[Federal Register Volume 69, Number 57 (Wednesday, March 24, 2004)]
[Rules and Regulations]
[Pages 13717-13725]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-6479]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. 90N-0309]


Drug Labeling; Sodium Labeling for Over-the-Counter Drugs; 
Technical Amendment; Termination of Delay of Effective Date; Compliance 
Dates

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule; technical amendment; termination of delay of 
effective date; compliance dates.

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SUMMARY: The Food and Drug Administration (FDA) is amending the 
regulation that established conditions under which the labeling of 
over-the-counter (OTC) drug products intended for oral ingestion must 
include the sodium content and a general warning that persons who are 
on a sodium restricted diet should not take the product unless directed 
by a doctor. This final rule makes a few minor labeling changes and 
broadens the conditions for using the descriptive term ``sodium free.'' 
This document also terminates the delay of the effective date of the 
provisions concerning sodium labeling (Sec.  201.64(a) through (h)) and 
establishes compliance dates for the final rule.

DATES: The effective date for Sec.  201.64(a) through (h), added at 61 
FR 17806, April 22, 1996, and delayed at 62 FR 19923, April 24, 1997, 
as amended by this final rule is April 23, 2004. The amendments in this 
final rule are effective April 23, 2004.
    Compliance Dates: The compliance date for any single entity and 
combination products subject to drug marketing applications approved on 
or after April 23, 2004, is immediately upon approval of the 
application. The compliance date for all other OTC drug products, 
whether subject to drug marketing applications approved before April 
23, 2004, subject to any OTC drug monograph, or not yet the subject of 
any OTC drug monograph, is September 24, 2005.

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 amending the general labeling provisions for OTC drug 
products (Sec.  201.64) to: (1) Require that the sodium content of all 
OTC drug products intended for oral ingestion be included in labeling 
when the product contains 5 milligrams (mg) or more sodium per a single 
dose; (2) require that all OTC drug products intended for oral 
ingestion containing more than 140 mg sodium in the labeled maximum 
daily dose bear a general warning that persons who are on a sodium-
restricted diet should not take the product unless directed by a 
doctor; and (3) provide for the voluntary use of certain terms 
(``sodium free,'' ``very low sodium,'' and ``low sodium'') relating to 
an OTC drug product's sodium content per labeled maximum daily dose. 
The effective date of the final rule was April 22, 1997. In the final 
rule, FDA also sought comments whether the rule should be amended to 
include sodium content labeling for OTC rectal laxative, vaginal, 
dentifrice, mouthwash, and mouth rinse drug products.
    Interested persons were invited to submit comments by July 22, 
1996. In response to two requests for extension of time to file 
comments to the final rule, FDA published a document in the Federal 
Register of July 22, 1996 (61 FR 38046), extending the comment period 
until September 20, 1996.
    In response to the final rule, FDA received comments from four 
manufacturers and two trade associations. Two of the comments requested 
that the effective date of the final rule be extended for at least an 
additional 6 months, to October 1997 or later. One comment mentioned 
the need for ongoing technical work, noting that manufacturers have 
undertaken formal product testing to ascertain precise sodium content 
before preparing new labels with accurate content declarations. The 
comment identified several problems with the sodium content of inactive 
ingredients. Specifications for some OTC drug ingredients do not 
include limits for sodium; suppliers often do not provide entire 
formulation information to companies; and sodium content may vary from 
lot to lot and/or supplier to supplier, especially for ingredients of 
natural origin. The comment stated that it would be difficult for some 
companies to complete product testing in time to have new labeling 
prepared by April 1997. The other comment stated that additional time 
would reduce label obsolescence, allow the use of already printed 
labeling, and allow labeling to be changed using current staff levels.
    Both comments emphasized that FDA should delay implementation of 
the

[[Page 13718]]

sodium labeling final rule until the proposed rule on labeling for OTC 
drug products containing calcium, magnesium, and potassium (61 FR 
17807, April 22, 1996) was finalized. The comments contended that 
coordinating the effective date of both rules, which could apply to any 
single product, would avoid two label changes and the related economic 
impact of phasing in label changes for two separate rulemakings. One 
comment added that no major public health consequence should be 
expected from this delay for the sodium labeling because OTC drug 
products with relatively high sodium contents, e.g., antacids and 
laxatives, already bear a restricted sodium-use warning.
    FDA agreed with the comments' rationale that it was desirable to 
coordinate implementation of the sodium labeling with the calcium, 
magnesium, and potassium labeling. A single effective date for both 
final rules avoids two labeling changes and reduces the economic impact 
of phasing in labeling changes for two separate, but related, 
rulemakings. In addition, a delay would provide manufacturers 
additional time that should be sufficient to complete all product 
analyses. FDA notified all commentors of its intentions in a feedback 
letter (Ref. 1) and asked the Consumer Healthcare Products Association 
(formerly the Nonprescription Drug Manufacturers Association) to notify 
its members and suggest that they incorporate calcium, magnesium, and 
potassium analyses into current plans to do sodium analyses so that all 
analyses can be completed and new labeling implemented by the effective 
date. FDA also concurred with one comment that there should be no major 
public health consequences because of this delay.
    In the Federal Register of April 24, 1997 (62 FR 19923), FDA 
delayed the effective date of Sec.  201.64(a) through (h) until further 
notice. The current final rule terminates the delay of the effective 
date, establishes a new effective date of 30 days after the date of 
publication in the Federal Register, and sets dates for manufacturers 
to be in compliance with the final rule.
    Elsewhere in this issue of the Federal Register, FDA is publishing 
a final rule containing the labeling requirements for orally ingested 
OTC drug products containing calcium, magnesium, and potassium. That 
final rule also becomes effective 30 days after the date of publication 
in the Federal Register, and has the same compliance dates as this 
final rule for sodium labeling.

II. FDA's Response to the Comments

A. Situations Where Rule Should Not Apply

    1. Two comments disagreed with across-the-board sodium labeling for 
all orally ingested OTC drug products. The comments favored a category-
by-category approach for considering warnings and cited the review of 
OTC antacid and laxative drug products as examples that had 
successfully established the need for sodium warnings for those 
products. One comment added that FDA should not require sodium-related 
warnings on additional categories of OTC drug products without 
sufficient evidence of a public health need. The comment contended that 
people who have been advised by a physician or decided on their own to 
monitor their sodium intake are able to use content declarations to 
make food selections in their targeted limit and would be able to 
similarly use the content declaration on OTC drug products. The comment 
argued that the warning to avoid the product if on a sodium-restricted 
diet, unless directed by a doctor, is not needed and would not help 
consumers make decisions. The comment acknowledged, however, that 
information about the sodium content in a dosage unit is useful for 
people who are monitoring sodium intake.
    A third comment contended that a warning statement is not necessary 
or helpful and is not a good use of limited OTC drug label space. The 
comment stated that people on a restricted diet are typically 
instructed by a medical professional to be aware of certain habits and 
monitor their intake using information provided by the declared sodium 
level on a product. The comment added that the sodium content per dose 
declaration helps those people make choices in order to limit sodium 
intake and contended that the content labeling on a per dose basis 
alone is the most useful information for the consumer. The comment 
endorsed the proposed declaration of sodium content on OTC drug labels 
but opposed the warning statement. The comment concluded that the 
warning statement does not help people on a sodium-restricted diet make 
decisions, is unnecessary for the general population, tends to confuse 
consumers, and is inconsistent with FDA's position that warning 
statements be clinically significant and important for the safe and 
effective use of a product by consumers.
    FDA appreciates the one comment's endorsement of the sodium content 
declaration part of the regulation, but disagrees with the comments' 
arguments that the warning statement is unnecessary and should not 
apply to all orally ingested OTC drug products.
    FDA addressed this issue in comment 4 of the sodium labeling final 
rule (61 FR 17798 at 17799 to 17800). FDA stated that across-the-board 
labeling has been used during the OTC drug review, instead of category-
by-category, when the situation warrants, such as the pregnancy-nursing 
warning for OTC drug products in Sec.  201.63 (21 CFR 201.63). FDA 
indicated that there was sufficient evidence of a public health need 
for this warning because a certain level (140 mg) of sodium may present 
a potential safety problem, regardless of the source of the sodium, and 
an across-the-board approach was based on sodium being present in any 
OTC drug product. FDA also believes that the warning is necessary for 
the entire population. Currently, there is no reliable genetic marker 
to determine susceptibility to sodium-induced hypertension. Because 
salt sensitive persons cannot be identified, FDA believes that it is 
prudent to recommend caution concerning sodium intake for the general 
population. Therefore, FDA deemed a category-by-category or limited 
approach inappropriate.
    FDA also pointed out that implementation of a warning on a 
category-by-category basis would result in a lack of uniformity in OTC 
drug product labeling until FDA's evaluation of each drug category was 
completed. FDA notes that one of the comments also stated that the 
sodium labeling final rule affects thousands of OTC drug products. FDA 
finds that another important reason why sodium labeling requirements 
should be implemented across-the-board and become effective at the same 
time.
    FDA notes that a number of the comments submitted in response to 
the April 25, 1991 (56 FR 19222), proposal to require sodium labeling 
stated that this labeling would be especially helpful to those 
individuals who must restrict their sodium intake, especially the 
elderly. (See comment 1 at 61 FR 17798.) FDA strongly believes that the 
addition of sodium content (per dosage unit) information in OTC drug 
product labeling will assist consumers in selecting the desirable and 
appropriate product. However, FDA has determined that this information 
alone may not provide consumers complete and adequate guidance. FDA 
firmly believes that consumers on a sodium-restricted diet should be 
informed to check with their doctor not to use a particular product if 
it contains above a certain level of sodium in the labeled maximum

[[Page 13719]]

daily dose of the product. A warning of this type has been required on 
OTC antacid drug products for almost 30 years, and there is no evidence 
that it has confused consumers. FDA concludes that this warning 
statement will help consumers make better-informed decisions and will 
result in safer use of OTC drug products containing sodium by those 
consumers who must or wish to monitor their sodium intake.
    2. One comment noted that liquid and chewable products, many of 
which are intended for use in children because of difficulty or 
reluctance to swallow a whole tablet, are likely to have a higher 
sodium content. The sodium comes from inactive ingredients such as 
flavors and sweeteners (e.g., sodium saccharin) used to make the 
products more palatable. The comment stated that it would be 
unfortunate if a child was not given a product because of the sodium 
content labeling. The comment added that the advantages of using the 
more suitable dosage forms of children's products outweighed any risk 
from ingestion of small amounts of sodium. The comment contended that 
children are not likely to require such a restriction and that the 
sodium declaration on children's products is unnecessary information 
that is likely to confuse consumers because the information is meant 
for people who are not likely to use the product. The comment asked FDA 
to reconsider the necessity for sodium labeling on OTC drug products 
directed for intermittent use in children.
    FDA has reconsidered the sodium labeling requirements for liquid 
and chewable products, including those directed for use in children, 
and determined that the labeling serves several useful functions. 
First, some children need to limit sodium intake for medical reasons. 
Second, and more important, a number of adults, especially the elderly, 
prefer liquid and chewable dosage forms because of swallowing problems 
or reluctance to swallow a whole tablet or capsule. Sodium labeling 
information is especially important for elderly people who may have to 
limit their sodium intake for medical reasons.
    FDA concludes that sodium labeling information on liquid and 
chewable tablet products will be useful to consumers who need or desire 
this information and will not be confusing to those consumers who have 
no need for the information. FDA believes the same reasoning applies to 
inactive ingredient information. This information is not of interest to 
every consumer, but is important for those consumers who need or want 
it. According to a 1988 Diet and Health Survey (Ref. 2), sodium remains 
the most commonly mentioned component that consumers try to avoid in 
their diet. Moreover, another survey (Ref. 3) reported that 88 percent 
of shoppers felt label information on sodium was either very or 
somewhat important. FDA has not received any reports that this 
information is confusing to consumers who have no interest in it.
    3. Five comments responded to FDA's request about expanding the 
sodium content labeling to OTC rectal laxative, vaginal, dentifrice, 
mouthwash, and mouth rinse drug products. All felt strongly that such 
labeling would be inappropriate and unnecessary for these products. The 
comments pointed out that dentifrices, mouthwashes, and mouth rinses 
are intended to be spit out and not swallowed. The comments mentioned 
that if a consumer swallowed a small amount of the product the amount 
of sodium ingested would be minuscule. Two comments added that the 
amount of sodium absorbed from the oral mucosa during approximately 30 
seconds to 1 minute of use would be insignificant. The comments 
contended that quantification of any amount of potentially absorbed 
sodium from dentifrices, mouthwashes, and mouth rinses would be 
difficult and meaningless because these products are used and spit out 
in varying quantities. The comments concluded that sodium content 
labeling would not provide consumers who use these products any useful 
information. Two comments added that FDA had reached the same 
conclusion when it changed the scope of the sodium labeling regulation 
from ``orally administered OTC drug products'' to ``OTC drug products 
intended for oral ingestion.''
    Two comments stated that products intended for vaginal or rectal 
administration should not be labeled for sodium content. The comments 
contended that consumers would likely be confused by this labeling, 
which is viewed as nutritional content labeling, and would not know how 
to use the information. The comments added that such labeling might 
cause consumers to mistakenly assume such products are meant for 
ingestion and thus orally use suppositories or liquid meant for vaginal 
or rectal use.
    FDA generally concurs with the comments and, at this time, 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 phosphate/sodium biphosphate 
(where 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 and may 
represent a problem to people who need to limit sodium intake. 
Elsewhere in this issue of the Federal Register, FDA is proposing to 
amend Sec.  201.64 to include sodium content labeling for OTC rectal 
drug products containing sodium phosphate/sodium biphosphate.

B. Dose That Triggers Sodium Content Declaration

    4. One comment requested that Sec.  201.64(a) be amended to state 
the specific recommended dose, which presumably is the maximum 
recommended dose, that triggers the requirement to declare the sodium 
content on the product label. The comment contended that some of the 
preamble to the final rule appears to be inconsistent with Sec.  
201.64(a), which states that the criterion for a required declaration 
of sodium content is 5 mg or more sodium in a ``single recommended dose 
of the product (which may be one or more dosage units).'' The comment 
felt that the statement that ``The agency * * * decided to use 5 mg of 
sodium per maximum recommended dose as the basis for including sodium 
content in the labeling of OTC drug products'' (61 FR 17798 at 17800) 
was inconsistent with Sec.  201.64(a).
    FDA addressed this issue in comment 8 of the preamble to the final 
rule (61 FR 17798 at 17800). We acknowledge that the discussion might 
have been confusing in some regards. FDA stated that a 5 mg maximum 
labeled dose is consistent with the antacid monograph, which has been 
in effect since 1974. FDA noted that the requirement for OTC antacid 
drug products in Sec.  331.30(f) (21 CFR 331.30(f)), which was removed 
in the sodium labeling final rule, provides that the labeling include 
sodium content per dosage unit if it contains 5 mg or more. Because the 
sodium content declaration can vary from product to product if based on 
the maximum daily dose of the product, FDA deemed it important to have 
a fixed number at which the sodium content per dosage unit would have 
to be declared. FDA determined that the amount per single recommended 
dose was the most useful information to consumers.
    The criterion in Sec.  201.64(a) determines whether there is a need 
for a sodium content declaration. The intent of the final rule was to 
require content declaration based on the amount of sodium present in 
the maximum number of dosage units

[[Page 13720]]

recommended for a single dose. Thus, if one tablet contains 4 mg of 
sodium and the recommended dosage range is ``one or two'' tablets, 
sodium content labeling (in mg per dosage unit) would be required 
because two tablets exceed the 5 mg threshold. Because a single 
recommended dose may include one or more dosage units, FDA believes the 
term ``single maximum recommended dose'' is a better term than ``single 
recommended dose'' to state the basis for requiring sodium content 
labeling. Accordingly, FDA is amending Sec.  201.64(a).

C. Placement of the Sodium Content Declaration

    5. One comment requested that FDA allow flexibility in the 
placement of the sodium content declaration so that it would not have 
to be on a separate line, as required by Sec.  201.64 (b). The comment 
requested that the information be allowed to be part of a paragraph 
listing of ingredients that would include other cations, e.g., calcium, 
magnesium, and potassium, per the FDA proposed rule for orally ingested 
OTC drug products containing those ingredients (61 FR 17807, April 22, 
1996). The comment stated that such a paragraph listing could include 
as many content declarations as required and appear as follows: ``Each 
tablet contains: sodium (------ mg), calcium (------ mg), magnesium (--
---- mg), potassium (------ mg).'' The comment contended that such 
flexibility was especially important for small packages where economy 
of space is important and placement of sodium content on a separate 
line would be difficult.
    The comment also requested as another alternative that other means, 
such as color, boldface, underlining, etc., be allowed to give 
prominence to a new type of information within the listing of 
ingredients so that the sodium content declaration is readily visible 
within the paragraph listing of inactive ingredients. In addition, the 
comment requested clarification whether the sodium declaration is 
supposed to follow the required listing of active ingredients or the 
voluntary listing of inactive ingredients.
    Since the sodium labeling final rule was published on April 22, 
1996, FDA has addressed this issue in a final rule on a general 
labeling format for all OTC drug products (64 FR 13254, March 17, 
1999). That final rule established a specific order and format in which 
information must appear in OTC drug product labeling. Section 
201.66(c)(7)(i) (21 CFR 201.66(c)(7)(i)) states that required 
information about certain ingredients in OTC drug products (e.g., 
sodium in Sec.  201.64(b)) shall appear as follows: ``each (insert 
appropriate dosage unit) contains:'' [in bold type] (insert name(s) of 
ingredient(s) and the quantity of each ingredient). This information 
shall be the first statement under the heading ``Other information.'' 
Concurrently, FDA revised the last sentence in Sec.  201.64(b) to 
state: ``The sodium content per dosage unit shall follow the heading 
``Other information'' as stated in Sec.  201.66(c)(7).'' (See 64 FR 
13254 at 13286.) Elsewhere in this issue of the Federal Register, FDA 
is revising Sec.  201.66(c)(7)(i) to include calcium, magnesium, and 
potassium and their CFR citations as other examples covered by that 
section.

D. Rounding-off to the Nearest 5 Mg

    6. Three comments disagreed with the sodium content having to be 
rounded-off to the nearest whole number. The comments argued that this 
requirement was inconsistent with the food labeling regulations, which 
allow rounding to the nearest 5-mg level rather than to the nearest 
whole number (1-mg level). One comment contended that allowing for the 
5-mg increment in sodium labeling for OTC drug products would reduce 
the cost of label changes for lot-to-lot variations in sodium content 
and would protect consumers from industry label conversion costs 
associated with minor reformulations that result in minor sodium 
content changes. The comment stated that FDA had presented no basis for 
requiring drug products to contain more accurate sodium content 
labeling than food products. Another comment mentioned the potential 
variability in the sodium content of ingredients of natural origin, as 
occurs with food products. The comment was concerned that the additive 
effect of sodium as an unassayed component in multiple raw materials 
could result in an OTC drug product containing greater than 5 mg sodium 
per dosage unit and thus result in inaccurate labeling. For this 
reason, the comment contended that manufacturers should be permitted to 
round the sodium content declaration to the nearest 5-mg level, as 
permitted in food product labeling.
    FDA discussed this issue in response to a comment's concern in 
comment 3 of the preamble of the final rule for sodium labeling (61 FR 
17798 at 17799). The author of the comment was concerned that 
descriptive terms based on sodium content using rounded-off numbers 
could be different from descriptive terms based on sodium content using 
actual numbers.
    FDA discussed how rounding-off could result in potential 
discrepancies between the actual and apparent sodium content in OTC 
drug products, and may lead to consumer confusion. For instance, if the 
actual sodium content of a product is 8 mg per dosage unit and the 
product is to be taken four times daily, the labeled maximum daily dose 
is 32 mg. Because the sodium content is less than 35 mg (per labeled 
maximum daily dose), the term ``very low sodium'' could be used. 
However, if the actual dosage unit (8 mg) is rounded-off to 10 mg, the 
apparent labeled maximum daily dose for that product would be 40 mg and 
the descriptive term would be ``low sodium''. FDA did note that 
regulations for labeling food provide for the rounding-off to the 
nearest 5 to 10 mg sodium per serving. We explained that a larger 
rounding-off range is more appropriate in the context of food because 
most food products contain naturally occurring sodium and variation in 
sodium content is expected. On the other hand, most OTC drug products 
are manufactured and the amount of sodium in products can be strictly 
controlled. Thus, the sodium content of OTC drug products is expected 
to be less variable than that of foods and can be more accurately 
described on the label. Based on this discussion, FDA concluded that 
the 5-mg rounding rule for foods should not be used in the OTC drug 
content even if it results in different criteria for food and drug 
products.
    FDA has considered the current comments' concerns, but is not 
persuaded to change its position. Based on the example discussed 
herein, minor reformulation of a drug product may result in a change in 
descriptive category when using the 5-mg rounding rule for foods, but 
no change if the foods rule is not applied. For example, if the sodium 
content of a drug product that is taken four times a day increases from 
7 mg [5 mg under the 5-mg rounding rule] to 8 mg [10 mg under the same 
rule] per dosage unit, that increase would change the descriptive 
category from ``very low sodium'' (20 mg per labeled maximum daily 
dose) to ``low sodium'' (40 mg per labeled maximum daily dose). 
However, when the 5-mg rounding rule is not applied, the descriptive 
category (``very low sodium'') is the same before and after 
reformulation (28 and 32 mg, respectively).
    Further, FDA notes that the amount of sodium (140 mg) present in a 
product to require the warning in Sec.  201.64 (c) is much lower than 
the amount of calcium (3.2 g), magnesium (600 mg), or potassium (975 
mg) that trigger a similar warning for these cations. Therefore, 
rounding-off to the nearest 1 mg provides consumers more accurate

[[Page 13721]]

information about sodium content in OTC drug products.
    FDA believes that because the sodium content in drug products is 
less variable than for foods, and can be determined more accurately, 
consumers should have the more accurate information. Thus, providing 
consumers attempting to monitor their sodium intake with more accurate 
information, to use in their ingredient calculations, should increase 
consumer safety. FDA continues to believe that rounding-off to the 
nearest whole number will result in less consumer confusion and add to 
consumer safety, and that any associated industry label conversion 
costs associated with minor reformulations that may result in minor 
sodium content changes will be minimal. The comment provided no 
information to indicate what these conversion costs might be or that 
they would have any impact on consumers. Analysis of product lots for 
variations in sodium content is discussed in section II.G, comment 11 
of this document.

E. Sodium Versus Sodium Chloride Content

    7. One comment disagreed with FDA's conclusion that sodium content 
labeling should reflect sodium content without regard to the anion 
(e.g., chloride) with which the sodium is associated in the drug 
product formulation. The comment referred to its previous comments on 
this issue, which FDA addressed in comment 16 of the preamble of the 
final rule for sodium labeling (61 FR 17798 at 17803 to 17804). 
Referring to that response, the comment noted that FDA had stated that 
hypertension was not the sole reason for adoption of sodium labeling 
requirements and that the only other example that FDA mentioned was 
that sodium bicarbonate had been reported to exacerbate congestive 
heart failure. The comment added that it had reviewed the rulemakings 
for other sodium labeling proceedings and they showed that hypertension 
has been, if not the only, certainly the principal rationale supporting 
sodium content labeling and warning requirements. The comment indicated 
that the scientific literature did not support the very low levels of 
sodium present in OTC drug products as being of significant concern in 
the management of congestive heart failure. The comment concluded that 
the final rule should have required salt (sodium chloride) content 
labeling and not just sodium content labeling.
    FDA can appreciate the comment's views, but does not agree with 
them. FDA recognized in comment 16 of the preamble of the final rule 
for sodium labeling that there were differences of opinion on the 
relationship of sodium and hypertension. FDA provided an extensive 
discussion on this issue there and sees no reason to repeat it here. 
FDA also pointed out that sodium labeling is not aimed specifically at 
persons with hypertension, but is intended to benefit all people who 
need or wish to monitor their sodium intake for whatever reason. 
Accordingly, FDA is not changing the sodium labeling requirement from 
``sodium'' content to ``sodium chloride (salt)'' content.

F. Descriptive Terms

    8. Two comments contended that the descriptive terms ``sodium 
free,'' ``very low sodium,'' and ``low sodium'' should be based on the 
amount of sodium in a single dose rather than on the total content in 
the labeled maximum daily dose. The comments noted that these 
descriptive terms for food labeling are based on the content in one 
serving. One comment added that labeling OTC drug products on the basis 
of dosage unit is more consistent with the food labeling system, in 
which content labeling and voluntary descriptive terms are based on a 
``serving.'' The other comment added that consumers often use only one 
dose of an OTC drug product and, because of the inconsistency with the 
food labeling regulations, it is more relevant and consistent to 
describe the sodium content of OTC drug products on a per dose basis.
    FDA disagrees with the comments. Many OTC drugs that contain sodium 
have daily dosing that involves more than one dose. Basing the 
descriptive terms on a single dose would potentially be misleading to 
consumers because it is the maximum daily dose of the product that 
determines the consumer's daily sodium intake from the OTC drug 
product.
    9. Two comments requested that FDA change the requirement for use 
of the term ``sodium free.'' One comment stated that, as a practical 
matter, it would seem reasonable to allow a product containing less 
than 0.5 mg of sodium per dosage unit to be called ``sodium free,'' 
even though the amount was not zero, if the labeled maximum daily dose 
contains less than 5 mg of sodium. The comment stated that the addition 
of this amount of sodium to a consumer's sodium load is comparably 
negligible from a clinical standpoint. The comment noted FDA's 
statement in the preamble to the sodium labeling final rule (61 FR 
17798 at 17800) that ``the agency considers a sodium level below 5 mg 
per dose to be physiologically insignificant.''
    The other comment pointed out that it marketed a product with a 
sodium content between 0.1 to 0.2 mg per tablet and less than 5 mg in 
the maximum labeled daily dose. The comment complained that the final 
rule would prevent this product from being labeled as ``sodium free,'' 
when it has been labeled as ``sodium free'' for over 10 years. The 
comment contended that the final rule allowing ``sodium free'' to be 
used only when the maximum daily dose contains less than 0.5 mg sodium 
is more stringent than necessary for consumer protection and avoiding 
consumer confusion. The comment stated that the final rule as written 
would effectively eliminate the use of the term ``sodium free'' from 
OTC drug product labeling. The comment suggested that Sec.  201.64(d) 
be revised to read: The term ``sodium free'' may be used in the 
labeling of OTC drug products intended for oral ingestion if the amount 
of sodium in the labeled maximum daily dose is less than 5 milligrams 
and the amount of sodium per dosage unit is 0 milligram (when rounded-
off as per paragraph (b) of this section).
    The comment noted that its proposed revision, like the final rule, 
eliminates the possibility that products labeled ``sodium free'' will 
at the same time be labeled with a sodium content greater than ``0 
mg,'' which would be a potential basis for consumer confusion. The 
comment concluded that consumers would be better served by the 
suggested revision of the final rule, and that the minor change also 
accomplishes FDA's objectives.
    FDA agrees with the comments. Accordingly, in this technical 
amendment, FDA is revising Sec.  201.64(d) to read: ``The term ``sodium 
free'' may be used * * * if the amount of sodium in the labeled maximum 
daily dose is 5 milligrams or less and the amount of sodium per dosage 
unit is 0 milligram (when rounded-off in accord with paragraph (b) of 
this section).''

G. Economic Impact

    10. One comment stated that the economic impact of the final rule 
is substantially greater than presumed by FDA, based on information 
that companies provided. The comment stated that the sodium labeling 
requirement could potentially add costs for manufacturers, and 
therefore for consumers, when labels must be changed even if a minor 
reformulation results in a relatively minor change in the amount of 
sodium in a finished OTC drug product. The comment added that companies 
were still assessing the actual economic impact related to

[[Page 13722]]

product analysis for sodium, calcium, magnesium, and potassium, and 
would submit additional information when it becomes available.
    Another comment stated that it was uncertain of the full impact of 
the final rule. It estimated that the rule has the potential to impact 
an estimated 1,500 stockkeeping units (SKUs), which could result in a 
$1 million impact for art and obsolescence costs alone.
    FDA notes that, unfortunately, industry did not provide any 
comments on the agency's economic impact determination that appeared in 
the proposed rule for sodium labeling (56 FR 19222 at 19225). At that 
time (April 25, 1991), FDA estimated the relabeling cost for 
manufacturers who marketed products containing sodium to be less than 
$500,000 for the entire industry. That estimate was based on the number 
of products that would be affected by the final rule, the number of 
distinct label changes, and the cost of printing new labels. The 
estimate did not include any projections for product analyses because 
that issue had not been raised in the rulemaking. FDA did state in the 
final rule for sodium labeling (61 FR 17798 at 17799) that most OTC 
drug products are manufactured and the amount of sodium in products can 
be strictly controlled. The industry has indicated that it would 
provide additional information on the cost of product analyses when 
available, but has not done so to date. The current final rule provides 
for coordination of the sodium labeling requirements with the 
implementation of the rule requiring calcium, magnesium, and potassium 
labeling, published elsewhere in this issue of the Federal Register. 
This coordination should reduce the economic impact for products 
containing sodium and one or more of the other cations.
    11. One comment asked whether FDA expected cation analysis for 
every manufactured lot of OTC drug products and, if yes, whether the 
labeling had to bear the exact amount of assayed cation. The comment 
stated that if this were required to be done, this would mean that 
labeling needed to be printed for each lot, which would have a 
significant economic implication. The comment asked whether a company 
can base cation content on average values (taken from historical lots) 
and known lot-to-lot variations, and what amount of variation would be 
acceptable without a need for a change in the sodium content 
declaration.
    FDA's position is that manufacturers must use the same standards 
for labeling of sodium (or other cations) as used to assure accurate 
content labeling of active ingredients in OTC drug products. 
Manufacturers are expected to follow good manufacturing practices (21 
CFR part 211) and general guidance provided by the United States 
Pharmacopeia/National Formulary in determining a product's cation 
content.
    FDA recognizes that there is some acceptable variation between 
different product lots that bear the same labeling. The amount of an 
ingredient declared in the labeling is a composite value derived from a 
number of product samples. Some content determinations for some lots 
may be based, in part, on average values (taken from historical lots) 
and on known lot-to-lot variations. However, manufacturers should be 
able to ascertain when it is necessary to do new analyses, e.g., when a 
raw material is purchased from a new supplier or the raw material 
contains a sodium declaration that differs from previous lots. Many 
compendial monographs provide that a product contains not less than 90 
percent and not more than 110 percent of the labeled amount of an 
active ingredient. FDA considers this 10 percent 
criterion as acceptable for cation content labeling. FDA does not see a 
need for cation content information from individual batch analysis to 
appear in product labeling. However, when batch analyses reflect 
greater than 10 percent in cation content, 
relabeling should occur. Therefore, there should not be a significant 
economic implication for manufacturers.

III. Summary of Significant Changes

    1. This final rule terminates the delay of the effective date of 
paragraphs (a) through (h) of Sec.  201.64 and establishes compliance 
dates for sodium labeling of OTC drug products. (See the DATES section 
and section I of this document.)
    2. FDA is revising Sec.  201.66(a) to more clearly state the basis 
for requiring sodium content labeling. (See section II.B, comment 4 of 
this document.)
    3. The sodium content per dosage unit follows the heading ``Other 
information'' as stated in Sec.  201.66(c)(7). (See section II.C, 
comment 5 of this document.)
    4. FDA is revising Sec.  201.64(c) to state the sodium-restricted 
diet warning in the new OTC drug product labeling format.
    5. FDA is revising Sec.  201.64(d) to expand the conditions for use 
of the term ``sodium free'' for products containing 5 mg or less of 
sodium in the labeled maximum daily dose. This technical amendment 
allows for the use of the term ``sodium free'' when the amount of 
sodium per dosage unit is 0 mg (when rounded-off in accord with Sec.  
201.64(b)) and the labeled maximum daily dose contains 5 mg or less 
sodium. (See section II.F, comment 9 of this document.)

IV. FDA's Final Conclusions on Sodium Labeling

A. 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 implementing the following content and warning requirements 
for OTC drug products intended for oral ingestion: Content--if the 
product contains 5 mg sodium or more per single maximum recommended 
dose; warning--if the product contains more than 140 mg sodium in the 
labeled maximum daily dose. The content labeling shall be rounded-off 
to the nearest whole number and shall appear after the heading ``Other 
information.'' The sodium labeling requirements apply to OTC drug 
products intended for oral ingestion, whether marketed under an OTC 
drug monograph, the ongoing OTC drug review, an approved application, 
or no application. This final rule terminates the delay of the 
effective date of paragraphs (a) through (h) of Sec.  201.64 and 
establishes compliance dates for sodium labeling of OTC drug products.

B. Statement About Warnings

    Mandating warnings in an OTC drug product regulation does not 
require a finding that any or all of the OTC drug products covered by 
the regulation 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 regulations 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 (the 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

[[Page 13723]]

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 the final rule 
entitled ``Labeling of Diphenhydramine-Containing Drug Products for 
Over-the-Counter Human Use'' (67 FR 72555, December 6, 2002).

C. Statutory Authority

    In this final rule, FDA is addressing legal issues relating to the 
agency's action to require sodium content labeling for OTC drug 
products. FDA is relying on section 502(e) of the act (21 U.S.C. 
352(e)) to require disclosure in the labeling of OTC drug products of: 
(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) 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 which 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 usual (see Sec.  1.21 (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 IV of this document and in the 
final rule (61 FR 17798), FDA has determined that for OTC drug products 
containing more than the specified amount of sodium, the quantity of 
this substance as an inactive ingredient in OTC drug products is 
material with respect to consequences that may result from use of such 
products within the meaning of section 201(n) of the act. 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. 
Absent mandatory sodium content labeling, these people would not be 
able to understand the relative contribution that OTC drug products 
make to their intake of sodium, and would not be able to compare the 
sodium content of various OTC drug products.

D. The First Amendment

    This final rule passes muster under the first amendment. FDA's 
requirement of sodium content labeling for OTC drug products (where 
sodium is an 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 consumption of 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 their intake of sodium-containing OTC 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 sodium consumption. 
Finally, it is not ``unduly burdensome'' to require an additional 
disclosure of this kind.
    In any event, this final rule passes muster when analyzed under the 
four-part test in Central Hudson Gas and Electric Corporation v. Public 
Service Commission, 447 U.S. 557 (1980), because it is necessary for 
the labeling of OTC 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 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 final 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 drug 
products make to their sodium intake and to compare the sodium content 
of OTC drug 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 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 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 ingestion. And establishing limits on sodium content would be 
more harmful to the public health. It is unnecessary for consumers who 
are not

[[Page 13724]]

at risk to reduce or closely monitor their added daily sodium intake 
from OTC drug products. Further, some consumers may wish to use OTC 
drug products to enrich the amount of sodium in their diets. Finally, 
for many products, the 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 drug product labeling.

V. Analysis of Impacts

    FDA discussed the impacts of this sodium labeling requirement in 
the final rule for sodium labeling (61 FR 17798 at 17805 to 17806) and 
noted that no comments were received in response to the agency's 
request for specific comment on the economic impact of this rulemaking. 
Since that time, FDA has received two comments. (See section II.G, 
comments 10 and 11 of this document.)
    FDA has examined the impacts of this final 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 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 concludes that this final rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
As discussed in this section, the final 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. 
The Unfunded Mandates Reform Act of 1995 does not require FDA to 
prepare a statement of costs and benefits for the final rule, because 
the final rule in 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 final rule is to provide two minor labeling 
revisions, terminate the delay in the effective date, and set 
compliance dates for the final rule. The labeling revisions will not 
have any further economic impact. The termination of the delay in the 
effective date and the establishment of compliance dates will not have 
any additional economic impact above that stated in the preamble to the 
final rule (61 FR 17798). Accordingly, FDA has not reconsidered its 
earlier certification that the final rule will not have a significant 
economic impact on a substantial number of small entities. For the 
reasons stated in this section and under the Regulatory Flexibility Act 
(5 U.S.C. 605(b)), FDA certifies that this rule will not have a 
significant economic impact on a substantial number of small entities.

VI. 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 
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 final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the 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, the agency has concluded 
that the 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. 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, and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    (1) Letter from D. Bowen, FDA, to L. Totman, NDMA, January 14, 
1999, coded LET 3.
    (2) Levy, A. S. and J. T. Heimbach, Division of Consumer Studies, 
FDA, ``Recent Public Education Efforts About Health and Diet in the 
United States,'' 200 C. St. SW., Washington, DC 20204, 1989.
    (3) National Food Processors Association, ``Summary of Findings, 
Food Labeling and Nutrition * * * What Americans Want,'' Washington, 
DC, 1990.

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

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

PART 201--LABELING

0
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.

0
2. Section 201.64 is amended by revising paragraphs (a), (c), and (d) 
and by adding paragraph (j) to read as follows:


Sec.  201.64  Sodium labeling.

    (a) The labeling of over-the-counter (OTC) drug products intended 
for oral ingestion shall contain the sodium content per dosage unit 
(e.g., tablet, teaspoonful) if the sodium content of a single maximum 
recommended dose of the product (which may be one or more dosage units) 
is 5 milligrams or more. OTC drug products intended for oral ingestion 
include gum and lozenge dosage forms, but do not include

[[Page 13725]]

dentifrices, mouthwashes, or mouth rinses.
* * * * *
    (c) The labeling of OTC drug products intended for oral ingestion 
shall contain the following statement under the heading ``Warning'' (or 
``Warnings'' if it appears with additional warning statements) if the 
amount of sodium present in the labeled maximum daily dose of the 
product is more than 140 milligrams: ``Ask a doctor before use if you 
have [in bold type] [bullet]\1\ a sodium-restricted diet''. The 
warnings in Sec. Sec.  201.64(c), 201.70(c), 201.71(c), and 201.72(c) 
may be combined, if applicable, provided the ingredients are listed in 
alphabetical order, e g., a calcium or sodium restricted diet.
---------------------------------------------------------------------------

    \1\ See Sec.  201 .66(b)(4) of this chapter for definition of 
bullet symbol.
---------------------------------------------------------------------------

    (d) The term sodium free may be used in the labeling of OTC drug 
products intended for oral ingestion if the amount of sodium in the 
labeled maximum daily dose is 5 milligrams or less and the amount of 
sodium per dosage unit is 0 milligram (when rounded-off in accord with 
paragraph (b) of this section).
* * * * *
    (j) Any product subject to paragraphs (a) through (h) of this 
section that is not labeled as required and that is initially 
introduced or initially delivered for introduction into interstate 
commerce after the following dates is misbranded under sections 201(n) 
and 502(a) and (f) of the Federal Food, Drug, and Cosmetic Act.
    (1) As of the date of approval of the application for any single 
entity and combination products subject to drug marketing applications 
approved on or after April 23, 2004.
    (2) Septemeber 24, 2005, for all OTC drug products subject to any 
OTC drug monograph, not yet the subject of any OTC drug monograph, or 
subject to drug marketing applications approved before April 23, 2004.

    Dated: March 15, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-6479 Filed 3- 23-04; 8:45 am]
BILLING CODE 4160-01-S