[Federal Register Volume 61, Number 98 (Monday, May 20, 1996)]
[Rules and Regulations]
[Pages 25142-25147]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-12499]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310 and 341

[Docket No. 94N-0247]
RIN 0910-AA01


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the final 
monograph for over-the-counter (OTC) bronchodilator drug products by 
removing pressurized metered-dose aerosol container dosage forms for 
the ingredients epinephrine, epinephrine bitartrate, and racepinephrine 
hydrochloride. This action is being taken because the OTC marketing of 
such drug products will require an approved application containing 
certain information not required by the monograph. The agency is also 
amending the regulation that lists nonmonograph active ingredients by 
adding any ingredient(s) in a pressurized metered-dose aerosol 
container for OTC bronchodilator drug products. This final rule is part 
of the ongoing review of OTC drug products conducted by FDA.

EFFECTIVE DATE:June 19, 1996.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug 
Evaluation and Research (HFD-105), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2304.

SUPPLEMENTARY INFORMATION: 

-I. Background

     In the Federal Register of October 2, 1986 (51 FR 35326), FDA 
issued a final monograph establishing conditions

[[Page 25143]]

under which OTC bronchodilator drug products are generally recognized 
as safe and effective and not misbranded. Section 341.76(d)(2)(i) (21 
CFR 341.76(d)(2)(i)) provides for products containing epinephrine, 
epinephrine bitartrate, and racepinephrine hydrochloride for use in a 
pressurized metered-dose aerosol container (hereinafter referred to as 
an inhaler or MDI). The agency stated in the final monograph (51 FR 
35326 at 35333 to 35334) that data and information available at that 
time concerning the technology to produce reliable MDI dosage forms 
allowed the agency to generally recognize OTC MDI drug products as safe 
and effective. Further, the agency had anticipated that MDI drug 
products would continue to contain a chlorofluorocarbon (CFC) 
propellant and that marketing would continue under approved 
applications, as stated in Sec. 2.125(d) (21 CFR 2.125(d)), containing 
information on manufacturing controls for the MDI.
     In the Federal Register of March 9, 1995 (60 FR 13014), FDA issued 
a notice of proposed rulemaking to amend the final monograph for OTC 
bronchodilator drug products to remove pressurized MDI aerosol 
container dosage forms for the ingredients epinephrine, epinephrine 
bitartrate, and racepinephrine hydrochloride. The agency also proposed 
to amend the regulation that lists nonmonograph active ingredients to 
add any ingredient(s) in a pressurized MDI aerosol container for OTC 
bronchodilator drug products.
     In the proposal, the agency discussed several developments that 
changed its view about the inclusion of pressurized MDI dosage forms in 
the final monograph for OTC bronchodilator drug products. The agency 
determined that an assessment of the safety and effectiveness of each 
MDI aerosol drug product must be made based on a reconsideration of the 
nature of MDI aerosol drug products, potential future reformulations to 
include new propellants, and the recommendations of various 
international workshops and FDA advisory committee discussions. The 
agency proposed that all MDI aerosol dosage forms must have premarket 
approval to ensure their safety and effectiveness.
     Interested persons were invited to file by May 23, 1995, written 
comments or objections on the proposed regulation. Interested persons 
were invited to file comments on the agency's economic impact 
determination by May 23, 1995.
     In response to the proposal, one drug manufacturer and an 
association of pharmaceutical scientists submitted comments. Copies of 
the comments are on public display in the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. Final agency action on OTC MDI aerosol drug 
products containing epinephrine, epinephrine bitartrate, and 
racepinephrine hydrochloride occurs with the publication of this final 
rule amending the final monograph for OTC bronchodilator drug products.
     As discussed in the proposal (60 FR 13014), the agency advised 
that the conditions under which the drug products that are subject to 
this amendment to the final monograph will no longer be generally 
recognized as safe and effective and are misbranded (nonmonograph 
conditions) will be effective 30 days after the date of publication in 
the Federal Register. Therefore, on or after June 19, 1996, no OTC drug 
product that is subject to the monograph and that contains a 
nonmonograph condition, i.e., a condition that would cause the drug to 
be not generally recognized as safe and effective or to be misbranded, 
may be initially introduced or initially delivered for introduction 
into interstate commerce unless it is the subject of an approved 
application or abbreviated application (hereinafter called 
application). Manufacturers are encouraged to comply voluntarily with 
the final rule at the earliest possible date.
     All ``OTC Volumes'' cited throughout this document refer to the 
submissions made by interested persons pursuant to the call-for-data 
notice published in the Federal Register of August 9, 1972 (37 FR 
16029), or to additional information that has come to the agency's 
attention since publication of the advance notice of proposed 
rulemaking. The volumes are on public display in the Dockets Management 
Branch.-

-II. The Agency's Conclusions on the Comments

     One comment, from a pharmaceutical scientists' association, agreed 
with the agency's proposal to amend the final monograph for OTC 
bronchodilator drug products to remove MDI aerosol dosage forms for the 
ingredients epinephrine, epinephrine bitartrate, and racepinephrine 
hydrochloride. The comment also agreed that such products should have 
premarket approval to ensure their safety and effectiveness. The 
comment explained that changes in an MDI aerosol could have significant 
effects on the distribution characteristics of the drug in the airways, 
produce a pharmacological interaction, and/or enhance toxicity of the 
drug product. With the phaseout of CFC-containing propellants in MDI 
aerosol drug products, the comment mentioned that the safety and 
effectiveness of the replacement propellants in these products will 
need to be established.
     The comment stated that appropriately focused and well-designed 
clinical studies will be necessary to establish the clinical safety and 
effectiveness of new non-CFC-containing MDI aerosol formulations. New 
chemistry, manufacturing, and controls evaluations will be needed to 
document that the new formulation is compatible with the bronchodilator 
active ingredient and that drug delivery from the new system is 
comparable to the old system. The comment added that much of the 
testing needed to confirm the integrity and proper functioning of MDI 
aerosol drug products containing non-CFC propellants can be determined 
by in vitro testing. Such testing could determine particle size, total 
canister contents, and consistency and reproducibility of dose delivery 
through the life of the dosage form, as well as assess drug related 
impurities and leakage rate.
     The comment expressed some concern about epinephrine, epinephrine 
bitartrate, and racepinephrine hydrochloride used in a hand-held rubber 
bulb nebulizer. The comment stated that the agency's concerns about MDI 
aerosol dosage forms, particularly changes in the distribution 
characteristics of the drug in the airways, are equally applicable to 
hand-held rubber bulb nebulizers and spraying devices currently 
available. The comment also questioned the emphasis placed on many of 
the comments and conclusions drawn by the authors of articles cited 
within the proposed amendment because many of those references did not 
provide details of the composition of MDI aerosol drug products 
discussed. The comment did not specify which references failed to 
provide sufficient details.
     Another comment, from a drug manufacturer, disagreed with the 
agency's proposal. The comment claimed that the proposal does not 
provide a reasonable basis to support the revocation of the ``generally 
recognized as safe and effective'' status of these OTC MDI aerosol drug 
products. The comment contended that the proposal raises questions 
about the safety and effectiveness of these drug products in the 
absence of any data showing that epinephrine-containing MDI aerosol 
drug products are not safe and effective when used according to

[[Page 25144]]

the labeling. The comment stated that the safety information discussed 
in the proposal relates to MDI aerosol products containing albuterol, 
and it does not raise any questions with respect to the safety of 
epinephrine-containing MDI aerosol drug products. The comment argued 
that because all CFC-containing MDI aerosol drug products must now be 
the subject of an approved new drug application (NDA), there is no 
public health issue concerning these drug products and, therefore, no 
need for this proposed monograph amendment.
     The comment added that in the final monograph for OTC 
bronchodilator drug products (51 FR 35326 at 35333), the agency 
recognized that manufacturer compliance with FDA's current good 
manufacturing practice (CGMP) regulations would adequately address the 
control of the quality of drug product containers, components, and the 
drug product itself, and that specific requirements for MDI aerosol 
drug delivery systems in the monograph were unnecessary. The comment 
indicated that while CGMP compliance is important to assure the proper 
use of MDI aerosol delivery systems, the proposed amendment provides no 
evidence that CGMP compliance is a concern for currently-marketed 
epinephrine MDI aerosols.
     The comment agreed with the agency that non-CFC propellants could 
render an MDI aerosol product a ``new drug'' under Sec. 310.3(h)(1) (21 
CFR 310.3(h)(1)). In that case, additional data would be required to 
support safety and effectiveness. However, the comment argued that new 
propellant formulations can be reviewed under an NDA without revoking 
the OTC monograph status of currently marketed CFC-containing MDI 
aerosol formulations.
     The comment mentioned that the proposal to remove OTC MDI aerosol 
drug products from the final monograph for OTC bronchodilator drug 
products is not based on the deliberations of any advisory committee 
and is in conflict with the determination of the Advisory Review Panel 
on OTC Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug 
Products that epinephrine-containing OTC MDI aerosol drug products are 
``generally recognized as safe and effective.'' The comment stated that 
the agency should withdraw the proposal until such time as an advisory 
committee has reviewed the data and voted on a recommendation.
     The comment also expressed concern that the agency's action could 
unnecessarily raise the data burden of NDA's for epinephrine-
containing, CFC-propelled MDI's by imposing, without justification, new 
safety and effectiveness data requirements that are satisfied by the 
current monograph status. The comment noted that in Sec. 330.11 (21 CFR 
330.11), if an OTC drug product meets all the conditions of an 
applicable monograph, only a review of information pertaining to 
deviations from those conditions is necessary. The comment contended 
that Sec. 330.11 encourages innovation and improvement in the 
pharmaceutical industry without unnecessary regulatory delays and 
unjustified data burdens. The comment added that, if new NDA's need to 
be submitted, the additional data required could have the effect of 
forcing from the market a product that has been the subject of an 
approved NDA and has had a safe marketing history for many years. 
Therefore, for these reasons, the comment requested that the agency 
withdraw the proposed amendment and take no further steps to complete 
this rulemaking.
     The agency has considered the information presented by the 
comments and determined that marketing of pressurized MDI aerosol 
bronchodilator drug products containing CFC propellants requires an 
approved NDA containing information beyond that required by the final 
monograph for OTC bronchodilator drug products. Since publication of 
that final monograph in 1986, the agency has reconsidered the nature of 
MDI aerosol drug products, potential future reformulations to include 
new propellants, and the recommendations of various international 
organizations and agency advisory committees concerning the regulatory 
and data requirements needed to assure the clinical community and 
patients of the safety and effectiveness of MDI aerosol drug products.
     In the proposed monograph amendment (60 FR 13014 to 13020), the 
agency discussed several specific developments that have changed its 
views about MDI aerosol dosage forms. These included: (1) Recent 
publications reporting chemistry, manufacturing, and controls problems 
resulting from changes to the container and closure system of 
redesigned MDI aerosol dosage forms; (2) the need for safety and 
effectiveness data for the new drug products as a result of those 
chemistry, manufacturing, and controls changes; (3) international 
workshops and FDA advisory committee discussions focusing on regulatory 
requirements for modifications to an approved innovator MDI and 
bioequivalence of generic MDI aerosol drug products; (4) legislation 
that requires a phaseout of ozone-depleting substances, including CFC 
propellants in MDI aerosol drug products; and (5) the need for safety 
data on the alternative propellants that will replace CFC's in MDI 
aerosol dosage forms, as well as evidence that the new MDI's deliver 
the drug effectively.
     The agency's decision to remove epinephrine ingredients in 
pressurized MDI aerosol dosage forms from the final monograph for OTC 
bronchodilator drug products is not based on a specific safety or 
effectiveness concern that has been identified for any of the currently 
marketed OTC MDI aerosol drug products. All such products are currently 
the subject of an approved NDA based on agency regulations in 
Sec. 2.125(d). The removal of these OTC drug products from the 
monograph is being done to ensure continued safety and effectiveness of 
these products and to provide a regulatory basis for adequate 
regulation of the manufacture of all future OTC MDI aerosol drug 
products, including those with the new propellants. This action is 
based on the agency's increased awareness that minor modifications in 
the manufacturing procedures of these products and the proposed 
phaseout of CFC propellants have the potential for substantial impact 
on the safety and effectiveness of these OTC drug products and are not 
adequately addressed by CGMP guidelines.
     In response to the comment regarding the ``generally recognized as 
safe and effective'' status of currently marketed OTC MDI aerosol drug 
products containing epinephrine, epinephrine bitartrate, and 
racepinephrine hydrochloride, the agency maintains that its 
preclearance of these products under NDA's alleviates concerns about 
the safety and effectiveness of these drug products. However, the 
agency now considers preclearance of the manufacturing processes of 
these products an important part of assuring their continued safe and 
effective use.
     The agency points out that the safety information discussed in the 
proposal relates not only to MDI aerosol drug products containing 
albuterol, but to all such products in pressurized MDI dosage form. 
Recent data presented to the agency indicate that variability in the 
performance of an MDI aerosol may result from the physical 
characteristics of the drug substance, formulation differences, valve 
and actuator design, and the adequacy of control parameters, 
specifications, and test methods for each component and the final drug 
product. Design modification of any component of the drug product may 
result in significant alterations of the dose delivered to the lung. In 
addition,

[[Page 25145]]

changes in the source or the composition of the drug product may 
introduce unknown contamination or impurities (extractables) when the 
propellant comes in contact with the plastic or rubber components of 
the canister (Ref. 1).
     Because all currently marketed OTC CFC-containing MDI aerosols 
containing epinephrine are the subject of approved applications, the 
agency does not agree with one comment that this monograph amendment 
will require additional data or new applications to support the safety 
and effectiveness of these bronchodilator drug products. Based on 
agency preclearance under existing applications, the safety and 
effectiveness of currently marketed OTC MDI drug products are not in 
question. However, the agency does consider it necessary that OTC 
marketing of new or reformulated MDI aerosol drug products or products 
manufactured by a different manufacturer or in a different facility 
require preclearance via an approved application containing information 
not required by the monograph to assure the continued safe and 
effective use of these drug products.
     An NDA deviation (Sec. 330.11) applies to products whose 
ingredient(s) is included in an OTC drug monograph. OTC MDI aerosol 
drug products already require an NDA for marketing because of the CFC 
propellants (Sec. 2.125(d)). A change in manufacturing procedures may 
only require a supplement to an NDA. If a change in manufacturing 
facilities occurs or a product is manufactured by a different company, 
the affected manufacturer should consult with the agency to ascertain 
what will be required in the supplemental application.
     In the proposed amendment (60 FR 13014 at 13018), the agency cited 
several international workshops and agency advisory committee 
discussions that identified the regulatory requirements necessary to 
determine the safety and effectiveness of reformulated bronchodilator 
drug products. The Commission of the European Communities, the Drug 
Information Association, and the agency's Generic Drugs Advisory 
Committee with representatives from the Pulmonary-Allergy Drugs 
Advisory Committee (Refs. 2, 3, and 4, respectively) agreed that any 
change in excipients (including propellants) might result in changes in 
drug deposition patterns within the lung and might affect absorption 
and systemic safety. Further, these organizations and committees stated 
that premarket approval is essential to ensure the identity, strength, 
quality, and purity of pressurized OTC and prescription bronchodilator 
drug products.
     In response to some of the comment's concerns regarding the use of 
ephinephrine, epinephrine bitartrate, and racepinephrine hydrochloride 
in hand-held rubber bulb nebulizers, the agency agrees that some of 
these concerns about MDI aerosol dosage forms, particularly changes in 
the distribution characteristics of the drug in the airways, are 
equally applicable to hand-held rubber bulb nebulizers and spraying 
devices. The agency intends to reexamine the use of these OTC 
bronchodilator drugs in hand-held rubber bulb nebulizers in a future 
issue of the Federal Register.
     The agency does not agree with one comment that this amendment 
should be withdrawn until an advisory committee has provided its 
recommendation. As stated earlier, the agency is not questioning the 
safety and effectiveness of currently marketed OTC MDI aerosol drug 
products. However, the agency considers it necessary to review and 
evaluate the manufacturing controls for these drug products to assure 
their continued safe and effective use. This monograph amendment deals 
with process issues (the procedure by which the product gets on the 
market or how manufacturing changes occur), and in this particular case 
the agency does not consider it necessary to bring this amendment to an 
advisory committee for deliberation. However, in some cases, it may be 
appropriate to bring procedural issues to an advisory committee.
     In the proposed monograph amendment (60 FR 13014 at 13020), the 
agency indicated that there is a statutory phaseout of CFC propellants 
used in these MDI aerosol products, although an exemption for MDI's for 
the treatment of asthma and chronic obstructive pulmonary disease 
exists through 1997. Based on the intended phaseout of CFC-containing 
propellants in MDI aerosol dosage forms, the agency is aware that the 
pharmaceutical and other industries are investigating alternative 
propellants to replace CFC's in MDI's. Given the complexity of MDI 
aerosol formulations and the interdependence of each of the MDI 
components, the agency is concerned that the use of new excipients, 
including non-CFC-containing propellants, could change the distribution 
characteristics of the MDI bronchodilator drug in the airways, produce 
a pharmacological interaction, or enhance toxicity of the active drug 
substance. Such changes in MDI aerosol formulations might alter 
pulmonary absorption, potentially resulting in changes in the safety 
and/or therapeutic effectiveness of the bronchodilator drug product. 
Thus, the agency intends to require manufacturers who reformulate 
currently approved MDI aerosol drug products with new propellants to 
submit additional data or a new NDA to demonstrate that inhalation and 
ingestion of new formulations will not result in local tissue 
irritation effects or other undesirable consequences, such as loss of 
effectiveness or local retention, resulting from inappropriate drug 
deposition characteristics. The additional data must include an 
assessment of the absorption, distribution, and retention 
characteristics of new propellant systems in man following inhalation. 
Drug deposition profiles including the quantity of drug reaching the 
respiratory airways and its depth of penetration must also be 
characterized.
     Based on the above discussion, the agency considers it essential 
that any reformulated MDI aerosol (including use of a new propellant or 
component design alterations) have premarket approval under an approved 
NDA to ensure the safety and effectiveness of the bronchodilator drug 
product. Therefore, the agency is removing the ingredients epinephrine, 
epinephrine bitartrate, and racepinephrine hydrochloride in pressurized 
MDI aerosol dosage forms from the final monograph for OTC 
bronchodilator drug products because such products will continue to 
require an approved NDA containing certain information not required by 
the monograph. However, the monograph status of these ingredients when 
used in a hand-held rubber bulb nebulizer is not changed. Such products 
will remain in the final monograph at this time.

III. References

     The following references are on display in the Dockets Management 
Branch (address above) and may be seen by interested persons between 9 
a.m. and 4 p.m., Monday through Friday.
    (1) Adams, W. P. et al., ``Regulatory Aspects of Modifications 
to Innovator Bronchodilator Metered Dose Inhalers and Development of 
Generic Substitutes,'' Journal of Aerosol Medicine, 7:119-134, 1994.
    -(2) ``Report of the Commission of the European Communities' 
Committee for Proprietary Medicinal Products, Matters Relating to 
the Replacement of CFCs in Medicinal Products,'' December 15, 1993, 
in OTC Vol. 04BFMA3.
    -(3) Drug Information Association, MDI's in the Milennium: 
Workshop on Regulatory Issues of Efficacy, Safety, and Quality with 
Metered Dose Inhalers (MDI's) Drug Dosage Forms, October 18 and 19, 
1993, in OTC Vol. 04BFMA3.-
    (4) Transcripts of the FDA Generic Drugs Advisory Committee 
Meeting with

[[Page 25146]]

Pulmonary-Allergy Drugs Advisory Committee Representation, September 
14 and 15, 1993, identified as TS, Docket No. 94N-0247, Dockets 
Management Branch.

-IV. The Agency's Final Conclusions

     In this amendment, the agency is removing the ingredients 
epinephrine, epinephrine bitartrate, and racepinephrine hydrochloride 
in pressurized MDI aerosol dosage forms from the final monograph for 
OTC bronchodilator drug products. Accordingly, the agency is amending 
Sec. 341.76(d)(2) to remove Sec. 341.76(d)(2)(i)(a) and (d)(2)(i)(b). 
The agency is also amending Sec. 310.545(a)(6)(iv) for bronchodilator 
drug products by adding new paragraph (a)(6)(iv)(C) and listing 
thereunder ``any ingredient(s) in a pressurized metered-dose aerosol 
container.'' In addition, the agency is removing Sec. 341.76(e) from 
the final monograph because that information now appears in 
Sec. 330.1(i) (21 CFR 330.1(i)) as part of the general labeling policy 
for OTC drug products.
     The agency points out that incorrect dates were inadvertently 
inserted in Sec. 310.545(a)(6)(iv)(C) and (d)(26) of the proposed 
amendment (60 FR 13014 at 13020). Consequently, the agency is revising 
the dates in these sections to indicate that the conditions of this 
final rule will be effective 30 days after the date of publication in 
the Federal Register. Further, proposed Sec. 310.545(d)(26) is 
renumbered in this final rule as Sec. 310.545(d)(25).

-V. Analysis of Impacts

     The agency received one comment in response to the agency's 
request for comments on any substantial or significant economic impact 
that this rulemaking would have on OTC bronchodilator MDI aerosol drug 
products that contain epinephrine, epinephrine bitartrate, and 
racepinephrine hydrochloride (60 FR 13014 at 13020). The comment 
indicated that this rulemaking would have a significant impact on the 
OTC bronchodilator industry and itself if additional data or new NDA's 
were requested for existing NDA-approved MDI aerosol drug products. As 
discussed above, this monograph amendment should have minimal impact on 
any existing MDI aerosol drug product marketed under an approved NDA. 
Any changes in manufacturing procedures will require a standard 
supplemental application that would have been required before the 
amendment was finalized.
     FDA has examined the impacts of this final 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 final rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the final 
rule is not a significant regulatory action as defined by the Executive 
Order and so 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 monograph amendment does not change the status 
of any currently marketed MDI aerosol drug products. All such products 
are currently the subject of an approved application. As is currently 
the case for marketed MDI aerosol products, in the interest of public 
health and safety, an approved application will be required for any 
product that is reformulated to contain a non-CFC propellant. In 
addition, there are a limited number of MDI aerosol bronchodilator drug 
product manufacturers. Accordingly, the agency certifies that this 
final 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.

-VI. Environmental Impact

     The agency has determined 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.

-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, 21 CFR 
parts 310 and 341 are 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)(C) and (d)(25) 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.
* * *
     (C) Approved as of June 19, 1996. Any ingredient(s) in a 
pressurized metered-dose inhaler container.
 * * * * *
     (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)(25) of this section.
 * * * * *
     (25) June 19, 1996, for products subject to paragraph 
(a)(6)(iv)(C) 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. 341.76   [Amended]

     4. Section 341.76 is amended by removing paragraphs (d)(2)(i) and 
(e), redesignating paragraph (d)(2)(ii) as paragraph (d)(2), and 
revising the heading of newly redesignated paragraph (d)(2) to read as 
follows:


Sec. 341.76   Labeling of bronchodilator drug products.

-* * * * *
     (d) * * *
    -(2) For products containing epinephrine, epinephrine bitartrate, 
and racepinephrine hydrochloride identified

[[Page 25147]]

in Sec. 341.16(d), (e), and (g) for use in a hand-held rubber bulb 
nebulizer.
* * *

    Dated: April 11, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-12499 Filed 5-17-96; 8:45 am]
BILLING CODE 4160-01-F