[Federal Register Volume 69, Number 57 (Wednesday, March 24, 2004)]
[Proposed Rules]
[Pages 13765-13769]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-6481]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. 1990N-0309]


Drug Labeling; Sodium Labeling for Over-the-Counter Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a proposed 
rule that would amend the regulations for sodium labeling for over-the-
counter (OTC) drug products by extending the sodium content labeling 
requirement to rectal drug products containing sodium phosphate/sodium 
biphosphate (sodium phosphates). FDA is taking this action because 
people with

[[Page 13766]]

certain medical conditions are at risk for an electrolyte imbalance to 
occur when using rectal sodium phosphates products. Serious adverse 
events and deaths have occurred because of the high level of sodium 
present in these products. This proposal is part of FDA's ongoing 
review of OTC drug products.

DATES: Submit written or electronic comments by June 22, 2004. Submit 
written or electronic comments on FDA's economic impact determination 
by June 22, 2004. See section IX of this document for the effective 
date of any final rule that may publish based on this proposal.

ADDRESSES: Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Robert L. Sherman, 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

    In the Federal Register of April 22, 1996 (61 FR 17798), FDA issued 
a final rule on sodium labeling for OTC drug products that included 
sodium content labeling for products intended for oral ingestion. FDA 
provided an opportunity for comment on whether the final rule should be 
amended to include sodium content labeling for OTC rectal laxative, 
vaginal, dentifrice, mouthwash, and mouth rinse drug products. FDA 
noted that sodium labeling is important because a substantial portion 
of daily sodium intake can come from OTC drugs, especially those used 
frequently, such as laxatives. Interested persons were given until July 
22, 1996, to submit comments on labeling for those products. In the 
Federal Register of July 22, 1996 (61 FR 38046), FDA published a notice 
extending the comment period until September 20, 1996.
    Elsewhere in this issue of the Federal Register, FDA responds to 
the comments submitted in response to the final rule. At this time, FDA 
is not requiring sodium labeling for OTC vaginal, dentifrice, 
mouthwash, or mouth rinse drug products. Because of reports of problems 
associated with rectal enemas containing sodium phosphates and because 
the sodium is absorbed in the body when the product has not produced a 
bowel movement and has been retained in the body, FDA is proposing 
sodium content labeling for these products. These products contain a 
high sodium content (9.5 grams (g) monobasic sodium phosphate and 3.5 g 
dibasic sodium phosphate per 59 milliliters) and the sodium content per 
delivered dose is 4.4 g for the adult product and 2.2 g for the 
children's product (Ref. 1). This amount of sodium may represent 
problems to people who need to limit sodium intake.
    In the Federal Register of May 21, 1998 (63 FR 27886), FDA 
published a proposal to amend the tentative final monograph for OTC 
laxative drug products to include additional general and professional 
labeling for oral and rectal sodium phosphates drug products. That 
proposal includes a discussion of a number of situations where people 
with different medical conditions are at risk for an electrolyte 
imbalance to occur with use of oral and rectal sodium phosphates 
products. Because of this risk for an electrolyte imbalance to occur, 
FDA proposed new warnings and directions for these sodium phosphates 
products. However, that proposal did not contain any requirement for 
the sodium phosphates enemas to bear sodium content labeling. FDA 
considers it important for both consumers and health care professionals 
to have such information. The current proposal is intended to require 
sodium content labeling for these rectal products.

II. FDA's Proposal

    FDA considers it important that consumers be aware of the sodium 
content of OTC sodium phosphates rectal drug products and that this 
information appear in product labeling so that it will be readily 
available to physicians. Section 201.64 (21 CFR 201.64) requires orally 
ingested sodium phosphates products to bear this information. Some OTC 
laxative drug products intended for rectal administration can contain 
very high levels of sodium from both active and inactive ingredients. 
Significant amounts of some of these products may be absorbed causing 
an electrolyte imbalance (61 FR 17798 at 17800). Therefore, FDA is 
proposing to add paragraph (k) to Sec.  201.64 to require sodium 
content information to appear in the labeling of rectal drug products 
containing dibasic sodium phosphate and/or monobasic sodium phosphate.

III. FDA's Tentative Conclusions on Sodium Labeling for Rectal Drug 
Products

A. Proposed New Labeling Requirements

    FDA concludes that public interest and public health consequences 
related to sodium intake have produced a need for more informative and 
consistent sodium content and warning information in the labeling of 
OTC drug products. This is especially true for individuals with 
hypertension, heart failure, or other conditions, who must monitor 
their sodium intake.
    FDA is proposing to require sodium content information to appear in 
the labeling of OTC rectal drug products containing dibasic sodium 
phosphate and/or monobasic sodium phosphate. Warnings for these 
products will be addressed in the final monograph for OTC laxative drug 
products.

B. Statutory Authority

    In this proposed rule, FDA is addressing legal issues relating to 
the agency's action to require sodium content labeling for OTC rectal 
drug products. FDA is relying on section 502(e) of the Federal Food, 
Drug, and Cosmetic Act (the act) (21 U.S.C. 352(e)) to require 
disclosure in the labeling of OTC rectal drug products of the 
following: (1) The presence and quantity of sodium that is an active 
ingredient and (2) the presence of sodium that is an inactive 
ingredient. To require disclosure of the quantity of sodium that is an 
inactive ingredient, FDA is relying on sections 502(a) and 201(n) of 
the act (21 U.S.C. 321(n)).
    Section 502(e) of the act deems a drug to be misbranded unless its 
label bears the established name and quantity of each active ingredient 
or, if determined to be appropriate by the Secretary of Health and 
Human Services (the Secretary), the proportion of each active 
ingredient (21 U.S.C. 352(e)(1)(A)(ii)). That provision also deems a 
drug to be misbranded unless its label bears the established name of 
each inactive ingredient on the outside container, and if determined 
appropriate by the Secretary, on the immediate container (21 U.S.C. 
352(e)(1)(A)(iii)). Under section 502(a) of the act, a drug is deemed 
to be misbranded if its labeling is ``false or misleading in any 
particular.'' Section 201(n) of the act amplifies what is meant by 
``misleading'' in section 502(a). Section 201(n) of the act states 
that, in determining whether labeling is misleading, FDA shall take 
into account not only representations made about the product, but also 
the extent to which the labeling fails to reveal facts material in the 
light of such representations or material with respect to consequences 
that may result from the use of the article to which the labeling 
relates under the conditions of use prescribed in the labeling, or 
under such conditions of use as are customary or

[[Page 13767]]

usual (see 21 CFR 1.21). Finally, FDA has authority under section 
701(a) of the act (21 U.S.C. 371(a)) to issue regulations for the 
efficient enforcement of the act.
    As discussed in sections I, II, and III of this document, FDA has 
tentatively determined that for OTC rectal drug products containing 
more than the specified amount of sodium, the quantity of this 
substance as an active or inactive ingredient in these drug products is 
material with respect to consequences that may result from their use. 
Certain levels of sodium present a potential safety problem. People 
with hypertension, heart failure, or other conditions need to monitor 
their intake of sodium, which can cause serious toxicity in persons 
with these conditions. Many people are on sodium-restricted diets. 
Other people must monitor their intake of sodium from foods (including 
dietary supplements) and OTC drugs for other medical or health reasons. 
Without mandatory sodium content labeling, these people would not be 
able to understand the relative contribution that OTC rectal drug 
products containing sodium make to their intake of sodium, and would 
not be able to compare the sodium content of various OTC rectal drug 
products.

C. The First Amendment

    This proposed rule passes muster under the first amendment. FDA's 
proposed requirement of sodium content labeling for OTC rectal drug 
products (where sodium is an active or inactive ingredient and is 
present beyond the specified threshold level) is constitutionally 
permissible because it is reasonably related to the Government's 
interest in preventing deception of consumers and because it is not an 
``unjustified or unduly burdensome'' disclosure requirement that 
offends the First Amendment. (See Zauderer v. Office of Disciplinary 
Counsel, 471 U.S. 626, 651 (1985); see also Ibanez v. Florida Dep't of 
Bus. and Prof'l Regulation, 512 U.S. 136, 146 (1994)). Such a 
reasonable relationship is plain here. The prescribed labeling 
disclosure would contribute directly to the use of products containing 
quantities of sodium that do not threaten the health of people for whom 
sodium use has material consequences. Some people, newly informed by 
the required labeling, will properly reduce or discontinue using 
sodium-containing OTC rectal drug products and thereby protect and 
promote their own health. By encouraging such changes in behavior, the 
labeling requirement is rationally related to the Government's goal of 
ensuring appropriate use of rectal drug products containing sodium. 
Finally, it is not ``unduly burdensome'' to require an additional 
disclosure of this kind.
    In any event, this proposed rule passes muster when analyzed under 
the four-part test in Central Hudson Gas & Electric Corporation v. 
Public Service Commission, 447 U.S. 557 (1980), because it is necessary 
for the labeling of OTC rectal drug products containing sodium in 
excess of the threshold amount to be nonmisleading (Id. at 563-564). As 
discussed in this document, FDA has determined that the failure to 
disclose in an OTC rectal drug product's labeling the amount of sodium 
in the product when it is present in amounts exceeding a certain 
threshold misbrands the product because the failure causes the labeling 
to be false or misleading under sections 502(a) and 201(n) of the act.
    Although this determination obviates the need for FDA to address 
the other three parts of the Central Hudson test, we believe that the 
sodium content labeling requirement satisfies each of these parts. With 
respect to the second part, FDA's interest in requiring sodium content 
labeling under this proposed rule is to ensure that people who must 
monitor their sodium intake for health reasons have information 
necessary to understand the relative contribution that OTC rectal drug 
products make to their sodium intake and to compare the sodium content 
of such products. FDA's interest in protecting the public health has 
been previously upheld as a substantial government interest under 
Central Hudson. (See Pearson v. Shalala, 164 F.3d 650, 656 (D.C. Cir. 
1999) (citing Rubin v. Coors Brewing Co., 514 U.S. 476, 484-485 
(1995)). The labeling requirement directly advances this interest, 
thereby satisfying the third part of the Central Hudson test, because 
by requiring labeling disclosure of the presence and quantity of sodium 
in OTC rectal drug products, the rule gives people the precise 
information they need to determine whether a particular product is 
consistent with their health requirements.
    Finally, under the fourth part of the Central Hudson test, there 
are not numerous and obvious (Cincinnati v. Discovery Network, 507 U.S. 
410, 418 n. 13 (1993)) alternatives to mandatory sodium content 
labeling of OTC rectal drug products that directly advance the 
Government's interest but are less burdensome to speech. Consumers are 
accustomed to using the label as their primary source of information 
about a product's contents. Neither a public education campaign, nor 
encouraging OTC drug product marketers to provide information on sodium 
content in the labeling of their products, would ensure that people 
have the information they need about sodium content at the point of 
sale or use. And establishing limits on sodium content would be more 
harmful to the public health. It is unnecessary for consumers who are 
not at risk to reduce or closely monitor their added daily sodium 
intake from OTC rectal drug products. For these rectal products, sodium 
content is linked to product design and determined by pharmaceutical 
necessity. Requiring disclosure here meets the fourth part of the test.
    In conclusion, FDA believes it has complied with its burdens under 
the First Amendment to support mandatory disclosure of the amount of 
sodium above a specified level in OTC rectal drug product labeling.

IV. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, if a rule has a significant economic impact on a 
substantial number of small entities, an agency must analyze regulatory 
options that would minimize any significant impact of the rule on small 
entities. Section 202(a) of the Unfunded Mandates Reform Act of 1995 
requires that agencies prepare a written statement of anticipated costs 
and benefits before proposing any rule that may result in an 
expenditure in any one year by State, local, and tribal governments, in 
the aggregate, or by the private sector, of $100 million (adjusted 
annually for inflation).
    FDA believes that this proposed rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
As discussed in this section, the proposed rule will not be 
economically significant as defined by the Executive order. With 
respect to the Regulatory Flexibility Act, FDA does not believe the 
rule would have a significant economic impact on a substantial number 
of small entities, but FDA cannot be certain. Thus, this preamble 
contains FDA's regulatory flexibility analysis. The Unfunded

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Mandates Reform Act of 1995 does not require FDA to prepare a statement 
of costs and benefits for the 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 extend the requirement for 
sodium content labeling to OTC rectal drug products that contain sodium 
phosphates so that the information is available to individuals who need 
to limit their sodium intake. The proposed rule would require minor 
relabeling of sodium phosphates rectal products. There are fewer than 
five manufacturers of these products in the OTC drug marketplace. One 
company manufactures a nationally branded product with the others 
producing private label products. One large manufacturer produces about 
one-half to two-thirds of the products covered by this proposed rule. 
Three small manufacturers account for the remainder of the market. 
There may be other manufacturers/marketers not identified in sources 
FDA reviewed, but FDA believes there are a limited number and they 
would be small manufacturers. FDA does not believe that this proposed 
rule would have a significant economic impact on small entities, using 
the U.S. Small Business Administration designations for this industry 
(750 employees). Together, the manufacturers will have to relabel fewer 
than 300 stockkeeping units (SKUs). The manufacturer of the nationally 
branded product and some private label manufacturers of these products 
already include sodium content information in the labeling of their 
products. This relabeling (addition of sodium content labeling) will 
impose direct one-time costs on some manufacturers. FDA has been 
informed that the cost to relabel these products ranges from $500 to 
$3,500. Using the conservative estimate of $3,500 per SKU, and assuming 
all SKUs would need to be relabeled, the total one-time cost to relabel 
these products would be $1,050,000. Actual costs will be lower because 
of current voluntary compliance.
    Manufacturers that have not voluntarily included sodium content 
information may also incur one-time costs to test their products. The 
cost to test for one cation is about $150 for private label 
manufacturers. Assuming they repeat the testing, the total one-time 
costs for an estimated 10 products would be $3,000.
    FDA considered but rejected several labeling alternatives: (1) A 
longer implementation period and (2) an exemption from coverage for 
small entities. A longer time period would unnecessarily delay the 
benefit of the new labeling to consumers who self-medicate with these 
products. FDA rejected an exemption for small entities because the 
labeling is also needed by consumers who purchase products marketed by 
those entities.
    This analysis shows that FDA has considered the burden to small 
entities. Thus, this economic analysis, together with other relevant 
sections of this document, serves as FDA's initial regulatory 
flexibility analysis, as required under the Regulatory Flexibility Act.
    FDA invites public comment regarding any substantial or significant 
economic impact that this proposed rule would have on manufacturers or 
marketers of OTC rectal drug products containing sodium phosphates. 
Comments regarding the impact of this proposed rule on OTC rectal drug 
products containing sodium phosphates should be accompanied by 
appropriate documentation. FDA is providing a period of 90 days from 
the date of publication of this proposed rule in the Federal Register 
for development and submission of comments on this subject. FDA will 
evaluate any comments and supporting data that are received and will 
reassess the economic impact of this proposed rule in the preamble to 
the final rule.

V. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the labeling requirement proposed in 
this document is not subject to review by the Office of Management and 
Budget because it does not constitute a ``collection of information'' 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). 
Rather, the proposed labeling statement 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)).

VI. Environmental Impact

    FDA has determined under 21 CFR 25.31(a) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VII. Request for Comments

    FDA is providing interested persons 90 days after the date of 
publication of this proposed rule in the Federal Register to submit 
written or electronic comments on the proposed rule and FDA's economic 
impact determination 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. FDA is requesting 
that comments be submitted within 90 days because it wants to finalize 
this proposal as quickly as possible to coordinate this proposed 
labeling addendum with other labeling changes that are occurring for 
these products. Received comments may be seen in the Division of 
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

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 effect 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 is not 
required.

IX. Proposed Effective Date

    FDA proposes that any final rule based on this proposal become 
effective 12 months after its date of publication in the Federal 
Register.

X. Reference

    The following reference is on display in the Division of Dockets 
Management (see ADDRESSES) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Enema label, OTC Vol. 090TFM3, Docket No. 78N-036L.

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.
    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 201 be amended as follows:

[[Page 13769]]

PART 201--LABELING

    1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.
    2. Section 201.64 is amended by adding paragraph (k) to read as 
follows:


Sec.  201.64  Sodium labeling.

* * * * *
    (k) The labeling of OTC drug products intended for rectal 
administration containing dibasic sodium phosphate and/or monobasic 
sodium phosphate shall contain the sodium content per delivered dose if 
the sodium content is 5 milligrams or more. The sodium content shall be 
expressed in milligrams or grams. If less than 1 gram, milligrams 
should be used. The sodium content shall be rounded-off to the nearest 
whole number if expressed in milligrams (or nearest tenth of a gram if 
expressed in grams). The sodium content per delivered dose shall follow 
the heading ``Other information'' as stated in Sec.  201.66(c)(7). Any 
product subject to this paragraph that contains dibasic sodium 
phosphate and/or monobasic sodium phosphate as an active ingredient 
intended for rectal administration and that is not labeled as required 
by this paragraph and that is initially introduced or initially 
delivered for introduction into interstate commerce after [date 12 
months after date of publication in the Federal Register], is 
misbranded under sections 201(n) and 502(a) and (f) of the act.

    Dated: March 15, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-6481 Filed 3-23-04; 8:45 am]
BILLING CODE 4160-01-S