

using the U.S. Small Business Administration designation for this

industry (750 employees).

Manufacturers of these products will no longer be able to market

products containing the ephedrine or atropine ingredients included in

this final rule after its effective date. However, the manufacturers

will be able to reformulate these products and continue to market them

with proposed monograph ingredients. The cost of reformulation and

relabeling to any one manufacturer should be minimal as only one

product per manufacturer appears to be affected. Total costs should be

minimal ($500,000 to $1 million) as only a limited number of products

appear to be affected. The lost sales from the products containing

nonmonograph ingredients may be offset by sales of the substitute

products containing monograph ingredients. In addition, manufacturers

have been aware of the status of these products since 1988 and have not

submitted any safety and effectiveness data to the agency.

The agency considered but rejected not acting on these ingredients

in advance of the finalization of other monograph conditions. The final

monographs for OTC orally administered menstrual and internal

analgesic, antipyretic, and antirheumatic drug products are not

expected to be completed for a period of time. The agency also

considered publishing an additional notice alerting manufacturers that

the ingredients in this final rule would be removed earlier. However,

safety and effectiveness have not been established for these

ingredients and manufacturers have not submitted the necessary data.

Based on past experience, FDA has found that manufacturers do not

submit the necessary data after a proposed rule is published when no

data or petitions have been submitted in response to prior requests. In

addition, consumers will benefit from the early removal from the

marketplace of products containing ingredients for which safety and

effectiveness have not been established. Consumers can then purchase

products containing only ingredients proposed for monograph status.

Manufacturers who choose to reformulate or replace affected products

will be able to use alternative ingredients that are proposed as

monograph conditions without incurring any additional expense of

clinical testing for those ingredients.

While this final rule may cause manufacturers to discontinue

marketing or to reformulate some products prior to issuance of the

applicable final monograph, these manufacturers have known for some

time that if adequate data were not submitted to support safety and

effectiveness, cessation of marketing of the current products would be

required, in any event, when the final monographs are published.

Because this rule imposes no additional reporting or recordkeeping

requirements, no additional professional skills are necessary to

comply.

The analysis shows that this final rule is not economically

significant under Executive Order 12866 and that the agency has

considered the burden to small entities. Based on the above analysis,

the agency does not believe that the few affected manufacturers will

incur a significant economic impact, although there may be some

reformulation costs or inventory losses. Thus, this economic analysis,

together with other relevant sections of this document, serves as the

agency's regulatory flexibility analysis, as required under the

Regulatory Flexibility Act. Finally, this analysis shows that the

Unfunded Mandates Act does not apply to the final rule because it would

not result in an expenditure in any 1 year by State, local, and tribal

governments, in the aggregate, or by the private sector, of $100

million.

V. Paperwork Reduction Act of 1995

This final rule contains no collections of information. Therefore,

clearance by the Office of Management and Budget under the Paperwork

Reduction Act of 1995 is not required.

VI. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is

of a type that is categorically excluded from the preparation of an

environmental assessment because these actions, as a

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class, will not result in the production or distribution of any

substance and therefore will not result in the production of any

substance into the environment.

List of Subjects in 21 CFR Part 310

Administrative practice and procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping requirements.

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

authority delegated to the Commissioner of Food and Drugs, 21 CFR part

310 is amended as follows:

PART 310--NEW DRUGS

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

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 360b-

360f, 360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a),

262, 263b-263n.

2. Section 310.545 is amended by redesignating the text of

paragraphs (a)(23) and (a)(24) as paragraphs (a)(23)(i) and (a)(24)(i),

respectively; by adding paragraphs (a)(23)(i) and (a)(24)(i) headings,

by adding paragraphs (a)(23)(ii), (a)(24)(ii), and (d)(26); and by

revising paragraph (d)(11) to read as follows:

Sec. 310.545 Drug products containing certain active ingredients

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

(a) * * *

(23) Internal analgesic drug products--(i) Approved as of November

10, 1993. * * *

(ii) Approved as of February 22, 1999.

Any atropine ingredient

Any ephedrine ingredient

(24) Orally administered menstrual drug products--(i) Approved as

of November 10, 1993. * * *

(ii) Approved as of February 22, 1999.

Any atropine ingredient

Any ephedrine ingredient

* * * * *

(d) * * *

(11) November 10, 1993, for products subject to paragraphs

(a)(8)(ii), (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (except

products that contain ferric subsulfate) through (a)(18)(vi),

(a)(22)(ii), (a)(23)(i), (a)(24)(i), and (a)(25) of this section.

* * * * *

(26) February 22, 1999, for products subject to paragraphs

(a)(23)(ii) and (a)(24)(ii) of this section.

Dated: August 11, 1998.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 98-22568 Filed 8-21-98; 8:45 am]

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