[Federal Register Volume 69, Number 211 (Tuesday, November 2, 2004)]
[Proposed Rules]
[Pages 63482-63489]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-24423]


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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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Federal Register / Vol. 69, No. 211 / Tuesday, November 2, 2004 / 
Proposed Rules

[[Page 63482]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 341

[Docket No. 1976N-0052N]
RIN 0910-AF34


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
the final monograph (FM) for over-the-counter (OTC) nasal decongestant 
drug products (drug products used to relieve nasal congestion due to a 
cold, hay fever, or other upper respiratory allergies) to add 
phenylephrine bitartrate as generally recognized as safe and effective 
(GRASE) when used in an effervescent tablet. An effervescent tablet is 
intended to be dissolved in water before taking by mouth. This proposal 
is part of FDA's ongoing review of OTC drug products.

DATES: Submit written or electronic comments and comments on FDA's 
economic impact determination by January 31, 2005. Please see section X 
of this document for the effective date of any final rule that may 
publish based on this proposal.

ADDRESSES: You may submit comments, identified by Docket No. 1976N-
0052N and/or RIN number 0910-AF34, by any of the following methods:
    <bullet> Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
    <bullet> Agency Web site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
    <bullet> E-mail: <a href="/cdn-cgi/l/email-protection#accac8cdc8c3cfc7c9d8dfecc3cf82cac8cd82cbc3da"><span class="__cf_email__" data-cfemail="660002070209050d0312152609054800020748010910">[email protected]</span></a>. Include Docket No. 1976N-
0052N and/or RIN number 0910-AF34 in the subject line of your e-mail 
message.
    <bullet> FAX: 301-827-6870.
    <bullet> 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-0052N or Regulatory Information Number 0910-AF34 
(RIN) for this rulemaking. All comments received will be posted without 
change 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://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number(s), found in brackets in the heading of 
this document, into the ``Search'' box and follow the prompts and/or go 
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Houda Mahayni, 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)

1. OTC Cough-Cold Drug Products
    In the Federal Register of September 9, 1976 (41 FR 38312), FDA 
published the report of the Advisory Review Panel on OTC Cold, Cough, 
Allergy, Bronchodilator, and Antiasthmatic Drug Products (Cough-Cold 
Panel). That Panel reviewed oral and topical nasal decongestant drug 
products and found phenylephrine hydrochloride to be a safe and 
effective ingredient for OTC use (41 FR 38312 at 38399 and 38400). The 
Cough-Cold Panel did not evaluate phenylephrine bitartrate.
2. OTC Oral Health Care Drug Products
    In the Federal Register of May 25, 1982 (47 FR 22760), FDA 
published the report of the Advisory Review Panel on OTC Oral Cavity 
Drug Products (Oral Cavity Panel). That Panel reviewed the safety and 
effectiveness of two oral nasal decongestant ingredients, phenylephrine 
hydrochloride and phenylpropanolamine hydrochloride (in lozenge form), 
and classified these ingredients as Category III (more data needed) (47 
FR 22760 at 22911 through 22914). The Oral Cavity Panel did not 
evaluate phenylephrine bitartrate.

B. Tentative Final Monograph (TFM)

1. OTC Cough-Cold Drug Products
    In the Federal Register of January 15, 1985 (50 FR 2220), FDA 
published the TFM for OTC nasal decongestant drug products. The TFM 
proposed phenylephrine hydrochloride as a monograph ingredient but did 
not address phenylephrine bitartrate.
2. OTC Oral Health Care Drug Products
    In the Federal Register of January 27, 1988 (53 FR 2436), FDA 
published the TFM for OTC oral health care (anesthetic/analgesic, 
astringent, debriding agent/oral wound cleanser, and demulcent) drug 
products. FDA referred the data on the oral nasal decongestant 
ingredients phenylephrine hydrochloride and phenylpropanolamine 
hydrochloride to the rulemaking for OTC nasal decongestant drug 
products because that was the primary rulemaking for these ingredients 
(53 FR 2436 at 2448 and 2449).

C. Final Monograph (FM)

1. OTC Cough-Cold Drug Products
    In the Federal Register of August 23, 1994 (59 FR 43386), FDA 
published the FM for OTC nasal decongestant drug products. The 
monograph included phenylephrine hydrochloride as GRASE for oral and 
topical use as a nasal decongestant (Sec.  341.20(a) and (b)(8) (21 CFR 
341.20(a) and (b)(8))). FDA acknowledged that phenylephedrine 
bitartrate was submitted as an oral nasal decongestant active 
ingredient in an effervescent combination cold tablets for OTC use. FDA 
noted that the ingredient was not reviewed by the Cough-Cold Panel or 
included in its report, or addressed in the TFM for OTC nasal

[[Page 63483]]

decongestant drug products (59 FR 43386 at 43394 and 43395). FDA 
reviewed data on phenylephedrine bitartrate submitted in a comment and 
concluded that the data were inadequate to demonstrate the safety and 
effectiveness of phenylephrine bitartrate as an OTC oral nasal 
decongestant ingredient. Consequently, this ingredient was not included 
in the FM.
2. OTC Oral Health Care Drug Products
    FDA has not published an FM for these products.

II. Citizen Petition

    A manufacturer submitted a citizen petition (Ref. 1) requesting FDA 
to amend the OTC nasal decongestant FM to include the ingredient 
phenylephrine bitartrate as GRASE in an effervescent tablet. The 
manufacturer stated:
    <bullet> Domestic and international marketing experiences meet 
FDA's material time and extent criteria for inclusion in an OTC drug 
monograph.
    <bullet> In vitro and in vivo studies demonstrate comparability of 
phenylephrine bitartrate with phenylephrine hydrochloride, an approved 
monograph active ingredient.
    <bullet> Phenylephrine bitartrate would provide consumers a greater 
choice in combination nasal decongestant/analgesic cough-cold 
formulations.
    The manufacturer requested GRASE status for phenylephrine 
bitartrate for use as a single ingredient or in combination with any 
monograph cough-cold active ingredient(s) when delivered in an 
effervescent tablet.

III. FDA's Comments on the Citizen Petition

A. Marketing History

    According to the manufacturer, consumers have used phenylephrine 
hydrochloride and bitartrate domestically and globally as a nasal 
decongestant for decades. In terms of domestic marketing experience, 
the following drug products containing phenylephrine bitartrate have 
been marketed in the United States: (1) An effervescent product 
containing aspirin, chlorpheniramine maleate, and phenylephrine 
bitartrate marketed OTC from 1968 to 1976, before being voluntarily 
discontinued by its manufacturer, and (2) an inhalation product 
containing isoproterenol hydrochloride and phenylephrine bitartrate 
marketed by prescription and later discontinued. Phenylephrine 
bitartrate containing products have been marketed outside the United 
States (Central America, Mexico, Australia, and Spain) since 1978. As 
of 2002, a total of 1.16 billion tablets have been distributed in these 
countries (Ref. 1).
    Products containing bitartrate are presently sold by prescription 
in the United States as a salt of hydrocodone, dihydrocodone, and 
dihydrocodeine. Phenylephrine bitartrate is similar to phenylephrine 
hydrochloride, which is currently included as an oral nasal 
decongestant active ingredient in Sec.  341.20(a)(1). Both 
phenylephrine salts have the same pharmacologic activity and similar 
side effects. FDA is aware that phenylephrine bitratrate effervescent 
tablets were marketed in the United States in the 1960s and 1970s and 
had a similar use and adverse reaction profile as products containing 
phenylephrine hydrochloride. The citizen petition provides sufficient 
information of marketing outside the United States since 1978 to allow 
FDA to determine that phenylephrine bitartrate as a nasal decongestant 
has been marketed to a material time and to a material extent. In 
addition, the citizen petition contains recent data demonstration that 
the phenylephrine bitartrate salt is bioavailable and comparable to the 
phenylephrine hydrochloride salt.

B. Safety and Effectiveness

1. Review of Adverse Event Databases (AEDs)
    The manufacturer conducted a safety review of the FDA and World 
Health Organization's (WHO) AEDs concerning phenylephrine bitartrate 
for the period from 1969 to 1997. The review included all dosage forms 
of phenylephrine but was nonspecific for the phenylephrine salt (e.g., 
hydrochloride or bitartrate). The review identified 22 reports for 
phenylephrine bitartrate out of approximately 900 reports for 
phenylephrine administered orally. There were five reports of ``no drug 
effect'', two reports of nervousness, and 15 different single events 
reported such as rash, vomiting, diarrhea, and insomnia. The 
manufacturer commented that causality and preexisting conditions in the 
22 reported subjects could not be established from the available data. 
The manufacturer noted that:
    <bullet> The FDA database does not indicate the relationship of 
adverse events or preexisting medical conditions of consumers to the 
administration of phenylephrine.
    <bullet> The WHO database revealed five different single event 
reports for products containing phenylephrine bitartrate as an active 
ingredient.
    <bullet> Reports provided by the manufacturer's affiliate from 
other countries in which phenylephrine bitartrate products are marketed 
provided no information on adverse events relative to phenylephrine 
bitartrate.
    FDA finds these data suggest that there are no significant safety 
concerns reported from the use of phenylephrine bitartrate in the 
countries where it is currently used. Safety information from various 
U.S. databases is not available specifically for phenylephrine 
bitartrate because it has not been marketed for the past 30 years. 
Safety information from U.S. databases indicate that phenylephrine 
hydrochloride is safe for OTC use within the label warnings in Sec.  
341.80(c)(1) (21 CFR 341.80(c)(1)). Based on their similar 
pharmacologic activity and side effects, FDA has determined that both 
phenylephrine salts are safe for OTC use.
2. Pharmacokinetic Study
    In a meeting held on February 15, 2002 (Ref. 2), FDA suggested that 
the manufacturer conduct a bioequivalence study. FDA recommended that 
the manufacturer follow FDA's Guidance for Industry entitled 
``Bioavailability and Bioequivalence Studies for Orally Administered 
Drug Products General Considerations'' (the Guidance) (Ref. 3). The 
Guidance describes a single-dose pharmacokinetic study of both 
immediate and modified release drug products to demonstrate 
bioequivalence. FDA generally considers a single-dose study to be more 
sensitive than a multiple-dose study in assessing the release of the 
drug substance from the drug product into the systemic circulation. 
Further, if a multiple-dose study design is necessary, the Guidance 
recommends performing appropriate dosage administration and sampling to 
document that ``steady-state'' is attained. At steady-state, the rate 
of drug leaving the body is equal to the rate of drug entering the 
body.
    The manufacturer submitted an open-label, four-way crossover, 
multiple-dose study in healthy volunteers to evaluate the 
pharmacokinetic profiles of the following equivalent phenylephrine 
doses of phenylephrine hydrochloride and phenylephrine bitartrate in 
two different dosage forms and different weights because of the 
different salts forms:
    <bullet> An effervescent phenylephrine hydrochloride 10 milligram 
(mg) tablet
    <bullet> An effervescent phenylephrine bitartrate 15.6 mg tablet

[[Page 63484]]

    <bullet> an encapsulated\1\ phenylephrine hydrochloride 10 mg 
capsule
---------------------------------------------------------------------------

    \1\ Encapsulated is a capsule dosage form that was termed 
``encapsulated'' by the manufacturer in this study.
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    <bullet> an encapsulated phenylephrine bitartrate 15.6 mg capsule
    Twenty-five subjects completed the study and were considered 
evaluable for the pharmacokinetic analysis. All subjects were treated 
with four oral doses of phenylephrine over a 12-hour period. The first 
dose was administered at 7 a.m. Subsequent doses were administered 4, 
8, and 12 hours later. The analysis provided the mean ratio and 90 
percent confidence interval of the derived pharmacokinetic parameters, 
area under the concentration-time curve (AUC) and maximum plasma 
concentration (Cmax), after single dose and at steady-state for each 
treatment.
3. FDA's Evaluation of the Pharmacokinetic Study
    Bioequivalence may be determined from a multiple-dose study only 
after a steady-state plasma drug level has been reached. The time 
needed to reach the steady-state plasma level is related to the 
elimination half-life of the drug. It takes approximately 6.6 half-
lives to reach 99 percent of steady-state plasma level. If steady-state 
blood levels are going to be used for the determinations of 
bioequivalence, both drug products must be administered to steady-
state. Based on the comparison of the pharmacokinetic parameters 
obtained, the bioequivalence or lack of bioequivalence may be 
determined.
    The manufacturer did not conduct a single-dose pharmacokinetic 
study. The manufacturer performed a study in which four doses of the 
phenylephrine formulations were administered every 4 hours in 1 day. 
The elimination half-life of phenylephrine is between 2 and 3 hours. 
Therefore, it takes between 13.2 (2 x 6.6) and 19.8 (3 x 6.6) hours to 
reach steady-state, at which time blood levels could be obtained to 
compare and determine bioequivalence. Thus, the study was not designed 
to achieve steady-state, nor did the manufacturer document that steady-
state was reached, which is necessary to establish bioequivalence. 
Therefore, the study can only demonstrate comparable bioavailability or 
similarity, but not bioequivalence. Independent scientific study, did 
not allow enough time between doses.
    Table 1 of this document provides a summary of total phenylephrine 
pharmacokinetic parameters derived from the first-dose data. First-dose 
data are being considered because attainment of steady-state was not 
documented and because it is the most robust observation of the data.

 Table 1.--Summary of Total Phenylephrine Pharmacokinetic Parameters-Derived from First-Dose Data-Mean Ratio, 90
                       Percent Confidence Interval (CI), and Significance (p=0.05) (n=25)
----------------------------------------------------------------------------------------------------------------
                                                      Actual       log AUC[tgr]       Actual
              Treatment Comparison                AUC[tgr] Ratio    Ratio CI p-   CmaxRatio CI p- log Cmax Ratio
                                                    CI p-value         value           value        CI p-value
----------------------------------------------------------------------------------------------------------------
PEB-E\1\ vs. PEH-E\2\                                       0.98            1.00            1.00            1.00
                                                       0.93-1.03       0.99-1.00       0.93-1.07       0.99-1.01
                                                          0.4298          0.5077           0.991          0.8642
----------------------------------------------------------------------------------------------------------------
PEB-C\3\ vs. PEH-C\4\                                       0.91            0.98            0.90            0.98
                                                       0.87-0.96       0.98-0.99       0.85-0.97       0.97-0.99
                                                          0.0050          0.0020          0.0137          0.0062
----------------------------------------------------------------------------------------------------------------
\1\Phenylephrine bitartrate in an effervescent tablet.
\2\Phenylephrine hydrochloride in an effervescent tablet.
\3\Phenylephrine bitartrate in a capsule.
\4\Phenylephrine hydrochloride in a capsule.

    Table 1 of this document shows that, for the effervescent tablet, 
the mean ratio (log transformed) for both the C<INF>max</INF> and AUC 
is 1.00 when comparing phenylephrine hydrochloride to phenylephrine 
bitartrate. The actual ratios range from 0.98 to 1.0. Therefore, the 
rate and extent of absorption after the first-dose of the phenylephrine 
bitartrate effervescent tablet are considered similar to those of the 
phenylephrine hydrochloride effervescent tablet.
    Although the manufacturer did not perform a single-dose or a 
multiple-dose study (to steady-state), the similarity in the rate and 
extent of absorption of phenylephrine hydrochloride and phenylephrine 
bitartrate in the effervescent tablets allows FDA to conclude that the 
bioavailability of the phenylephrine salts in the effervescent tablets 
is comparable.
    Table 1 of this document shows that, for the encapsulated 
formulation, the actual mean ratio for AUC and C<INF>max</INF> are 0.91 
and 0.90 for AUC and C<INF>max</INF> respectively. Because this study 
was not of optimal design, FDA has concerns about the plasma 
concentration-time curve that is not available because the second dose 
was administered. FDA cannot conclude that the in vivo performance of 
the products are similar because of the magnitude of the difference of 
the actual mean ratios of 0.90 and 0.91 from 1.0. The encapsulated 
capsule is bioavailable but not bioequivalent to the effervescent 
tablet.

IV. FDA's Tentative Conclusions

A. Single Ingredient Products

    FDA has tentatively determined that phenylephrine bitartrate has 
been marketed to a material extent and for a material time as a nasal 
decongestant with no indication of safety concerns. Based on the 
ingredient's marketing history, absence of safety concerns, and 
additional data provided in the manufacturer's citizen petition, FDA 
has determined that the pharmacokinetic study is acceptable in lieu of 
a clinical trial because of the similarity in the bioavailability of 
the two effervescent

[[Page 63485]]

tablets. Accordingly, FDA acknowledges that the two salts of 
phenylephrine could be used in the effervescent tablets interchangeably 
without any clinically significant impact on the performance of the 
formulations studied. FDA is proposing that phenylephrine bitartrate in 
an effervescent tablet be GRASE for use as an OTC oral nasal 
decongestant. Accordingly, FDA is proposing to amend Sec.  341.20(a)(4) 
of the FM for OTC nasal decongestant drug products to include 
phenylephrine bitartrate in an effervescent tablet. However, additional 
pharmacokinetic data are needed to include the phenylephrine bitartrate 
capsule formulation in the OTC nasal decongestant FM.

B. Combination Products

    The combination of single antihistamine, oral nasal decongestant, 
and analgesic-antipyretic active ingredients is included in 21 CFR 
341.40(c) of the Cough-Cold FM. FDA is proposing to include in the FM 
the combination of chlorpheniramine maleate (antihistamine), 
phenylephrine bitartrate (oral nasal decongestant), and aspirin 
(analgesic-antipyretic) in an effervescent tablet. FDA is including 
only this specific combination product for the following reasons:
    <bullet> This is the only combination containing phenylephrine 
bitartrate that has an OTC marketing history in the United States. It 
was marketed from 1968 to 1976.
    <bullet> The bitartrate salt form of the OTC nasal decongestant 
phenylpropanolamine was reviewed by the Cough-Cold Panel and 
recommended for monograph status as GRASE (41 FR 38312 at 38400 and 
38401).
    <bullet> The rate and extent of absorption of phenylephrine 
bitartrate effervescent tablet after the first-dose and at steady-state 
were similar to those of phenylephrine hydrochloride effervescent 
tablet. Thus, the two phenylephrine salts appear to have comparable 
bioavailability. A drug-drug interaction study is not necessary for the 
combination of chlorpheniramine maleate, phenylephrine bitartrate, and 
aspirin.
    FDA does not have data on any other combination products to include 
them in the FM at this time. FDA is not aware of other combination 
products containing phenylephrine bitartrate that may have been 
marketed. To market any other combination product containing 
phenylephrine bitartrate, manufacturers will need to submit a new drug 
application deviation (21 CFR 330.11).

C. Monograph Labeling

    FDA is proposing the same uses and warnings for phenylephrine 
bitartrate as appear in Sec.  341.80(b) and (c)(1) for phenylephrine 
hydrochloride because these are salt of the same ingredient. Based on 
historical marketing in the United States, more current marketing in 
foreign countries, and the pharmacokinetic study, FDA is proposing the 
following doses:
    <bullet> Adults and children 12 years of age and over: 15.6 
milligrams every 4 hours, not to exceed 62.4 milligrams in 24 hours
    <bullet> Children 6 to under 12 years of age: 7.8 milligrams every 
4 hours, not to exceed 31.2 milligrams in 24 hours
    <bullet> Children under 6 years of age: ask a doctor
    FDA proposes that manufacturers include in their product labeling 
information on the number of tablets and the quantity of water the 
tablets are to be dissolved in prior to administration.
    FDA is also proposing to define effervescent tablet in 21 CFR 341.3 
to state:
    Effervescent tablet. A tablet intended to be dissolved in water 
before administration. It contains, in addition to the active 
ingredient(s), mixtures of acids (citric acid, tartaric acid) and 
sodium bicarbonate, which release carbon dioxide when dissolved in 
water.

D. Statement About Warnings

    Mandating warnings in an OTC drug monograph does not require a 
finding that any or all of the OTC drug products covered by the 
monograph actually caused an adverse event, and FDA does not so find. 
Nor does FDA's requirement of warnings repudiate the prior OTC drug 
monographs and monograph rulemakings under which the affected drug 
products have been lawfully marketed. Rather, as a consumer protection 
agency, FDA has determined that warnings are necessary to ensure that 
these OTC drug products continue to be safe and effective for their 
labeled indications under ordinary conditions of use as those terms are 
defined in the Federal Food, Drug, and Cosmetic Act. This judgment 
balances the benefits of these drug products against their potential 
risks. (See 21 CFR 330.10(a).)
    FDA's decision to act in this instance need not meet the standard 
of proof required to prevail in a private tort action (Glastetter v. 
Novartis Pharmaceuticals Corp., 252 F.3d 986, 991 (8th Cir. 2001)). To 
mandate warnings, or take similar regulatory action, FDA need not show, 
nor do we allege, actual causation. For an expanded discussion of case 
law supporting FDA's authority to require such warnings, see Labeling 
of Diphenhydramine-Containing Drug Products for Over-the-Counter Human 
Use, Final Rule, 67 FR 72555 (December 6, 2002).

E. USP Monograph

    FDA's policy is that for an active ingredient to be included in an 
OTC drug FM, it is necessary to have publicly available chemical 
information that can be used by all manufacturers to determine that the 
ingredient is appropriate for use in their products. (See the Federal 
Register of April 3, 1989 (54 FR 13480 at 13486), and June 20, 1990 (55 
FR 25204 at 25215).) Because phenylephrine bitartrate is not currently 
standardized and characterized for quality and purity in the official 
compendium, i.e., the United States Pharmacopoeia (USP)-National 
Formulary (NF), it will not be included in the FM until such 
information is available. A proposed compendial monograph for 
phenylephrine bitartrate was published in the Pharmacopeial Forum for 
May-June 2004 (Ref. 4). When a final compendial monograph is published 
in the USP-NF, FDA intends to finalize its proposal to include 
phenylephrine bitartrate in an effervescent tablet in the FM. Interim 
marketing of phenylephrine bitartrate in an effervescent tablet before 
an amendment to include this ingredient in the FM is finalized is not 
allowed and may subject any such products to regulatory action.

V. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). 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 the 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, which includes and 
assessment of anticipated costs and benefits, before proposing ``any 
rule that

[[Page 63486]]

includes any Federal mandate that may result in an expenditure in any 
one year by State, local, and tribal governments, in the aggregate, or 
by private sector, of $100,000,000 (adjusted annually for inflation) in 
any one year.''
    FDA believes that this proposed rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
This proposed rule is not a significant regulatory action as defined by 
the Executive order and so is not subject to review under the Executive 
order. As discussed in this section, FDA has determined that this 
proposed rule, if finalized, will not have a significant economic 
impact on a substantial number of small entities. The Unfunded Mandates 
Reform Act of 1995 does not require FDA to prepare a statement of costs 
and benefits for this proposed rule, because the 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 include phenylephrine 
bitartrate in the monograph for OTC nasal decongestant drug products. 
This proposal, when finalized, would allow manufacturers who market 
products containing this ingredient in foreign countries and 
manufacturers who would like to market products containing this 
ingredient in the United States to enter the market place under the OTC 
drug monograph instead of a new drug application (NDA). Cost savings 
will occur from marketing without an NDA.
    Marketing a new OTC drug product containing phenylephrine 
bitartrate is optional for any interested manufacturer. The costs would 
involve the standard startup costs associated with marketing any new 
product under an OTC drug monograph. Manufacturers will not incur any 
costs determining how to state the product's labeling because the 
monograph amendment (and any eventual final rule) will provide that 
information. Any final rule that issues based on this proposal will not 
be expected to require any new reporting and recordkeeping activities. 
Therefore, no additional professional skills would be needed.
    FDA considered but rejected several alternatives: (1) Not including 
phenylephrine bitartrate in the monograph, (2) allowing other 
combinations, and (3) allowing interim marketing. FDA rejected the 
first alternative because it considers the data presented supportive of 
monograph status. FDA rejected the second alternative because it has no 
data to support other combinations at this time. FDA rejected the third 
alternative because there currently is no USP monograph for this 
ingredient. FDA considers it inappropriate to allow interim marketing 
until there are uniform standards for the ingredient in an official 
compendial monograph that all manufacturers can follow, and FDA 
publishes a notice in the Federal Register to allow interim marketing 
to begin.
    This analysis shows that FDA has considered the burden to small 
entities. FDA does not consider an exemption for small entities 
necessary because those manufacturers can enter the market place like 
larger entities anytime after this proposal is finalized. Therefore, 
FDA certifies that this proposed rule will not have a significant 
economic impact on a substantial number of small entities. No further 
analysis is required under the Regulatory Flexibility Act (5 U.S.C. 
605(b)).

VI. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the proposed labeling requirements 
in this document are not subject to review by the Office of Management 
and Budget because they do not constitute a ``collection of 
information'' under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 
et seq.). Rather, the monograph labeling is a ``public disclosure of 
information originally supplied by the Federal government to the 
recipient for the purpose of disclosure to the public'' (5 CFR 
1320.3(c)(2)).

VII. 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.

VIII. 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 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 tentatively concludes 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 has not 
been prepared.

IX. Comments

    FDA is providing a period of 90 days for interested persons to 
submit written or electronic comments on the proposed rule to the 
Division of Dockets Management (see ADDRESSES). Three copies of all 
written comments are to be submitted. Individuals submitting written 
comments or anyone submitting electronic comments may submit one 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.

X. Proposed Effective Date

    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.

XI. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) under Docket No. 1976N-0052N and may be seen 
by interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Comment No. CP18.
    2. Comment No. MM9.
    3. FDA ``Guidance for Industry, Bioavailability and 
Bioequivalence Studies for Orally Administered Drug Products-General 
Considerations,'' October 2000.
    4. ``Phenylephrine Bitartrate'' in Pharmacopeial Forum, The 
United States Pharmacopeial Convention, Inc., Rockville, MD, 
30(3):923-924, May-June 2004.

List of Subjects in 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 part 341 be amended as follows:

PART 341--COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC 
DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

    1. 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.
    2. Section 341.3 is amended by adding paragraph (i) to read as 
follows:


Sec.  341.3  Definitions.

* * * * *
    (i) Effervescent tablet. A tablet intended to be dissolved in water 
before

[[Page 63487]]

administration. It contains, in addition to the active ingredient(s), 
mixtures of acids (citric acid, tartaric acid) and sodium bicarbonate, 
which release carbon dioxide when dissolved in water.
    3. Section 341.20 is amended by adding paragraph (a)(4) to read as 
follows:


Sec.  341.20  Nasal decongestant active ingredients.

* * * * *
    (a) * * *
    (4) Phenylephrine bitartrate in an effervescent tablet.
* * * * *
    4. Section 341.40 is amended by revising paragraphs (b), (c), (e), 
(g), (i), (j), (m), (n), (p), (q), (r), (s), (t), (x), (y), (aa), and 
(bb) and by adding paragraph (cc) to read as follows:


Sec.  341.40  Permitted combinations of active ingredients.

* * * * *
    (b) Any single antihistamine active ingredient identified in Sec.  
341.12 may be combined with any single oral nasal decongestant active 
ingredient identified in Sec.  341.20(a)(1), (a)(2), and (a)(3) 
provided that the product is labeled according to Sec.  341.85.
    (c) Any single antihistamine active ingredient identified in Sec.  
341.12 may be combined with any single oral nasal decongestant active 
ingredient identified in Sec.  341.20(a)(1), (a)(2), and (a)(3) and any 
generally recognized as safe and effective single analgesic-antipyretic 
active ingredient, or any combination of acetaminophen with other 
analgesic-antipyretic active ingredients, or any aspirin and antacid 
combination provided that the product is labeled according to Sec.  
341.85.
* * * * *
    (e) Any single antihistamine active ingredient identified in Sec.  
341.12(a) through (e) and (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in Sec.  
341.14(a)(1) through (a)(4) and any single oral nasal decongestant 
active ingredient identified in Sec.  341.20(a)(1), (a)(2), and (a)(3) 
provided that the product is labeled according to Sec.  341.85(c)(4). 
Diphenhydramine citrate in Sec. Sec.  341.12(f) and 341.14(a)(5) or 
diphenhydramine hydrochloride in Sec. Sec.  341.12(g) and 341.14(a)(6) 
may be both the antihistamine and the antitussive active ingredient 
provided that the product is labeled according to Sec.  341.70(a).
* * * * *
    (g) Any single antihistamine active ingredient identified in Sec.  
341.12(a) through (e) or (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in Sec.  
341.14(a)(1) through (a)(4) and any single oral nasal decongestant 
active ingredient identified in Sec.  341.20(a)(1), (a)(2), or (a)(3) 
and any generally recognized as safe and effective single analgesic-
antipyretic active ingredient, or any combination of acetaminophen with 
other analgesic-antipyretic active ingredients, or any aspirin and 
antacid combination provided that the product is labeled according to 
Sec.  341.85(c)(4). Diphenhydramine citrate in Sec. Sec.  341.12(f) and 
341.14(a)(5) or diphenhydramine hydrochloride in Sec. Sec.  341.12(g) 
and 341.14(a)(6) may be both the antihistamine and the antitussive 
active ingredient provided that the product is labeled according to 
Sec.  341.70(a).
* * * * *
    (i) Any single oral antitussive active ingredient identified in 
Sec.  341.14(a) may be combined with any single oral nasal decongestant 
active ingredient identified in Sec.  341.20(a)(1), (a)(2), or (a)(3) 
provided that the product is labeled according to Sec.  341.85.
    (j) Any single oral antitussive active ingredient identified in 
Sec.  341.14(a)(1) through (a)(4) may be combined with any single oral 
nasal decongestant active ingredient identified in Sec.  341.20(a)(1), 
(a)(2), or (a)(3) and any single expectorant active ingredient 
identified in Sec.  341.18 provided that the product is labeled 
according to Sec.  341.85.
* * * * *
    (m) Any single oral antitussive active ingredient identified in 
Sec.  341.14(a) may be combined with any single oral nasal decongestant 
active ingredient identified in Sec.  341.20(a)(1), (a)(2), or (a)(3) 
and any generally recognized as safe and effective single analgesic-
antipyretic active ingredient, or any combination of acetaminophen with 
other analgesic-antipyretic active ingredients, or any aspirin and 
antacid combination provided that the product is labeled according to 
Sec.  341.85.
    (n) Any single oral antitussive active ingredient identified in 
Sec.  341.14(a)(1) through (a)(4) may be combined with any single oral 
nasal decongestant active ingredient identified in Sec.  341.20(a)(1), 
(a)(2), or (a)(3) and any single expectorant active ingredient 
identified in Sec.  341.18 and any generally recognized as safe and 
effective single analgesic-antipyretic active ingredient, or any 
combination of acetaminophen with other analgesic-antipyretic active 
ingredients, or any aspirin and antacid combination provided that the 
product is labeled according to Sec.  341.85.
* * * * *
    (p) Any single expectorant active ingredient identified in Sec.  
341.18 may be combined with any single oral nasal decongestant active 
ingredient identified in Sec.  341.20(a)(1), (a)(2), or (a)(3) provided 
that the product is labeled according to Sec.  341.85.
    (q) Any single expectorant active ingredient identified in Sec.  
341.18 may be combined with any single oral nasal decongestant active 
ingredient identified in Sec.  341.20(a)(1), (a)(2), or (a)(3) and any 
generally recognized as safe and effective single analgesic-antipyretic 
active ingredient, or any combination of acetaminophen with other 
analgesic-antipyretic active ingredients, or any aspirin and antacid 
combination provided that the product is labeled according to Sec.  
341.85.
    (r) Any single oral nasal decongestant active ingredient identified 
in Sec.  341.20(a)(1), (a)(2), or (a)(3) may be combined with any 
generally recognized as safe and effective single analgesic-antipyretic 
active ingredient, or any combination of acetaminophen with other 
analgesic-antipyretic active ingredients, or any aspirin and antacid 
combination provided that the product is labeled according to Sec.  
341.85.
    (s) Any single oral nasal decongestant active ingredient identified 
in Sec.  341.20(a)(1), (a)(2), or (a)(3) may be combined with any 
generally recognized as safe and effective single oral anesthetic/
analgesic active ingredient, or any combination of anesthetic/analgesic 
active ingredients provided that the product is available in either a 
liquid (to be swallowed) or a solid dosage form (to be dissolved in the 
mouth and swallowed) and provided that the product is labeled according 
to Sec.  341.85.
    (t) Any single oral nasal decongestant active ingredient identified 
in Sec.  341.20(a)(1), (a)(2), or (a)(3) may be combined with any 
single antitussive active ingredient identified in Sec.  341.14(a) or 
(b)(2) and any generally recognized as safe and effective single oral 
anesthetic/analgesic active ingredient, or any combination of 
anesthetic/analgesic active ingredients provided that the product is 
available in either a liquid (to be swallowed) or a solid dosage form 
(to be dissolved in the mouth and swallowed) and provided that the 
product is labeled according to Sec.  341.85. If the combination 
contains a topical antitussive, the product must be formulated in a 
solid dosage form to be dissolved in the mouth.
* * * * *
    (x) Any single oral nasal decongestant active ingredient identified 
in Sec.  341.20(a)(1), (a)(2), or (a)(3) may be

[[Page 63488]]

combined with any generally recognized as safe and effective single 
oral demulcent active ingredient provided that the product is available 
in either a liquid (to be swallowed) or a solid dosage form (to be 
dissolved in the mouth and swallowed) and provided that the product is 
labeled according to Sec.  341.85.
    (y) Any single antitussive active ingredient identified in Sec.  
341.14(a) or (b)(2) may be combined with any single oral nasal 
decongestant active ingredient identified in Sec.  341.20(a)(1), 
(a)(2), or (a)(3) and any generally recognized as safe and effective 
single oral demulcent active ingredient provided that the product is 
available in either a liquid (to be swallowed) or a solid dosage form 
(to be dissolved in the mouth and swallowed) and provided that the 
product is labeled according to Sec.  341.85. If the combination 
contains a topical antitussive, the product must be formulated in a 
solid dosage form to be dissolved in the mouth.
* * * * *
    (aa) Any single oral nasal decongestant active ingredient 
identified in Sec.  341.20(a)(1), (a)(2), or (a)(3) may be combined 
with any generally recognized as safe and effective single oral 
anesthetic/analgesic active ingredient, or any combination of oral 
anesthetic/analgesic active ingredients and any generally recognized as 
safe and effective single oral demulcent active ingredient provided 
that the product is available in either a liquid (to be swallowed) or a 
solid dosage form (to be dissolved in the mouth and swallowed) and 
provided that the product is labeled according to Sec.  341.85.
    (bb) Any single antitussive active ingredient identified in Sec.  
341.14(a) or (b)(2) may be combined with any single oral nasal 
decongestant active ingredient identified in Sec.  341.20(a)(1), 
(a)(2), or (a)(3) and any generally recognized as safe and effective 
single oral anesthetic/analgesic active ingredient, or any combination 
of anesthetic/analgesic active ingredients and any generally recognized 
as safe and effective single oral demulcent active ingredient provided 
that the product is available in either a liquid (to be swallowed) or a 
solid dosage form (to be dissolved in the mouth and swallowed) and 
provided that the product is labeled according to Sec.  341.85. If the 
combination contains a topical antitussive, the product must be 
formulated in a solid dosage form to be dissolved in the mouth.
    (cc) Phenylephrine bitartrate identified in Sec.  341.20(a)(4) may 
be combined with chlorpheniramine maleate identified in Sec.  341.12(c) 
and aspirin provided the product is available only in an effervescent 
tablet and provided that the product is labeled according to Sec.  
341.85.
    5. Section 341.80 is amended by revising the headings in paragraphs 
(c)(1)(i) and (c)(1)(ii), and by adding paragraph (d)(1)(iii) to read 
as follows:


Sec.  341.80   Labeling of nasal decongestant drug products.

* * * * *
    (c) * * *
    (1) Oral nasal decongestants--(i) For products containing 
phenylephrine hydrochloride, pseudoephedrine hydrochloride, 
pseudoephedrine sulfate, or phenylephrine bitartrate identified in 
Sec.  341.20(a)(1) through (a)(4) when labeled for adults. * * *
* * * * *
    (ii) For products containing phenylephrine hydrochloride, 
pseudoephedrine hydrochloride, pseudoephedrine sulfate, or 
phenylephrine bitartrate identified in Sec.  341.20(a)(1) through 
(a)(4) when labeled for children under 12 years of age. * * *
* * * * *
    (d) * * *
    (1) * * *
    (iii) For products containing phenylephrine bitartrate identified 
in Sec.  341.20(a)(4). Include information on the number of dosage 
units and the quantity of water the dosage units are to be dissolved in 
prior to administration as shown in the following table:

 
----------------------------------------------------------------------------------------------------------------
                        Age\1\                                                   Dose\1\
----------------------------------------------------------------------------------------------------------------
adults and children 12 years of age and over                    15.6 milligrams every 4 hours not to exceed 62.4
                                                                                          milligrams in 24 hours
----------------------------------------------------------------------------------------------------------------
children 6 to under 12 years of age                              7.8 milligrams every 4 hours not to exceed 31.2
                                                                                          milligrams in 24 hours
----------------------------------------------------------------------------------------------------------------
children under 6 years of age                                                                       ask a doctor
----------------------------------------------------------------------------------------------------------------
\1\ Headings are not required to appear in the product's labeling.

* * * * *
    6. Section 341.85 is amended by revising the headings in paragraphs 
(a)(1), (b)(1), (b)(2), (b)(3), and (c)(3).


Sec.  341.85   Labeling of permitted combinations of active 
ingredients.

* * * * *
    (a) * * *
    (1) For permitted combinations identified in Sec.  341.40(a), (c), 
(f), (g), (l), (m), (n), (o), (q), (r), and (cc) containing an 
analgesic-antipyretic active ingredient. * * *
* * * * *
    (b) * * *
    (1) For permitted combinations containing an analgesic-antipyretic 
active ingredient identified in Sec.  341.40(a), (c), (f), (g), (l), 
(m), (n), (o), (q), (r), and (cc) when labeled for relief of general 
cough-cold symptoms and/or the common cold. * * *
* * * * *
    (2) For permitted combinations containing an analgesic-antipyretic 
active ingredient identified in Sec.  341.40(a), (c), (f), (g), (m), 
(q), (r), and (cc) when labeled for relief of hay fever/allergic 
rhinitis and/or sinusitis symptoms. * * *
* * * * *
    (3) For permitted combinations containing an oral analgesic-
antipyretic active ingredient identified in Sec.  341.40(a), (c), (f), 
(g), (m), (q), (r), and (cc) when labeled for relief of general cough-
cold symptoms and/or the common cold and for relief of hay fever/
allergic rhinitis and/or sinusitis symptoms.* * *
* * * * *
    (c) * * *

[[Page 63489]]

    (3) For permitted combinations containing a nasal decongestant and 
an analgesic-antipyretic identified in Sec.  341.40(c), (g), (m), (n), 
(q), (r), and (cc). * * *
* * * * *

    Dated: October 26, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-24423 Filed 11-1-04; 8:45 am]
BILLING CODE 4160-01-S


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