[Federal Register: July 13, 2005 (Volume 70, Number 133)]
[Proposed Rules]               
[Page 40232-40237]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr13jy05-25]                         

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Proposed Rules
                                                Federal Register
________________________________________________________________________

This section of the FEDERAL REGISTER contains notices to the public of 
the proposed issuance of rules and regulations. The purpose of these 
notices is to give interested persons an opportunity to participate in 
the rule making prior to the adoption of the final rules.

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[[Page 40232]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310 and 341

[Docket No. 1976N-0052G] (formerly 76N-052G)
RIN 0910-AF33

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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
the tentative final monograph (TFM) for over-the-counter (OTC) cough-
cold combination drug products to remove the combination of an oral 
bronchodilator (products containing ephedrine or its salts) and an 
expectorant, and to reclassify this combination drug product as 
Category II (not generally recognized as safe and effective for OTC 
use). FDA is also proposing to classify the combination of an oral 
bronchodilator and an oral nasal decongestant as Category II. FDA is 
issuing this notice of proposed rulemaking after considering data and 
information on the appropriateness of these combination drug products 
to treat mild asthma. Elsewhere in this issue of the Federal Register, 
FDA is proposing to amend the final monograph (FM) for OTC 
bronchodilator drug products to require additional labeling for all 
ingredients included in the FM. These proposed rules are part of FDA's 
ongoing review of OTC drug products.

DATES: Submit written or electronic comments on the proposed monograph 
amendment and on FDA's economic impact determination by November 10, 
2005. See section IX of this document for the proposed effective date 
of any final rule that may publish based on this proposal.

ADDRESSES: You may submit comments, identified by Docket No. 1976N-
0052G by any of the following methods:
     Federal eRulemaking Portal: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov. 

Follow the instructions for submitting comments.
     Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments. 

Follow instructions for submitting comments on the agency Web site.
     E-mail: fdadockets@oc.fda.gov. Include Docket No. 1976N-
0052G in the subject line of your e-mail message.
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management, 5630 Fishers Lane, rm. 
1061, Rockville, MD 20852.
    Instructions: All submissions received must include the agency name 
and Docket No. 1976N-0052G. All comments received will be posted 
without change to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm, 

including any personal information provided. For detailed instructions 
on submitting comments and additional information on the rulemaking 
process, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION 
section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm 

and/or the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Cazemiro R. Martin or Gerald M. 
Rachanow, Center for Drug Evaluation and Research (HFD-560), Food and 
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-
2222.

SUPPLEMENTARY INFORMATION:

I. Background

A. Advance Notice of Proposed Rulemaking (ANPRM)

    In the Federal Register of September 9, 1976 (41 FR 38312), FDA 
published, under Sec.  330.10(a)(6) (21 CFR 330.10(a)(6)), an ANPRM to 
establish a monograph for OTC cold, cough, allergy, bronchodilator, and 
antiasthmatic (cough-cold) 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 
the combination of an oral bronchodilator and an expectorant be 
Category I (generally recognized as safe and effective), provided the 
product is labeled only for cough associated with asthma (41 FR 38312 
at 38326). The Panel did not provide any additional discussion of this 
combination. The Panel placed the combination of an oral bronchodilator 
with either an analgesic-antipyretic, anticholinergic, antihistamine, 
or antitussive (when the product is labeled only for cough associated 
with asthma) ingredient in Category II (not generally recognized as 
safe and/or effective) (41 FR 38312 at 38326).

B. TFM

    FDA concurred with the Panel in the cough-cold combinations TFM (53 
FR 30522 at 30556, August 12, 1988). FDA also classified the 
combination of caffeine and ephedrine or pseudoephedrine in Category II 
(53 FR 30522 at 30557). No comments on these specific combinations were 
submitted in response to the TFM.

C. FM

    In the Federal Register of October 2, 1986 (51 FR 35326), FDA 
issued a FM for OTC bronchodilator drug products. The oral active 
ingredients included in the bronchodilator monograph are ephedrine, 
ephedrine hydrochloride, ephedrine sulfate, and racephedrine 
hydrochloride (Sec.  341.16(a), (b), (c), and (f) (21 CFR 341.16(a), 
(b), (c), and (f))). The OTC bronchodilator FM also includes 
epinephrine, epinephrine bitartrate, and racepinephrine hydrochloride 
(Sec.  341.16(d), (e), and (g)) as active ingredients administered by 
``inhalation.'' Because this proposed rule addresses only oral 
bronchodilator ingredients, it does not apply to epinephrine and its 
salts.

D. Proposal to Remove Ephedrine From the Bronchodilator FM

    In the Federal Register of July 27, 1995 (60 FR 38643), FDA 
published a proposed rule to amend the FM for OTC bronchodilator drug 
products to remove

[[Page 40233]]

the ingredients ephedrine, ephedrine hydrochloride, ephedrine sulfate, 
and racephedrine hydrochloride and to classify those ingredients as 
Category II. In that proposal, FDA did not discuss the rationale of an 
ephedrine-guaifenesin combination product because the removal of 
ephedrine ingredients from the monograph would have eliminated such 
combination products from the market. After FDA published its 1995 
proposed rule, the Drug Enforcement Administration (DEA) issued new 
requirements restricting the sale of ephedrine, its salts, optical 
isomers, and salts of optical isomers. DEA allows continued, but 
restricted sales of these ephedrine drug products. In response to the 
changes in DEA's requirements and comments received on FDA's 1995 
proposal, FDA has reconsidered its proposed action and intends to allow 
continued OTC marketing of single ingredient ephedrine bronchodilator 
drug products. Elsewhere in this issue of the Federal Register, FDA is 
proposing to amend the FM for OTC bronchodilator drug products to 
require additional labeling for all ingredients included in the FM.

E. Bronchodilator Combination Drug Products

    In the Federal Register of September 27, 2001 (66 FR 49276), FDA 
issued a final rule establishing that cough-cold combination drug 
products containing any oral OTC bronchodilator active ingredient in 
combination with any analgesic(s) or analgesic-antipyretic(s), 
anticholinergic, antihistamine, oral antitussive, or stimulant active 
ingredient are not generally recognized as safe and effective and are 
misbranded for OTC use. In the Federal Register of December 23, 2002 
(67 FR 78158), FDA issued a final rule for OTC cough-cold combination 
drug products. That final rule did not address the combination of an 
oral bronchodilator and an expectorant or the combination of an oral 
bronchodilator and an oral nasal decongestant. Neither combination had 
been previously classified. FDA indicated that these two combination 
products would be addressed in a future issue of the Federal Register. 
FDA is addressing these combination products in this document.
    The only expectorant ingredient in the OTC cough-cold drug products 
monograph is guaifenesin (Sec.  341.18 (21 CFR 341.18)). Therefore, the 
only currently marketed OTC bronchodilator combination drug products 
contain an ephedrine component and guaifenesin.

II. FDA's Concerns About Ephedrine-Guaifenesin Combination Products

A. Asthma and Its Treatment

    Asthma is a chronic lung disease caused by inflammation of the 
airways, resulting in episodes of airway narrowing and obstruction. 
Common symptoms of asthma can include wheezing, shortness of breath, 
tightness of the chest, difficulty breathing after exercise, and 
coughing. This cough is not usually productive. People with asthma 
generally do not require therapy with an expectorant, because increased 
sputum production and expectoration are not important features of 
asthma (Ref. 1).
    The National Heart, Lung, and Blood Institute (NHLBI)/The World 
Health Organization (WHO) Global Initiative for Asthma (Ref. 2), the 
NHLBI'S National Asthma Education Prevention Program (Ref. 3), and the 
American Academy of Allergy Asthma and Immunology (Ref. 4), recommend 
pharmacological intervention to treat asthma. These organizations based 
this recommendation on the understanding that airway obstruction in 
asthma consists of bronchial smooth muscle spasm and variable degrees 
of airway inflammation. This inflammation is characterized by edema, 
mucous secretion, and the influx of a variety of inflammatory cells 
causing recurrent episodes of wheezing, shortness of breath, chest 
tightness, and coughing in susceptible individuals.
    These organizations recommend pharmacological intervention with 
what they term as ``controller'' and ``reliever'' medications (Refs. 2, 
3, and 4). Medications used to ``control'' asthma include what are 
commonly called ``anti-inflammatory'' agents (e.g., inhaled 
corticosteroids, antileukotrienes, cromones) and long-acting 
bronchodilators used daily on a long-term basis to lessen the severity 
of persistent asthma symptoms and signs. Medications used to relieve 
acute symptoms of asthma include the short-acting bronchodilators 
(primarily inhaled). None of the controller or reliever medications in 
these asthma guidelines include expectorants.

B. Monograph Uses of Ephedrine and Guaifenesin

    Ephedrine is a sympathomimetic drug currently labeled as a 
bronchodilator for OTC use. The current OTC indication is ``For 
temporary relief of shortness of breath, tightness of chest, and 
wheezing due to bronchial asthma'' (Sec.  341.76(b)(1) (21 CFR 
341.76(b)(1))). The labeling of the product may also state one or both 
of the following uses in Sec.  341.76(b)(2):
    (i) ``For the'' (select one of the following: ``temporary 
relief'' or ``symptomatic control'') ``of bronchial asthma'', and 
(ii) ``Eases breathing for asthma patients'' (which may be followed 
by: ``by reducing spasms of bronchial muscles'').
    Guaifenesin is the only expectorant active ingredient included in 
the cough-cold monograph (Sec.  341.18). It is labeled for OTC use to 
``help loosen phlegm (mucus) and thin bronchial secretions to'' (select 
one or more of the following: ``rid the bronchial passageways of 
bothersome mucus,'' ``drain bronchial tubes,'' and ``make coughs more 
productive'') (Sec.  341.78(b) (21 CFR 341.78(b))).
    In the FM for OTC expectorant drug products (54 FR 8494 at 8500, 
February 28, 1989), FDA stated that the effectiveness of guaifenesin in 
the symptomatic relief of sputum removal in asthmatics had not been 
demonstrated. Guaifenesin at the usual recommended dose is of doubtful 
value for asthma and the clinical data to support its efficacy is 
conflicting (Refs. 5 and 6). Moreover, in asthma, the drying of 
secretions along with the narrowing of the airways could potentially 
result in inspissated (thickened or dried) material and mucus plugs. 
This could then further increase airway obstruction and lead to further 
breathing difficulties. FDA pointed out that appropriate treatment for 
the condition of inspissated secretions is hydration, bronchoscopy with 
lavage and suctioning combined with anti-inflammatory drugs, and 
bronchodilators. FDA noted that without such an approach in the 
treatment of asthmatics, a safety concern may exist for the use of 
guaifenesin in asthma.
    When FDA made these statements in the expectorant section of the 
cough-cold drug products rulemaking in 1989, it did not change its 
proposed Category I categorization of a combination of an oral 
bronchodilator active ingredient and an expectorant active ingredient 
in the August 12, 1988, cough-cold combinations TFM (53 FR 30522 at 
30561). Likewise, FDA did not revise its categorization of this 
combination in the August 12, 1988, cough-cold combinations TFM when it 
published its proposal in 1995 to remove ephedrine from the OTC 
bronchodilator FM. The removal of ephedrine ingredients from the 
monograph would have eliminated such combination products from the 
market. FDA also did not discuss this combination in the December 23, 
2002, final rule for OTC cough-cold combination drug products because a 
decision on the status of ephedrine as an OTC bronchodilator

[[Page 40234]]

was still pending at that time. FDA discusses the rationale and the 
benefits/risks of ephedrine-guaifenesin combination drug products in 
this document (see section II.D of this document).

C. OTC Drug Monograph Combination Policy

    The policy for combination products included in OTC drug monographs 
in Sec.  330.10(a)(4)(iv) states:
    An OTC drug may combine two or more safe and effective active 
ingredients and may be generally recognized as safe and effective 
when each active ingredient makes a contribution to the claimed 
effect(s); when combining of the active ingredients does not 
decrease the safety or effectiveness of any of the individual active 
ingredients; and when the combination, when used under adequate 
directions for use and warnings against unsafe use, provides 
rational concurrent therapy for a significant proportion of the 
target population.

D. Rationale and Benefit/Risk of Ephedrine-Guaifenesin Combination 
Products

    Combination products containing ephedrine and guaifenesin can 
include in their labeling the indications in Sec. Sec.  341.76(b) and 
341.78(b) (see section II.B of this document). For example, the 
indications section for these combination products could read as 
follows:
    For temporary relief of shortness of breath, tightness of chest, 
and wheezing due to bronchial asthma. Eases breathing for asthma 
patients by reducing spasms of bronchial muscles. Helps loosen 
phlegm (mucus) and thins bronchial secretions to rid the bronchial 
passageways of bothersome mucus, drain bronchial tubes, and make 
cough more productive.
    Based on the pathogenesis of asthma, FDA considers the role of 
expectorants inappropriate in the routine pharmacological management of 
this disease. There is little evidence in the clinical literature to 
support the use of expectorants in asthma (Refs. 5 and 6). The use of 
expectorants in the treatment of asthma is also inconsistent with 
current asthma management guidelines (Refs. 2 through 5).
    The Panel's recommendation of monograph status for the combination 
of an oral bronchodilator and an expectorant was made in the early 
1970's. In 1995, the American Thoracic Society (ATS) discussed chronic 
obstructive pulmonary disease (COPD) and asthma (Ref. 9). ATS stated 
that in the past, asthma was generally included under the broad 
classification of COPD. According to ATS, patients with unremitting 
asthma are classified as having COPD, while patients with asthma whose 
airflow obstruction is completely reversible are not considered to have 
COPD. ATS stated that the pharmacotherapy of COPD is similar to that of 
asthma. ATS indicates that the goals of therapy for COPD are to induce 
bronchodilation, decrease the inflammatory reaction, and facilitate 
expectoration. In discussing drugs affecting mucus, ATS mentioned a 
study of organic iodide and stated that the values of other agents have 
not been clearly demonstrated. Expectorants are not included in ATS's 
recommended pharmacologic therapy for the management of mild or mild-
to-moderate COPD (Ref. 9).
    FDA no longer considers the combination of an oral bronchodilator 
(i.e., ephedrine) and an expectorant (i.e., guaifenesin) as providing 
rational concurrent therapy for a significant proportion of the asthma 
population for whom self-treatment with OTC drugs may be appropriate 
(i.e., people with mild asthma). FDA also no longer believes that each 
active ingredient in the combination makes a contribution to the 
claimed effect. Asthma patients with severe asthma exacerbations and 
status asthmaticus may develop mucus plugging in small airways causing 
severe airflow limitation. Current management in these situations often 
requires mechanical ventilation, bronchoscopy, and/or mucolytic therapy 
(Refs. 7 and 8), but not the use of an expectorant. Coughing that may 
accompany asthma is generally treated with the use of bronchodilators 
(inhaled and occasionally oral) and not with an expectorant, because 
increased sputum production is not usually problematic in mild asthma 
(Ref. 1). Use of an oral bronchodilator in combination with an 
expectorant is not part of the recommended pharmacological management 
of asthma (Refs. 2, 3, and 4). FDA believes a health care provider 
should make the determination whether an expectorant is needed and, in 
those minority of cases where it may be, then prescribe an expectorant 
or recommend an appropriate OTC drug product. OTC bronchodilator drug 
products are required to have the following warning in their labeling: 
``Do not use this product unless a diagnosis of asthma has been made by 
a doctor'' (Sec.  341.76(c)(1)). If a health care provider determines 
that an oral bronchodilator and an expectorant are both needed, any 
small proportion of people with asthma who would use both ingredients 
can obtain both drug products separately.

E. DEA Restrictions on OTC Ephedrine Drug Products

    FDA believes that most people who currently self-treat for mild 
asthma purchase and use the combination ephedrine-guaifenesin drug 
product primarily because it is more readily available than OTC single-
ingredient ephedrine drug products. As discussed elsewhere in this 
issue of the Federal Register, DEA regulations place restrictions on 
the sale of single-entity OTC ephedrine drug products. These 
restrictions include:
     Stocking the product behind the counter where only 
employees have access (21 CFR 1309.71(a)(2));
     Requiring a record of the purchaser's name and address, 
the quantity of drug product purchased, and the method of transaction 
(21 CFR 1310.06); and
     Seeing two forms of identification and obtaining a 
signature of the purchaser prior to completing the sale (21 CFR 
1310.07(d)).
    In contrast, the DEA restrictions on the sale of combination 
ephedrine drug products are not as stringent. Most importantly, DEA 
regulations currently do not require that OTC combination ephedrine 
drug products be stocked behind the counter (62 FR 52294, October 7, 
1997). In addition, retail distributors of combination ephedrine drug 
products are not required to do the following: (1) Register with the 
DEA (Sec.  1309.21 (21 CFR 1309.21)) or (2) make or keep records for 
certain sales (Sec.  1310.03 (21 CFR 1310.03)), such as:
     Sales limited to combination ephedrine drug products;
     Sales that do not exceed a single transaction amount of 24 
grams of ephedrine;
     Sales that are limited almost exclusively for personal 
use, either directly to walk-in customers or in face-to-face 
transactions by direct sales; and
     Sales that are to an individual for legitimate medical 
use.
    See 21 CFR 1300.02(b)(29) and Sec. Sec.  1309.21 and 1310.03 for 
DEA regulations applicable to single-entity ephedrine drug products.

III. FDA's Tentative Conclusion and Proposal

A. Bronchodilator and Expectorant Combination Drug Products

    FDA no longer considers ephedrine combination drug products as 
generally recognized as safe and effective for continued OTC 
availability. Based on the pathogenesis of asthma and the 
recommendations from various groups involved in the management of 
asthma (Refs. 2, 3, and 4), FDA tentatively concludes that there is 
currently no role for expectorants in the pharmacological management of 
this chronic lung disease for a significant proportion of people with 
mild asthma.

[[Page 40235]]

    FDA has tentatively determined that OTC combination products 
containing an oral bronchodilator and an expectorant should no longer 
be available because they do not meet the standards for safe and 
effective OTC drug products. These combination products are not 
rational therapy for the treatment of mild asthma because the 
expectorant component does not contribute to the relief of the 
condition (see section II.D of this document) for a significant portion 
of the population. Additionally, this combination is inconsistent with 
the combination requirements set forth in Sec.  330.10(a)(4)(iv) 
because the expectorant ingredient does not make a contribution to the 
claimed effects. Therefore, in this proposed rule, FDA is proposing to 
reclassify the combination of any single oral bronchodilator active 
ingredient and any single expectorant active ingredient (currently 
listed in Sec.  341.85(l) (21 CFR 341.85(l)) of the TFM, 53 FR 30522 at 
30561) from Category I to Category II.

B. Bronchodilator and Oral Nasal Decongestant Combination Drug Products

    During the rulemaking for OTC cough-cold drug products, no data or 
comments were submitted on the combination of an oral bronchodilator 
and an oral nasal decongestant active ingredient. This combination was 
not discussed by the Panel in its report or by FDA in the TFM or FM. 
FDA does not believe that this specific combination drug product is 
marketed OTC at this time. If such a product were marketed, the uses 
for this combination containing ephedrine and a nasal decongestant are 
found in Sec.  341.76(b) and 21 CFR 341.80(b). Thus, the labeling would 
include the bronchodilator claims discussed in section II.B of this 
document and the claim ``temporarily relieves nasal congestion.'' FDA 
does not have data showing that people who need relief of the symptoms 
of mild asthma (wheezing, tightness of chest, and shortness of breath) 
concurrently need relief of nasal congestion. FDA has not received any 
information that indicates this combination provides rationale 
concurrent therapy for a significant proportion of an asthmatic target 
population. Therefore, FDA considers this combination not to be 
generally recognized as safe and effective for OTC use. FDA is 
proposing to classify the combination of an oral bronchodilator 
(products containing ephedrine or its salts) and any oral nasal 
decongestant as Category II.

IV. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). 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 economic 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. Section 202(a) of the Unfunded Mandates Reform Act of 1995 
requires that agencies prepare a written statement of anticipated costs 
and benefits before proposing any rule that may result in an 
expenditure by state, local, and tribal governments, in the aggregate, 
or by the private sector, of $100 million in any one year (adjusted 
annually for inflation).
    FDA believes that this proposed rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
In addition, the proposed rule is not a significant regulatory action 
as defined by the Executive order.
    FDA is not required to prepare a statement of costs and benefits 
under the Unfunded Mandates Reform Act because this proposed rule is 
not expected to result in any 1-year expenditure that would exceed $100 
million adjusted for inflation. The current inflation adjusted 
statutory threshold is about $110 million.
    The purpose of this proposed rule is to reclassify the combination 
of any single oral bronchodilator active ingredient and any single 
expectorant active ingredient (currently listed in Sec.  341.85(l) of 
the TFM, 53 FR 30522 at 30561) from Category I to Category II 
(nonmonograph). Single entity oral bronchodilator and expectorant drug 
products will remain available OTC for consumer use at this time. This 
proposed rule also places the combination of an oral bronchodilator and 
an oral nasal decongestant in Category II. FDA does not believe this 
combination is currently marketed; therefore, there should be no 
economic impact on manufacturers.
    The potential benefits of this action include better self-treatment 
of the symptoms of mild asthma. Most people with mild asthma do not 
need an expectorant to control their symptoms. Nevertheless, FDA 
believes that some people with asthma continue to purchase the 
combination ephedrine-guaifenesin products affected by this rule mainly 
because they are more readily accessible than the single ingredient 
ephedrine products, which are subject to more DEA restrictions. People 
with mild asthma would continue to have access to single ingredient 
ephedrine products and could easily purchase an OTC expectorant. 
Although this action may pose some minor inconvenience to people with 
asthma who currently use the combination products, they will still be 
able to purchase single-ingredient ephedrine products from outlets that 
are in compliance with DEA single-ingredient ephedrine requirements.
    All of the currently marketed OTC ephedrine combination drug 
products known to FDA are combined with guaifenesin. After the 
effective date of any final rule based on this proposal, manufacturers 
will have the choice of either stopping the introduction of their 
combination product into interstate commerce or reformulating their 
combination product(s) to a single-ingredient ephedrine product and 
complying with DEA requirements for selling these products. FDA's Drug 
Listing System (DLS) identifies 14 manufacturers and 8 distributors/
repackers of 36 combination ephedrine hydrochloride and guaifenesin 
drug products. Other standard reference books (e.g., American Drug 
Index and Red Book) identify additional ephedrine combination drug 
products, and FDA is aware that products containing monograph labeling 
marketed via magazines and catalogues may not be included in the DLS 
database. Therefore, FDA estimates that there are about 25 
manufacturers and distributors/repackers of approximately 50 products 
that would be affected by the proposed rule. In many cases, 
manufacturers would bear the costs of stopping the introduction of 
their products into interstate commerce or the reformulation and 
subsequent relabeling of the affected products.
    The cost to reformulate a drug product varies greatly depending on 
the nature of the product and manufacturing process, and the size of 
the firm. No manufacturer would have to change its product dosage form 
to comply with this rule. However, some manufacturers may have to 
revalidate (e.g., product, process and/or new supplier), conduct 
stability tests, and change master production records in order to 
ensure compliance with good

[[Page 40236]]

manufacturing practice (21 CFR parts 210 and 211). FDA estimates that 
the cost of reformulation would range from $100,000 to $500,000 per 
product. However, many of these manufacturers already produce a single-
ingredient ephedrine product. Moreover, others had previously produced 
a single-ingredient product before switching to the combined ephedrine-
guaifenesin product and may, therefore, need only revalidate. Thus, FDA 
does not know how many products manufacturers will choose to fully 
reformulate. If 20 products were reformulated, and using the midpoint 
of the estimated cost to reformulate of $300,000, the cost to all 
manufacturers of reformulation would be approximately $6 million (20 
products x $300,000 per product). FDA believes that because some 
manufacturers currently marketing ephedrine combination drug products 
also market single-ingredient ephedrine products, the reformulation 
costs associated with this proposed rule may be lower. However, those 
manufacturers who market only the ephedrine combination drug product 
would incur the full costs to reformulate, if they so choose, to a 
single-ingredient ephedrine drug product.
    The cost to relabel OTC drug products also varies depending on the 
type of packaging, the outlet type, and the extent of the necessary 
labeling changes. FDA estimates that the cost of relabeling would 
generally be between $2,000 and $3,000 per product. Assuming a high-
cost scenario, and that all 50 estimated products would be relabeled, 
the total labeling cost would be approximately $150,000 (50 products x 
$3,000 per product).
    Based on Small Business Administration size standards, 
approximately 75 percent of the 14 domestic manufacturers of the 
affected products are small entities (e.g., fewer than 750 employees), 
as are most of the 8 distributors/repackers. FDA cannot assess the 
economic impact on all of these entities because sales data for 
products sold through all markets are not available. Based on IMS 
Health data, the two largest selling brands (produced by two different 
manufacturers and representing three individual products) of oral 
tablets containing a combination of ephedrine-guaifenesin active 
ingredients had sales of approximately $4.257 million in 2001 (Ref. 
10). This figure represents the sales of products affected by this 
proposed rule in pharmacies, chain drug stores, mass merchandisers, 
food stores with pharmacies, and proprietary stores (defined as stores 
under 10,000 square feet of floor space that sell OTC drug products, 
but do not have a pharmacy). These sales accounted for about 0.06 
percent of the total sales (approximately $7,715.703 million) of all 
respiratory therapy drugs (USC 28000, Respiratory Therapy) reported by 
IMS Health in 2001 (Ref. 11). FDA has no information on the sales 
volume of the affected combination products in other outlet types, 
e.g., convenience stores, magazine ads, and gas stations.
    FDA expects that the industry will experience little overall 
reduction in sales for the labeled use of ephedrine bronchodilator drug 
products, because those consumers using the combination product can 
switch to single ingredient products. FDA anticipates that the 
manufacturers of the two largest selling brands of oral tablets 
containing a combination of ephedrine-guaifenesin active ingredients 
will reformulate these products to single-ingredient ephedrine drug 
products. If reformulation does not occur upon issuance of a final 
rule, these manufacturers will incur lost sales of approximately $4 to 
$5 million annually. FDA cannot calculate the magnitude of lost sales 
for other companies that market these combination drug products because 
IMS data do not include specific sales information for products 
marketed by those companies. FDA believes that the sales of the 
combination ephedrine-guaifenesin bronchodilator drug products do not 
make up a large proportion of the total revenues of most of these 
firms. Consumers will still be able to purchase single-ingredient 
ephedrine bronchodilator drug products. Accordingly, an increase in 
sales may occur for current manufacturers of single-ingredient products 
and manufacturers who reformulate combination products to single-
ingredient products.
    FDA considered but rejected two alternatives for the proposed rule: 
(1) Additional labeling and (2) leaving the combination ephedrine-
guaifenesin drug products on the OTC market. FDA does not believe that 
additional labeling would ensure proper use of this combination product 
because FDA no longer considers it to be a rational concurrent therapy 
and because FDA believes that both active ingredients do not make a 
contribution to the claimed effect. Current treatment guidelines for 
mild asthma do not recommend the use of an expectorant. FDA believes 
that a doctor should make a case-by-case determination whether a person 
with mild asthma needs an expectorant drug product, and in those rare 
instances should prescribe or recommend an appropriate product. For the 
same reasons, FDA has tentatively concluded that it would be 
inappropriate to leave ephedrine-guaifenesin combination drug products 
in the OTC drug marketplace. FDA proposes that manufacturers be 
required to stop introducing their combination product into interstate 
commerce, or to implement any required reformulation and labeling 
changes to a single-ingredient product within 180 days after any final 
rule based on this proposal is published.
    There is one other federal rule--DEA regulations controlling the 
distribution of OTC ephedrine drug products--that is related to, but 
does not conflict with, this proposed rule. Manufacturers and other 
marketers of OTC ephedrine drug products must register with DEA (Sec.  
1309.21) and meet other DEA requirements.
    With regard to the Regulatory Flexibility Act, FDA does not believe 
that the proposed rule will have a significant economic impact on a 
substantial number of small entities. However, there is uncertainty 
concerning both the number of affected entities and products. This 
analysis of impacts, together with other relevant sections of this 
document, serves as FDA's initial regulatory flexibility analysis. FDA 
specifically requests detailed industry comment regarding both the 
number of small entities and products affected, as well as any 
potentially significant impact of this rule on small entities.

V. Paperwork Reduction Act of 1995

    FDA notes that this proposed rulemaking does not contain any 
labeling requirements. However, if a company chooses to reformulate its 
combination product(s) to a single-ingredient product, relabeling would 
be necessary. Those labeling requirements are found in the existing 
monograph for OTC bronchodilator drug products in Sec.  341.76. (See 
proposed changes to that monograph elsewhere in this issue of the 
Federal Register.)

VI. Environmental Impact

    FDA has determined under 21 CFR 25.31(a) 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.

VII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule does not contain policies that have

[[Page 40237]]

substantial direct effects on the States, on the relationship between 
the National Government and the States, or on the distribution of power 
and responsibilities among the various levels of government. 
Accordingly, FDA has tentatively concluded that the proposed rule does 
not contain policies that have federalism implications as defined in 
the Executive order and, consequently, a federalism summary impact 
statement is not required.

VIII. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or three paper copies of 
any mailed comments, except that individuals may submit one paper copy. 
Comments 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. Received comments may be seen in the Division of 
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

IX. Proposed Effective Date

    FDA is proposing that any final rule that may issue based on this 
proposal be effective 180 days after its date of publication in the 
Federal Register.

X. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) under Docket No. 1976N-0052G and may be seen 
by interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Woolcock, A. J., ``Asthma,'' Textbook of Respiratory 
Medicine, 2nd ed., W. B. Saunders Co., Philadelphia, PA, 2:1245-
1319, 1994.
    2. ``Global Strategy for Asthma Management and Prevention. 
NHLBI/WHO Workshop Report,'' National Institutes of Health 
Publication, no. 95-3659, January 1995.
    3. ``Guidelines for the Diagnosis and Management of Asthma. 
National Asthma Education and Prevention Program (NAEPP) Expert 
Panel Report,'' National Institutes of Health Publication, Update on 
Selected Topics 2002, pp. 115-116, 2002.
    4. ``Pediatric Asthma/Promoting Best Practice. Guide for 
Managing Asthma in Children,'' American Academy of Allergy, Asthma, 
and Immunology (AAAAI), 1999.
    5. American Academy of Allergy, Asthma, and Immunology. Practice 
Parameters for the Diagnosis and Treatment of Asthma, Journal of 
Allergy and Clinical Immunology, 96(5 Part 2):S707-S870, 1995.
    6. ``Airway Mucus and the Mucociliary System,'' in Allergy: 
Principles and Practice, edited by Middleton, E. M., et. al., 6th 
ed., Mosby-Year Book, Inc., St. Louis, Missouri, p. 753, 2003.
    7. Lemanski, R. F., and W. W. Busse, Journal of the American 
Medical Association, 278:1855-1873, 1997.
    8. Henke, C. et al., ``Combined Bronchoscopy And Mucolytic 
Therapy For Patients With Severe Refractory Status Asthmaticus On 
Mechanical Ventilation: A Case Report And Review Of The 
Literature,'' Critical Care Medicine, 22(2):1880-1883, 1994.
    9. ``Standards for the Diagnosis and Care of Patients with 
Chronic Obstructive Pulmonary Disease. American Thoracic Society 
Statement,'' American Journal of Respiratory Critical Care Medicine, 
152:S77-S120, 1995.
    10. IMS Health, Retail & Provider Perspective, Year 2001, Data 
Extracted December 2002. )(Proprietary data used by FDA with the 
permission of IMS Health.)
    11. IMS Health, Retail & Provider Perspective, 2:449, January-
December 2001. (Proprietary data used by FDA with the permission of 
IMS Health.)

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 (as proposed in the Federal 
Register of August 12, 1988 (53 FR 30522)) be 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, 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 adding paragraphs (a)(6)(iv)(E) 
and (d)(27) to read as follows:


Sec.  310.545  Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (6) * * *
    (iv) * * *
    (E) Approved as of [date 180 days after date of publication in the 
Federal Register]. Any oral bronchodilator active ingredient (e.g., 
ephedrine, ephedrine hydrochloride, ephedrine sulfate, racephedrine 
hydrochloride, or any other ephedrine salt) in combination with any 
expectorant active ingredient (listed in Sec.  341.18 of this chapter) 
or in combination with any oral nasal decongestant active ingredient 
(listed in Sec.  341.20 of this chapter).
* * * * *
    (d) * * *
    (27) [Date 180 days after date of publication in the Federal 
Register], for products subject to paragraph (a)(6)(iv)(E) 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: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.


Sec.  341.40  [Amended]

    4. Proposed Sec.  341.40 is amended by removing paragraph (l) and 
redesignating paragraphs (m) through (bb) as paragraphs (l) through 
(aa) respectively.

    Dated: June 30, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-13708 Filed 7-12-05; 8:45 am]

BILLING CODE 4160-01-S