[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:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://www.fda.gov/dockets/ecomments.
Follow the instructions for submitting comments on the agency Web site.
E-mail: [email protected]. Include Docket No. 1976N-
0052N and/or RIN number 0910-AF34 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-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:
Domestic and international marketing experiences meet
FDA's material time and extent criteria for inclusion in an OTC drug
monograph.
In vitro and in vivo studies demonstrate comparability of
phenylephrine bitartrate with phenylephrine hydrochloride, an approved
monograph active ingredient.
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:
The FDA database does not indicate the relationship of
adverse events or preexisting medical conditions of consumers to the
administration of phenylephrine.
The WHO database revealed five different single event
reports for products containing phenylephrine bitartrate as an active
ingredient.
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:
An effervescent phenylephrine hydrochloride 10 milligram
(mg) tablet
An effervescent phenylephrine bitartrate 15.6 mg tablet
[[Page 63484]]
an encapsulated\1\ phenylephrine hydrochloride 10 mg
capsule
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\1\ Encapsulated is a capsule dosage form that was termed
``encapsulated'' by the manufacturer in this study.
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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
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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
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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
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\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 Cmax 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 Cmax are 0.91
and 0.90 for AUC and Cmax 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:
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.
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).
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:
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
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
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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
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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) * * *
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(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