Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use; Amendment of Monograph for OTC Nasal Decongestant Drug Products, 43358-43363 [E6-12265]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 71, Number 147 (Tuesday, August 1, 2006)]
[Rules and Regulations]
[Pages 43358-43363]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E6-12265]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 341

[Docket No. 1976N-0052N] (formerly 76N-052N)
RIN 0910-AF34


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
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 (PEB), both individually and 
in combination drug products in an effervescent dosage form, as 
generally recognized as safe and effective (GRASE). An effervescent 
dosage form is intended to be dissolved in water before taking by 
mouth. This final rule is part of FDA's ongoing review of OTC drug 
products.

DATES: Effective Date: This rule is effective August 31, 2006.

FOR FURTHER INFORMATION CONTACT: Michael T. Benson, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, rm. 5484, Silver Spring, MD 20993, 301-796-
2090.

SUPPLEMENTARY INFORMATION:

I. Background

A. Advance Notice of Proposed Rulemaking (ANPR)

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 several active ingredients, including phenylephrine 
hydrochloride (PEH), to be safe and effective ingredients for OTC use 
(41 FR 38312 at 38399 and 38400). The Cough-Cold Panel did not evaluate 
PEB.

[[Page 43359]]

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, PEH and 
phenylpropanolamine hydrochloride (both in lozenge form for topical 
use), and classified these ingredients as Category III (more 
effectiveness data needed) (47 FR 22760 at 22911 through 22914). The 
Oral Cavity Panel did not evaluate PEB.

B. Tentative Final Monograph (TFM)

1. OTC Cough-Cold Drug Product
    In the Federal Register of January 15, 1985 (50 FR 2220), FDA 
published the TFM for OTC nasal decongestant drug products. The TFM 
proposed PEH as a monograph ingredient, but PEB was not addressed due 
to lack of available data.
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 PEH and phenylpropanolamine hydrochloride in lozenge form 
for topical use 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) 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 PEH as GRASE for oral and topical use as a nasal 
decongestant (21 CFR 341.20(a)(1) and (b)(8)). The monograph did not 
specify specific oral dosage forms. FDA acknowledged that PEB was 
submitted as an oral nasal decongestant active ingredient in an 
effervescent combination tablet for OTC use. FDA noted that PEB was not 
reviewed by the Cough-Cold Panel, or included in its report, and was 
not addressed in the FM for OTC nasal decongestant drug products (59 FR 
43386 at 43394 and 43395). FDA reviewed data on PEB submitted in a 
comment and concluded that the data were inadequate to demonstrate the 
safety and effectiveness of PEB in an effervescent dosage form as an 
OTC oral nasal decongestant ingredient. Consequently, this ingredient 
was not included in the FM.
    On March 20, 2002, a manufacturer submitted a citizen petition to 
amend the OTC nasal decongestant FM to include the ingredient PEB in an 
effervescent tablet as GRASE for use as a single ingredient or in 
combination with any monograph cough-cold active ingredient. The 
petition included:
     Domestic and international marketing experience to meet 
FDA's material time and extent criteria for inclusion in an OTC drug 
monograph (see 21 CFR 330.14)
     In vitro and in vivo studies to demonstrate comparability 
of PEB with PEH, an approved monograph active ingredient
     A proposal that PEB would provide consumers with greater 
choice in combination nasal decongestant/analgesic cough-cold 
formulations
    In the Federal Register of November 2, 2004 (69 FR 63482), FDA 
published a proposed rule to amend the FM for OTC nasal decongestant 
products to add PEB in an effervescent tablet as a single ingredient or 
in combination with aspirin and chlorpheniramine maleate. A drug 
manufacturer and an individual submitted comments, which included 
several issues that are discussed in section II of this document.

II. The Agency's Conclusion on the Comments

    (Comment 1) One comment asked FDA to expand the definition of an 
effervescent dosage form. FDA had proposed the following definition for 
an 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 releases carbon dioxide when dissolved in 
water.''
    The comment requested that FDA revise the proposed definition of 
effervescent tablet to permit additional inactive ingredients, claiming 
that its suggested revision would provide greater formulation 
flexibility. The comment based its revised definition upon definitions 
from pharmaceutical texts and reference books, including the United 
States Pharmacopeia (U.S.P.), the British/European Pharmacopeia (BP/
EP), and other pharmacopeial individual monographs. The comment 
requested that FDA revise the definition of effervescent tablet as 
follows: ``A tablet intended to be dissolved or dispersed in water 
before administration. It generally contains, in addition to the active 
ingredient(s), mixtures of acids/acid salts (citric acid, tartaric 
acid, malic acid, or any other suitable acid or acid anhydride), which 
release carbon dioxide when mixed with water. Occasionally, the active 
ingredient itself could act as the acid or alkali metal compound 
necessary for effervescent reaction.''
    FDA declines the request to revise the definition of effervescent 
tablet to permit additional inactive ingredients, but is expanding the 
definition in a different manner to provide manufacturers greater 
formulation flexibility. FDA's definition in the OTC nasal decongestant 
FM is substantially the same as the definitions for effervescent 
tablets in the U.S.P. (Ref. 1) and for effervescent tablets and 
granules in the FDA Center for Drug Evaluation and Research (CDER) Data 
Standards Manual (Ref. 2). All of these definitions describe a dosage 
form that contains citric acid, tartaric acid, and sodium bicarbonate 
as inactive ingredients to produce the effervescence, and the product 
releases gas (carbon dioxide) when added to water.
    FDA is not revising the definition in the manner suggested by the 
comment because the agency has concerns about the comment's proposed 
use of the term ``any other suitable acid or acid anhydride.'' This 
term is not sufficiently specific to ensure consistency with the 
current regulatory requirements for inactive ingredients. Under Sec.  
330.1(e) (21 CFR 330.1(e)), a product is required to contain only 
suitable inactive ingredients that meet certain criteria. These 
inactive ingredients must be safe in the amounts administered and must 
not interfere with the effectiveness of the preparation or with 
suitable tests or assays to determine if the product meets its 
professed standards of identity, strength, quality, and purity. The 
comment did not submit data to demonstrate that the additional inactive 
ingredients it requests are safe in the amounts administered or that 
they do not interfere with the effectiveness of the preparation or with 
suitable tests or assays. FDA is not aware of any such data for 
effervescent dosage forms that contain PEB. FDA is also not aware of 
PEB as the active ingredient in these products acting as ``the acid or 
alkali metal compound necessary for effervescent reaction.'' 
Accordingly, FDA is not adding this requested information to the 
definition at this time.
    Interested parties should contact U.S.P. for any change in the 
compendial definition of an effervescent tablet that would apply to all 
such products. The definition in Sec.  341.3(i) applies only to 
products containing PEB covered by this FM. Interested parties who wish 
to

[[Page 43360]]

include a PEB effervescent dosage form that contains different inactive 
ingredients than those listed in the definition in this FM may provide 
FDA specific data on such a product
    FDA is expanding the definition of ``effervescent tablet'' by 
replacing ``effervescent tablet'' in Sec.  341.3(i) of the proposed 
rule with ``effervescent dosage form'' in this final rule. We are 
making this change to provide greater formulation flexibility to permit 
other effervescent dosage forms (e.g., granules and powders) to be 
marketed. The FDA CDER Data Standards Manual (Ref. 2) defines an 
effervescent granule as ``a small particle or grain containing a 
medicinal agent in a dry mixture * * *.'' The pharmacokinetic data 
provided for the PEB effervescent tablet dosage form would also support 
use of an effervescent granule or powder dosage form, based on the 
smaller particle size of these dosage forms. Accordingly, the 
definition in Sec.  341.3(i) now reads: ``Effervescent dosage form. A 
dosage form 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.'' In conjunction with this 
change, we have also changed the proposed active ingredient description 
``phenylephrine bitartrate effervescent tablet'' in Sec.  341.20(a)(4) 
to ``phenylephrine bitartrate effervescent dosage form'' in this FM.
    (Comment 2) One comment requested FDA to allow PEB as an oral nasal 
decongestant in all combination products containing an oral nasal 
decongestant when formulated as an effervescent tablet and labeled in 
accordance with 21 CFR 341.80 and 21 CFR 341.85. The comment contended 
that PEH is included as a GRASE oral nasal decongestant ingredient in 
the monograph for OTC Cold, Cough, Allergy, Bronchodilator, and 
Antiasthmatic Drug Products and is included in 17 permitted 
combinations. The comment further stated that FDA acknowledged in the 
proposed rule that both phenylephrine salts (bitartrate and 
hydrochloride) have similar safety and efficacy profiles, and could be 
used in effervescent tablets interchangeably without any clinically 
significant impact on the performance of the formulations studied. The 
comment provided in-vitro data demonstrating comparable recovery of the 
active ingredient following dissolution in various solution media of 
effervescent tablets formulated with either PEH or PEB, in the presence 
or absence of other common cough/cold active ingredients.
    FDA agrees with the comment. In the Federal Register of January 15, 
1985 (50 FR 2220), FDA affirmed the Cough-Cold Panel recommendations 
for numerous combinations containing an oral nasal decongestant and 
other active ingredients. PEH was one of those active ingredients. In 
the proposed rule of the current rulemaking (69 FR 63482 at 63485, 
November 2, 2004), FDA acknowledged that the two phenylephrine salts in 
effervescent tablets could be used interchangeably. The similarity in 
the rate and extent of absorption of PEH and PEB in the effervescent 
tablets allows FDA to conclude that the bioavailability of the 
phenylephrine salts in the effervescent tablets is comparable (69 FR 
63482, November 2, 2004). With regard to PEB and other combinations:
     PEH is similarly bioavailable to PEB, as stated 
previously, and in-vitro dissolution data demonstrate that recovery of 
phenylephrine from formulations of either salt is virtually 
indistinguishable (PEH v PEB). FDA believes that PEB would have also 
been among the ingredients recommended for inclusion in the same 
combinations as PEH, had the Cough-Cold Panel considered that 
ingredient. Accordingly, FDA is including PEB in an effervescent dosage 
form as a permitted active ingredient as follows:
     In the same types of combination products as the other 
oral nasal decongestant active ingredients under Sec. Sec.  341.40 (b), 
(c), (e), (g), (i), (j), (m), (n), (p), (q), (r), (s), (t), (x), (y), 
(aa), and (bb),
     With labeling for combination products under Sec.  341.85 
(b)(1), (b)(2), (b)(3), and (c)(3).
    (Comment 3) One comment contended that FDA should not approve PEB 
for OTC use until an official compendium exists to define the quality 
and purity of its effervescent dosage form. FDA does not agree with the 
comment's suggestion. PEB as a drug substance became official in the 
U.S.P. on August 1, 2005 (Ref. 3). FDA's regulation in 21 CFR 330.14(i) 
sets forth criteria and procedures for classifying OTC drugs as GRASE 
and not misbranded. It states that ``any active ingredient or botanical 
drug substance included in a final OTC drug monograph * * * must be 
recognized in an official USP-NF drug monograph that sets forth its 
standards of identity, strength, quality, and purity.'' While FDA's 
regulation mentions a U.S.P.-N.F. drug monograph for the active 
ingredient, it does not also require a U.S.P.-N.F. drug monograph for 
the active ingredient in a specific dosage form. Accordingly, FDA 
concludes that a U.S.P. compendial monograph for the PEB drug substance 
is a sufficient basis for including PEB as an active ingredient in an 
effervescent tablet or other effervescent dosage form in the FM for OTC 
nasal decongestant drug products.

III. Submission of Pharmacokinetic Data for Other Solid Dosage Forms of 
PEB

    FDA notes in the proposed rule that the rate and extent of 
absorption after the first dose of PEB capsules are not similar to PEH 
capsules. FDA is willing to consider pharmacokinetic data in support of 
other PEB solid dosage forms (e.g., capsule, or noneffervescent tablet, 
granule, or powder) and invites interested persons to submit such data 
in the form of a petition under 21 CFR 10.30 to amend the monograph for 
OTC nasal decongestant drug products.

IV. Labeling Change from the Proposed Rule

    At the time of the proposed rule, sinusitis would have been a 
permitted indication for OTC combination drug products that include PEB 
in an effervescent dosage form as an oral nasal decongestant. 
Subsequently, FDA revised the labeling for these products. In the 
Federal Register of October 11, 2005 (70 FR 58974), FDA published a 
final rule to eliminate the term ``sinusitis'' from the labeling of OTC 
nasal decongestant drug products. Accordingly, FDA has revised the 
introductory language of Sec. Sec.  341.85(b)(2) and (b)(3) of the 
proposed rule to replace the term ``sinusitis'' with ``nasal 
congestion.'' Sections 341.85(b)(2) and (b)(3) of the final rule now 
read as follows:
    ``Sec.  341.85 Labeling of permitted combinations of active 
ingredients.
    (b)(2) For permitted combinations containing an analgesic-
antipyretic active ingredient * * * when labeled for relief of hay 
fever/allergic rhinitis and/or nasal congestion symptoms.
    (b)(3) For permitted combinations containing an oral analgesic-
antipyretic active ingredient * * * when labeled for relief of general 
cough-cold symptoms and/or the common cold and for relief of hay fever/
allergic rhinitis and/or nasal congestion symptoms.''

V. Summary of Agency Changes

    1. FDA is changing the definition of ``effervescent tablet'' in 
Sec.  341.3(i) to ``effervescent dosage form.'' In conjunction with 
this change, FDA is changing the active ingredient description in Sec.  
341.20(a)(4) from ``Phenylephrine bitartrate in an effervescent 
tablet'' to ``Phenylephrine bitartrate in an effervescent dosage

[[Page 43361]]

form'' (see section II, comment 1 of this document).
    2. In the proposed rule, FDA proposed to amend Sec.  341.40(b), 
(c), (e), (g), (i), (j), (m), (n), (p), (q), (r), (s), (t), (x), (y), 
(aa), and (bb) to exclude PEB in Sec.  341.20(a)(4). Now that FDA is 
allowing PEB in all of these combinations, there is no need to amend 
these paragraphs because the existing language therein already refers 
to all nasal decongestant active ingredients in Sec.  341.20(a).
    3. FDA is eliminating proposed Sec.  341.40 (cc) because the 
combination is now covered by Sec.  341.40(c). With the elimination of 
proposed Sec.  341.40(cc), the proposed amendments of the headings in 
Sec.  341.85(a)(1), (b)(1), (b)(2), (b)(3), and (c)(3) to add Sec.  
341.40(cc) are no longer needed and are withdrawn. However, the 
headings in Sec.  314.85(b)(2) and (b)(3) are being revised as 
discussed in section IV of this document.

VI. Analysis of Impacts

    FDA has examined the impacts of this final rule under Executive 
Order 12866, 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 of anticipated costs 
and benefits before enacting any rule 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 million (adjusted annually for 
inflation).
    FDA believes that this final rule is consistent with the principles 
set out in Executive Order 12866 and in these two statutes. This 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. As 
discussed in this section, FDA has determined that this final rule 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 final rule, 
because the final rule is not expected to result in any 1-year 
expenditure that would exceed $100 million adjusted for inflation. The 
current threshold after adjustment for inflation is $115 million, using 
the most current (2003) Implicit Price Deflator for the Gross Domestic 
Product.
    The purpose of this final rule is to include PEB in the monograph 
for OTC nasal decongestant drug products. This final rule will 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 PEB 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 provides 
that information. This final rule is not expected to require any new 
reporting and recordkeeping activities. Therefore, no additional 
professional skills will be needed.
    FDA considered but rejected the option of not including PEB in the 
monograph because it considers the data presented supportive of 
monograph status. The ingredient became official in the U.S.P. on 
August 1, 2005 (Ref. 3).
    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 FM becomes effective. Therefore, FDA 
certifies that this final 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)).

VII. Paperwork Reduction Act of 1995

    FDA concludes that the 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)).

VIII. 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.

IX. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
will have a preemptive effect on State law. Section 4(a) of the 
Executive order requires agencies to ``construe * * * a Federal statute 
to preempt State law only where the statute contains an express 
preemption provision or there is some other clear evidence that the 
Congress intended preemption of State law, or where the exercise of 
State authority conflicts with the exercise of Federal authority under 
the Federal statute.'' Section 751 of the Federal Food, Drug, and 
Cosmetic Act (the act) (21 U.S.C. 379r) is an express preemption 
provision. Section 751(a) of the act (21 U.S.C. 379r(a)) provides that: 
``* * * no State or political subdivision of a State may establish or 
continue in effect any requirement-- * * * (1) that relates to the 
regulation of a drug that is not subject to the requirements of section 
503(b)(1) or 503(f)(1)(A); and (2) that is different from or in 
addition to, or that is otherwise not identical with, a requirement 
under this Act, the Poison Prevention Packaging Act of 1970 (15 U.S.C. 
1471 et seq.), or the Fair Packaging and Labeling Act (15 U.S.C. 1451 
et seq.).'' Currently, this provision operates to preempt States from 
imposing requirements related to the regulation of nonprescription drug 
products. (See Section 751(b) through (e) of the act for the scope of 
the express preemption provision, the exemption procedures, and the 
exceptions to the provision.) This final rule would add PEB, 
individually and in combination drug products when used in effervescent 
dosage form, to the FM for OTC nasal decongestant drug products. 
Although this final rule would have a preemptive effect, in that it 
would preclude States from promulgating requirements related to these 
PEB drug products that are different from or in addition to, or not 
otherwise identical with a requirement in the final rule, this 
preemptive effect is consistent with what Congress set forth in section 
751 of the act. Section 751(a) of the act

[[Page 43362]]

displaces both State legislative requirements and State common law 
duties. We also note that even where the express preemption provision 
is not applicable, implied preemption may arise. See Geier v. American 
Honda Co., 529 US 861 (2000).
    FDA believes that the preemptive effect of the final rule would be 
consistent with Executive Order 13132. Section 4(e) of the Executive 
order provides that ``when an agency proposes to act through 
adjudication or rulemaking to preempt State law, the agency shall 
provide all affected State and local officials notice and an 
opportunity for appropriate participation in the proceedings.'' FDA 
provided the States with an opportunity for appropriate participation 
in this rulemaking when it sought input from all stakeholders through 
publication of the proposed rule in the Federal Register of November 2, 
2004 (69 FR 63482). FDA received no comments from any States on the 
proposed rulemaking.
    In addition, on June 19, 2006, FDA's Division of Federal and State 
Relations provided notice via fax and email transmission to elected 
officials of State governments and their representatives of national 
organizations. The notice provided the States with further opportunity 
for comment on the rule. It advised the States of the publication of 
the proposed rule and encouraged State and local governments to review 
the notice and to provide any comments to Docket No. 1976N-0052N, 
opened in the November 2, 2004, Federal Register notice, by a date 30 
days from the date of the notice (i.e., by July 19, 2006), or to 
contact certain named individuals. FDA received no comments in response 
to this notice. The notice has been filed in Docket No. 1976N-0052N.
    In conclusion, FDA believes that it has complied with all of the 
applicable requirements under the Executive order and has determined 
that the preemptive effects of this rule are consistent with Executive 
Order 13132.

X. Effective Date

    This final rule becomes effective August 31, 2006.

XI. References

    The following references are on display in the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852 under Docket No. 1976N-0052N and may be 
seen by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday. (FDA has verified the Web site address, but is not responsible 
for subsequent changes to the Web site after this document publishes in 
the Federal Register.)
    1. The United States Pharmacopeia 29-National Formulary 24, The 
United States Pharmacopeial Convention, Inc., Rockville, MD, pp 
3005, 2006.
    2. CDER Data Standards Manual (see sections entitled ``Tablet 
Effervescent'' and ``Granule Effervescent'') at https://www.fda.gov/
cder/dsm/DRG/drg00201.htm.
    3. The United States Pharmacopeia 28-National Formulary 23, 
Supplement 2, The United States Pharmacopeial Convention, Inc., 
Rockville, MD, pp 3520, 2005.

List of Subjects in 21 CFR Part 341

    Labeling, Over-the-counter drugs.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
341 is amended as follows:

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

0
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.

0
2. Section 341.3 is amended by adding paragraph (i) to read as follows:


Sec.  341.3  Definitions.

* * * * *
    (i) Effervescent dosage form. A dosage form 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.

0
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 dosage form.
* * * * *

0
4. 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    15.6 milligrams every 4 hours not to
 of age and over                 exceed 62.4 milligrams in 24 hours
------------------------------------------------------------------------
Children 6 to under 12 years    7.8 milligrams every 4 hours not to
 of age                          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

* * * * *

0
5. Section 341.85 is amended by revising the headings in paragraphs 
(b)(2) and (b)(3).


Sec.  341.85  Labeling of permitted combinations of active ingredients.

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


[[Page 43363]]


    Dated: July 24, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-12265 Filed 7-31-06; 8:45 am]
BILLING CODE 4160-01-S