[Federal Register: March 24, 2004 (Volume 69, Number 57)]
[Rules and Regulations]               
[Page 13725-13735]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr24mr04-6]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201 and 331

[Docket No. 1995N-0254]

 
Drug Labeling; Orally Ingested Over-the-Counter Drug Products 
Containing Calcium, Magnesium, and Potassium

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the general 
labeling provisions for over-the-counter (OTC) drug products to require 
that the labeling of all OTC drug products intended for oral ingestion 
include: The calcium content per dosage unit when the product contains 
20 milligrams (mg) or more per single dose; a warning statement that 
persons with kidney stones and persons on a calcium-restricted diet 
should ask a doctor before using when the product contains more than 
3.2 grams (g) of calcium in the labeled maximum daily dose; the 
magnesium content per dosage unit when the product contains 8 mg or 
more per single dose; a warning statement that persons with kidney 
disease and persons on a magnesium-restricted diet should ask a doctor 
before using if the product contains more than 600 mg magnesium in the 
labeled maximum daily dose; the potassium content per dosage unit when 
the product contains 5 mg or more per single dose; and a warning 
statement that persons with kidney disease and persons on a potassium 
restricted diet should ask a doctor before using if the product 
contains more than 975 mg potassium in the labeled maximum daily dose. 
FDA is issuing this final rule in order to provide uniform calcium, 
magnesium, and potassium content and warning labeling for all OTC drug 
products intended for oral ingestion whether marketed under an OTC drug 
monograph, the ongoing OTC drug review, a new drug application (NDA) or 
abbreviated new drug application (ANDA), or no application.

DATES: Effective Date: This final rule is 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 17807), FDA 
proposed to amend the general labeling provisions for OTC drug products 
to require that the labeling of all OTC drug products intended for oral 
ingestion include: (1) Content labeling for the cations calcium, 
magnesium, and potassium when a dosage unit of the product contains 
certain levels of the ingredient(s); and (2) warning statement(s) when 
the labeled maximum daily dose of the product contains a certain level 
of the ingredient(s). FDA proposed this labeling because of public 
interest in, and health consequences related to, calcium, magnesium, 
and potassium intake. These labeling requirements are needed to alert 
people with renal failure, kidney stones, or other conditions, and to 
assist people who wish to monitor their intake of calcium, magnesium, 
and potassium. Ingestion of large amounts of calcium can result in 
renal stones, and both potassium and magnesium can cause serious 
toxicity in people with impaired renal function (see 61 FR 17807 for a 
more complete discussion). Many consumers need to know their intake of 
these cations from foods, dietary supplements, and drugs. Therefore, 
FDA is issuing a final rule for calcium, magnesium, and potassium 
content and warning labeling for all OTC drug products intended for 
oral ingestion that contain certain levels of these ingredients 
(including both active and inactive ingredients). This final rule 
establishes calcium, magnesium, and potassium content labeling of OTC 
drug products similar to that used in food labeling.
    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 proposed rule, FDA published a notice in the Federal 
Register of July 22, 1996 (61 FR 38047), extending the comment period 
until September 20, 1996. Four manufacturers and one trade association 
submitted comments.

[[Page 13726]]

II. FDA's Response to the Comments

A. Effective Date of the Final Rule

    (Comment 1) One comment stated that it is currently performing the 
testing required to implement the sodium labeling final rule (61 FR 
17798, April 22, 1996), and that it plans to perform the required 
calcium, magnesium, and potassium testing after publication of that 
final rule. The comment requested that FDA provide 1 year for 
implementation. Another comment requested at least 18 months for 
implementation for economic reasons (see also section II.G, comment 8 
of this document), and that FDA coordinate the date with any label 
changes required for products containing sodium.
    FDA agrees that the effective date of this final rule and the 
effective date of the sodium labeling final rule should provide for 
implementation at the same time. Elsewhere in this issue of the Federal 
Register, FDA has provided the same compliance dates for the sodium 
labeling requirements. The same dates for both final rules allow a 
single labeling revision, thereby reducing the economic impact of 
phasing in labeling changes for two separate but related rulemakings. 
In addition, FDA is providing 18 months for implementation.

B. Situations Where Rule Should Not Apply

    (Comment 2) Two comments disagreed with across-the-board calcium, 
magnesium, and potassium labeling for all orally ingested OTC drug 
products. The comments favored a category-by-category approach for 
cation labeling as was done for OTC antacid and laxative drugs. One 
comment added that the across-the-board approach ignores the OTC drug 
review's well-established category-by-category mechanism for 
considering warnings related to levels of magnesium, potassium, and 
sodium in OTC antacid and laxative drug products. The comment contended 
that FDA gave no documented evidence for the need for the proposed 
warnings, that requiring warnings without adequate support results in 
the dilution of all warnings, and asked whether FDA conducted any label 
comprehension studies to support the proposed labeling.
    Another comment endorsed the proposed declaration of cation content 
on OTC drug labels for the benefit of people who monitor intake for 
medical reasons, but opposed a warning statement. The comment stated 
that cation content per dose is much more useful than a warning to 
inform consumers. The comment concluded that a warning statement does 
not help people on a calcium, magnesium, or potassium-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.
    Another comment stated that the proposed rule would be helpful to 
people who have a condition that requires close monitoring of various 
cation intakes, but for only a small group, mainly end-stage renal 
failure patients. The comment said cation information might detract 
from other important labeling information and recommended that cation 
information be provided directly to individual patients by 
pharmaceutical companies rather than in product labeling.
    FDA disagrees with the comments' arguments that the warning 
statements are unnecessary, do not need to appear in product labeling, 
and should not apply to all orally ingested OTC drug products. FDA 
addressed the issue of across-the-board labeling in comment 4 of the 
sodium labeling final rule (61 FR 17798 at 17799 to 17800). FDA stated 
that across-the-board content and warning labeling is important, useful 
information for OTC drug products intended for oral ingestion 
containing calcium, magnesium, and potassium, as well as sodium.
    In the proposed rule, FDA stated that it believes that the public 
interest in, and the public health consequences of, calcium, magnesium, 
and potassium intake have produced a need for more informative and 
consistent labeling information for these ingredients in OTC drug 
products (61 FR 17807 at 17809). FDA added that it believes that 
certain labeling requirements are needed to alert people with renal 
failure, kidney stones, or other conditions; and to alert people taking 
medications who wish to monitor their intake of calcium, magnesium, and 
potassium (61 FR 17807 at 17809). Certain levels of calcium, magnesium, 
and potassium present a potential safety problem, regardless of the 
source, and this rule affects thousands of OTC drug products. 
Implementation of warnings on a category-by-category basis would result 
in lack of uniformity in OTC drug product labeling until FDA's 
evaluation of each drug category is completed. Therefore, FDA finds an 
across-the-board labeling approach more appropriate than the category-
by-category approach.
    In the March 17, 1999, final rule for labeling requirements for OTC 
drug products (64 FR 13254 at 13263) (the March 17, 1999, final rule), 
in discussing present and future requirements for information to be 
included in the labeling of OTC drug products containing these 
ingredients, FDA stated: ``This information is significant for 
individuals who monitor their intake of certain nutrients, including 
persons with hypertension and renal insufficiency, and for persons who 
want to increase their intake of certain nutrients (e.g., calcium). The 
agency is requiring this important information to be the first 
statement under `Other information' to draw attention to it.'' FDA 
considers it misleading for consumers looking for this information not 
to have it uniformly in place and provided at the same time for all OTC 
drug products that contain certain levels of these ingredients.
    FDA has required a magnesium and potassium warning on OTC antacid 
drug products for almost 30 years, and there is no evidence that these 
warnings have confused consumers. FDA has no reports of any consumer 
label comprehension concerns and does not believe that label 
comprehension studies are necessary to support this type of labeling 
change. FDA concludes that the cation warning statements will help 
consumers who have kidney disease, get kidney stones, or wish to 
monitor their calcium, magnesium, or potassium intake, make better-
informed decisions, resulting in safer use of OTC drug products 
containing these cations.
    In discussing calcium, the Advisory Review Panel on OTC Antacid 
Drug Products (Antacid Panel) stated that hypercalcuria in response to 
calcium ingestion is not rare in the population and the danger of renal 
stone formation has to be considered in determining the intake of 
calcium antacids (see 61 FR 17807). The Advisory Review Panel on OTC 
Miscellaneous Internal Drug Products stated that adverse reactions 
associated with calcium carbonate, including hypercalcemia, alkalosis, 
acid rebound, milk-alkali syndrome, and constipation, usually occur 
with ingestion of larger than recommended doses and/or with chronic 
ingestion (see 61 FR 17807). In discussing magnesium, the Antacid Panel 
stated that hypermagnesemia toxicity may occur in renal dysfunction 
(see 61 FR 17807). In discussing potassium, the Antacid Panel concluded 
that potassium can accumulate in the body of people with impaired renal 
function and exert toxic effects (see 61 FR 17807 at 17808). FDA 
believes there is a large consumer population who will use this

[[Page 13727]]

information, and that it is not practical for these individuals to have 
to obtain it directly from a manufacturer when it can be readily 
provided in the product's labeling.
    (Comment 3) Three comments opposed cation content labeling for OTC 
drug products that are not intended for oral ingestion. The comments 
considered the labeling unnecessary, and said consumers may view such 
labeling as indicating that the product is for oral ingestion. Two 
comments contended that there is no reason to require cation content 
declarations on products such as dentifrices, mouthwashes, and mouth 
rinses, because the amount of cation absorbed or incidentally ingested 
is negligible. The comments stated that consumers would be confused by 
cation labeling on OTC vaginal or rectal drug products and could assume 
such products are meant for ingestion because this information is 
viewed as nutritional content labeling.
    At this time, FDA is not aware of any safety issues related to the 
calcium, magnesium, or potassium content of OTC dentifrice, mouthwash, 
mouth rinse, rectal, or vaginal drug products and is not requiring 
cation labeling for these products.

C. Dose That Triggers Labeling Requirements

    (Comment 4) One comment stated that the language regarding the 
criteria for requiring a cation declaration may cause confusion, and 
FDA should clearly state in the rule the specific recommended dose that 
triggers the requirement for a cation content declaration. The comment 
contended that the word ``single'' in ``single recommended dose'' was 
the problem. The comment argued that for products whose active 
ingredient has an established dosage range, a ``single recommended 
dose'' could be interpreted to be the ``minimum recommended dose,'' 
which would be given on the product label, whereas FDA more likely 
intends it to mean the ``maximum recommended dose.'' The comment 
concluded that if FDA intends the criteria to be the quantity of a 
specific cation in the ``maximum recommended dose,'' then the word 
``maximum'' should be used in place of the word ``single.''
    The proposed regulations in Sec. Sec.  201.70(a), 201.71(a), and 
201.72(a) (21 CFR 201.70(a), 201.71(a), and 201.72(a)) state the amount 
of cation per single recommended dose (calcium 20 mg, magnesium 8 mg, 
and potassium 5 mg, respectively) that triggers the content labeling 
requirements. The intent of the proposal was to require content 
declaration based on the amount of cation present in the maximum number 
of dosage units recommended for a single dose. Thus, if one tablet of a 
product contains 15 mg of calcium and the dosage range is ``one or two 
tablets,'' calcium content labeling (in mg per dosage unit) would be 
required because two tablets exceed the 20 mg threshold. FDA agrees 
that the term ``single recommended dose'' could be confusing because a 
single recommended dose may consist of more than one dosage unit. 
However, the term ``maximum recommended dose'' could be confused to 
mean ``maximum recommended daily dose.'' Therefore, FDA is revising the 
language in Sec. Sec.  201.70(a), 201.71(a), and 201.72(a) to state the 
amount of cation in a ``single maximum recommended dose'' that triggers 
the content labeling requirements.

D. Percentage Criterion for Cation Labeling

    (Comment 5) One comment noted that not all OTC drug ingredient 
specifications contain limits for cation content, and that some 
ingredients of natural origin are subject to the same variability in 
cation content as food products. Therefore, the additive effect of 
these cations as an unassayed component in multiple raw materials could 
result in a product containing more than the threshold limit of a given 
cation, resulting in inaccurate labeling of an OTC drug product. 
Another comment stated that establishing a criteria of  10 percent for cation labeling would meet the needs of 
many products but might be problematic for some products (e.g., 
antacids and laxatives). Another comment mentioned that according to 
the compendial monograph for magnesium stearate, the magnesium content 
can vary by  10 percent. Thus, lot-to-lot 
variation can occur for products manufactured in accord with compendial 
materials and good manufacturing practices. The comment recommended 
that the labeling provide an expected maximum level of the cation(s). 
The comment also asked whether it is necessary to test or report the 
amounts for cations not expected to be present in the final product as 
they are not contained in the product formula. The comment added that 
routine testing for cations in a product would be costly and 
recommended periodic testing to confirm the expected amount of 
cation(s) calculated from the product formula.
    FDA recognizes that some ingredients of natural origin have 
variable cation content and that there is some acceptable variation 
between different product lots that bear the same labeling. The amount 
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 variation. 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 cation declaration that differs from previous lots. Manufacturers 
should also be able to ascertain when it may be necessary to analyze 
the raw material or the finished product for a cation(s) not expected 
to be present in the ingredient or product. Many compendial monographs 
provide that a product contains no less than 90 percent and no more 
than 110 percent of the labeled amount of an active ingredient. FDA 
considers this criterion acceptable for cation content labeling. 
Manufacturers need 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.

E. Drug Labeling Versus Food Labeling

    (Comment 6) Three comments stated that cation content labeling on 
OTC drug products should be consistent with food labeling regulations. 
One comment endorsed the proposal to declare cation content on OTC drug 
labels if consistent with food labeling practices. However, the 
comments pointed out that the proposed drug regulations were different 
from the food labeling regulations in several ways. First, the 
``rounding'' rules are different. Two of the comments requested that 
manufacturers be permitted to round cation content labeling to the 
nearest 5 mg level, more consistent with food labeling, rather than to 
the nearest whole number. Second, FDA regulations (Sec.  101.9 (21 CFR 
101.9)) do not require magnesium or potassium content labeling on food 
products that do not make claims about these cations. Third, FDA 
regulations (Sec.  101.9) require that the percent of daily value for 
calcium be labeled to the nearest 2-percent increment up to and 
including the 10-percent level, the nearest 5-percent increment above 
10 percent and up to and including the 50-percent level, and the 
nearest 10-percent increment above the 50-percent level. One comment 
added that using these criteria for drug products would help reduce the 
cost of label changes for lot-to-lot variations in calcium content.

[[Page 13728]]

    The comments contended that magnesium and potassium content 
labeling should be optional unless magnesium or potassium claims are 
made. One comment added that it seems inconsistent to require magnesium 
and potassium declarations for OTC drug products when foods can contain 
as much as 451 mg potassium in a medium banana or 97 mg magnesium in 1 
cup of boiled baby lima beans and not list these amounts on their 
labels. One comment concluded that FDA should not require a cation 
content declaration on an OTC drug product that would not be required 
on a food when the same amount of the cation was present in a serving 
of the food and a dose of the drug product.
    FDA is aware that the cation content of foods and OTC drug products 
is different. Cations present in food are naturally occurring and 
information about the amount present appears in numerous publications. 
Most OTC drug products do not make claims about the cation present 
because the cation is often part of an inactive ingredient, e.g., 
magnesium hydroxide, potassium bicarbonate. Many consumers who must or 
wish to monitor specific cation intake would not know that many OTC 
drug products contain these cations, or the amount present, unless the 
labeling contains the information. While health professionals may 
generally advise consumers about the cation content of many foods 
(e.g., bananas contain large amounts of potassium), these health 
professionals would not be able to advise consumers of the cation 
content of OTC drug products unless the product labeling contains this 
information. Thus, FDA has determined it is important for OTC drug 
products to declare their calcium, magnesium, and potassium content. As 
one comment to this rulemaking noted, the proposed rule would affect 
thousands of OTC drug products. Accordingly, FDA concludes that OTC 
drug products containing magnesium or potassium must declare their 
content if it equals or exceeds the amounts listed in Sec. Sec.  201.71 
and 201.72, and that such labeling should not be optional.
    Section 101.9(c)(8) provides that the labeling of food products 
shall contain a statement of the amount per serving of the vitamins and 
minerals described in this paragraph as a percent of the reference 
daily intake (RDI) and expressed as a percent of the daily value. The 
percent of the daily value is required for calcium in all cases and for 
magnesium when it is added or when a claim is made about it. Section 
101.9(c)(8)(iii) provides for stating the percentages for vitamins and 
minerals as one comment previously noted, and Sec.  101.9(c)(8)(iv) 
establishes RDIs for calcium (1,000 mg) and magnesium (400 mg). FDA 
does not find this labeling scheme practical to use for OTC drug 
products containing calcium or magnesium because consumers do not 
routinely relate drug products to RDIs for vitamins and minerals and, 
in general, the space available on OTC drug labels is more limited than 
on food labels. Thus, FDA is including the necessary information (in mg 
units only) on OTC drug labels, using a minimum amount of space.
    Section 101.9(c)(5) provides that potassium content shall be 
expressed as zero when the serving contains less than 5 mg of 
potassium, to the nearest 5-mg increment when the serving contains less 
than or equal to 140 mg of potassium, and to the nearest 10-mg 
increment when the serving contains more than 140 mg. FDA notes that 
the proposed regulations in Sec. Sec.  201.70(b), 201.71(b), and 
201.72(b) already provide that the amount of calcium, magnesium, and 
potassium can be rounded-off to the nearest tenth of a g if over 1 g. 
This flexibility in rounding-off the higher levels of cation content in 
the labeling of OTC drug products is similar to the broader flexibility 
provided in Sec.  101.9(c) of the food labeling regulations when 
products contain larger amounts of these cations.
    FDA is willing to allow rounding of the calcium, magnesium, and 
potassium content declaration to the nearest 5 mg for two reasons. 
First, the amounts of calcium (3.2 g), magnesium (600 mg), and 
potassium (975 mg) that trigger the requirement for a warning are much 
greater than the amount of sodium (140 mg) that triggers the 
requirement for a warning in Sec.  201.64(c) (21 CFR 201.64(c)). 
Second, the calcium, magnesium, and potassium regulations do not 
contain a provision for descriptive terms, such as ``-------- free,'' 
``very low --------,'' ``low --------,'' as in the sodium regulation. 
In comment 3 of the preamble of the sodium labeling final rule (61 FR 
17798 at 17799), FDA provided an example of how this rounding rule 
could work to a manufacturer's disadvantage and, thus, this concern was 
sufficient reason not to use the 5-mg rounding rule for sodium 
labeling. Because this concern does not apply to calcium, magnesium, or 
potassium labeling, FDA sees no reason to not allow the 5-mg rounding 
rule for the labeling of OTC drug products containing these three 
cations. FDA concludes that the ability to round the calcium, 
magnesium, and potassium content declaration to the nearest 5 mg along 
with a  10 percent declaration range should help 
reduce the burden on industry in establishing the proper content 
declaration due to the variability of the cation content of some raw 
ingredients used in manufacturing OTC drug products.
    In conclusion, FDA has revised this aspect of the cation labeling 
requirements for OTC drug products to parallel the food labeling 
requirements.

F. Placement of the Cation Content Declarations

    (Comment 7) Two comments requested clarification on how the cation 
content declarations should appear in product labeling when the product 
contains more than one cation. The comments pointed out that each 
proposed content declaration regulation stated that the (name of 
cation) content shall be listed on a separate line after the heading 
``(name of cation) Content'' as the last statement in the ingredients 
section. The comments requested guidance as to the order these 
declarations should follow when more than one is required to appear. 
One comment requested that the information be allowed to be part of a 
paragraph listing of ingredients that would include other cations and 
appear as follows: ``Each tablet contains: sodium (-------- mg), 
calcium (-------- mg), magnesium (-------- mg), potassium (-------- 
mg).'' The comment contended that flexibility was important for small 
packages when economy of space is critically important and it would be 
difficult to place each cation content on a separate line.
    As another alternative, the comment also requested 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 cation content declarations are readily visible 
within the paragraph listing of inactive ingredients. Another comment 
requested that this information be allowed to be included in the 
inactive ingredient list if the labeling contains such information.
    Because the calcium, magnesium, and potassium labeling proposed 
rule was published on April 22, 1996, FDA addressed this issue in the 
March 17, 1999, final rule. The March 17, 1999, final rule establishes 
a specific order and format in which information must appear in OTC 
drug product labeling. New Sec.  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

[[Page 13729]]

the first statement under the heading ``Other information.''
    When Sec.  201.66(c)(7)(i) was finalized, calcium, magnesium, and 
potassium were not referenced because the regulations for these cations 
were not completed at that time. Now that those regulations are being 
finalized, FDA is amending Sec.  201.66(c)(7)(i) to cross-reference 
these three cations in addition to sodium. FDA has also determined that 
there is a need for uniformity in when more than one cation content 
declaration needs to appear in the labeling. Therefore, FDA is further 
revising Sec.  201.66(c)(7)(i) to state that when more than one cation 
declaration is required, the declarations shall appear in alphabetical 
order. Revised Sec.  201.66(c)(7)(i) now reads as follows:
    Required information about certain ingredients in OTC drug 
products (e.g, sodium in Sec.  201.64(b), calcium in Sec.  
201.70(b), magnesium in Sec.  201.71(b), and potassium in Sec.  
201.72(b)) shall appear as follows: ``each (insert appropriate 
dosage unit) contains:'' [in bold type] (insert name(s) of 
ingredient(s) (in alphabetical order) and the quantity of each 
ingredient). This information shall be the first statement under 
this heading.

G. Economic Impact

    (Comment 8) One comment stated that the OTC drug industry was not 
currently able to provide an estimate of the total economic impact of 
the proposed rule on industry because individual companies do not yet 
know how to estimate their full costs. The comment added that the 
industry's expenditure of labor and other resources to comply with the 
sodium labeling final rule has made it difficult to gather data on the 
precise contents of other cations in finished drug products. The 
comment noted that there would be additional relabeling and other 
technical costs and asked FDA to be open to receiving additional data 
on the economic impact of the proposed cation labeling requirements 
when those costs were calculated.
    Another comment identified the following several cost factors: (1) 
The testing of multiple lots of finished products to determine a 
``mean'' for each specific cation was resource intense, (2) a large 
number of products requiring analysis would be a sizable resource 
investment, and (3) the relabeling costs included both the printing of 
new labels and the loss of some label inventory that would no longer be 
in compliance. A third comment stated that costs included label 
obsolescence and analytical, marketing, and regulatory review costs. 
The comment mentioned that it would incur label conversion costs of 
$2.7 million due to the far-reaching scope of the proposed rule. The 
comment concluded that coordinating the calcium, magnesium, and 
potassium labeling changes with the sodium labeling changes and 
allowing an 18-month implementation date would permit it to handle the 
labeling changes at current staff levels, to use preprinted labeling, 
and to reduce the cost of compliance significantly.
    A fourth comment stated that validation of classical cation 
measurements and methods would be time consuming and expensive for OTC 
drug products. The comment mentioned that it did not currently test any 
of its products for these measurements, and testing would involve 
incremental costs and resources to validate these methods for its 
products.
    To date, the industry has not provided any additional comments on 
the economic impact of this rule. This final rule provides for 
coordination of the calcium, magnesium, and potassium, labeling 
requirements with the sodium labeling requirements and with an 18-month 
implementation period to reduce the economic impact of this rule. FDA 
previously encouraged industry to concomitantly plan product analyses 
for all of the cations at the same time to reduce costs and obtain the 
needed information at the earliest possible time (Ref. 1).

III. Summary of Significant Changes

    1. The calcium, magnesium, and potassium content per dosage unit 
follows the ``Other information'' heading and appears in alphabetical 
order as stated in revised Sec.  201.66(c)(7). (See section II.F, 
comment 7 of this document.)
    2. FDA is allowing the calcium, magnesium, and potassium content 
declaration to be rounded-off to the nearest 5 mg instead of the 
nearest whole number in milligrams. (See section II.E, comment 6 of 
this document.)
    3. FDA is revising the language in Sec. Sec.  201.70(a), 201.71(a), 
and 201.72(a) to state the amount of cation in a ``single maximum 
recommended dose'' that triggers the content labeling requirements. 
(See section II.C, comment 4 of this document.)
    4. FDA is changing the format of the warning statements to follow 
the new OTC drug labeling requirements in Sec.  201.66(c)(5)(iv). The 
warning statements appear in the following format in this final rule: 
``Ask a doctor before use if you have [in bold type] [bullet]\1\ kidney 
disease [or stones in one case] [bullet] a (insert name of cation)-
restricted diet''. If more than one cation is present in the product, 
the names of the cations can be inserted in the blank space in 
alphabetical order, e.g., a magnesium or potassium-restricted diet.
---------------------------------------------------------------------------

    \1\ See Sec.  201.66(b)(4) of this chapter for definition of 
bullet symbol.
---------------------------------------------------------------------------

IV. FDA's Final Conclusions on Calcium, Magnesium, and Potassium 
Labeling

A. New Labeling Requirements

    FDA concludes that public interest and public health consequences 
related to calcium, magnesium, and potassium intake have produced a 
need for more informative and consistent cation content and warning 
information in the labeling of OTC drug products. This is especially 
true for individuals with kidney disease or kidney stones, or who need 
or want to monitor their intake of any or all of these cations.
    FDA is implementing the following content and warning requirements 
for OTC drug products intended for oral ingestion: Content--if the 
product contains 20 mg calcium, 8 mg magnesium, or 5 mg potassium or 
more per single maximum recommended dose; warning--if the product 
contains more than 3.2 g calcium, 600 mg magnesium, or 975 mg potassium 
in the labeled maximum daily dose. The content labeling may be rounded-
off to the nearest 5 mg (if less than 1 g) or nearest tenth of a g (if 
over 1 g) and shall appear after the heading ``Other information.'' The 
new calcium, magnesium, and potassium 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. The existing requirements relating to 
magnesium and potassium labeling in Sec.  331.30(c)(4) and (c)(5) (21 
CFR 331.30(c)(4) and (c)(5)) of the final monograph for OTC antacid 
drug products are being deleted because they are superseded by the new 
requirements of this final rule. Any proposed calcium, magnesium, or 
potassium labeling requirements in other ongoing OTC drug rulemakings 
will be deleted when final monographs for those drug classes are issued 
in a future issue of the Federal Register.

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

[[Page 13730]]

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 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).

C. Statutory Authority

    In this final rule, FDA is addressing legal issues relating to the 
agency's action to require cation 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 cations that are active ingredients 
and (2) the presence of cations that are inactive ingredients. To 
require disclosure of the quantity of cations that are inactive 
ingredients, FDA is relying on sections 502(a) and 201(n) of the act 
(21 U.S.C. 352(a) and 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, 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) of the act. 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 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 
proposed rule (61 FR 17807), FDA has determined that for OTC drug 
products containing more than the specified amount of cations, the 
quantity of these substances as inactive ingredients 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 calcium, magnesium, and potassium present a potential 
safety problem. People with renal failure, kidney stones, or other 
conditions need to monitor their intake of calcium, which can result in 
kidney stones, and both potassium and magnesium can cause serious 
toxicity in persons with impaired renal function. Many people are on 
calcium, magnesium, or potassium-restricted diets. Other people must 
monitor their intake of calcium, magnesium, and potassium from foods 
(including dietary supplements) and OTC drugs for other medical or 
health reasons. Absent mandatory cation content labeling, these people 
would not be able to understand the relative contribution that OTC drug 
products make to their intake of cations, and would not be able to 
compare the cation contents of various OTC drug products.

D. The First Amendment

    This final rule passes muster under the First Amendment. FDA's 
requirement of cation content labeling for OTC drug products (where 
cations are inactive ingredients and are 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 cations that do not threaten the 
health of people for whom cation use has material consequences. Some 
people, newly informed by the required labeling, will properly reduce 
or discontinue their intake of cation-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 cation 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 & Electric Corporation v. Public 
Service Commission, 447 U.S. 557 (1980), because it is necessary for 
the labeling of OTC drug products containing cations in excess of the 
threshold amount to be non-misleading (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 cations in the product when 
they are 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 
cation content labeling requirement satisfies each of these parts. With 
respect to the second part, FDA's interest in requiring cation content 
labeling under this final rule is to ensure that people who must 
monitor their intake of cations for health reasons have information 
necessary to understand the relative contribution that OTC drug 
products make to their intake of cations and to compare the cation 
contents 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 
cations 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.

[[Page 13731]]

    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 cation 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 cation 
content in the labeling of their products, would ensure that people 
have the information they need about cation content at the point of 
sale or ingestion. And establishing limits on cation 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 cation 
intake from OTC drug products. Further, some consumers may wish to use 
OTC drug products to enrich the amount of cations in their diets. 
Finally, for many products, the cation 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 
cations above a specified level in OTC drug product labeling.

V. Analysis of Impacts

    FDA has examined the impacts of this final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (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 1 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 of the document, the final rule will not 
be economically significant as defined by the Executive order. With 
respect to the Regulatory Flexibility Act, the rule may have a 
significant economic impact on a substantial number of small entities. 
Thus, this preamble contains FDA's regulatory flexibility analysis. 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 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 final rule is to add calcium, magnesium, and 
potassium content and warning information to the labeling of OTC drug 
products containing these ingredients. This rule is intended to help 
ensure the safe and effective use of all OTC drug products that contain 
these ingredients. Potential benefits include reduced toxicity when 
consumers use such products.
    OTC antacid drug products containing the threshold amounts of 
magnesium and potassium have had a magnesium or potassium warning in 
their labeling since 1974. The final rule revises the wording of this 
warning and requires the magnesium and potassium content to be added to 
product labeling if the amount exceeds the threshold amounts. The final 
rule also requires calcium, magnesium, and potassium labeling for other 
OTC drug products for the first time if those products contain above 
the threshold amounts stated in the final rule.
    FDA discussed the impacts of the calcium, magnesium, and potassium 
labeling requirement in the proposed rule (61 FR 17807 at 17810). Four 
of the comments submitted in response to the proposal addressed FDA's 
economic impact determination. (See section II.G, comment 8 of this 
document.)
    One of the comments stated that the rule would affect thousands of 
OTC drug products. However, the comment provided no additional 
information. Another comment discussed the large number of formulations 
requiring analyses, stating that there would be over 50 for its 
company, and the company would be faced with sizable resource 
investments. However, the comment did not provide any estimates of the 
cost of product analyses for calcium, magnesium, or potassium content 
or the cost of its resource investments.
    FDA's Drug Listing System (DLS) and standard texts can identify OTC 
drug products containing calcium, magnesium, and potassium as active 
ingredients. However, these sources do not identify those products 
containing these cations as inactive ingredients or indicate whether 
the inactive ingredient quantities meet the threshold levels that 
require content labeling and warnings to appear in product labeling. 
Therefore, FDA is unable to accurately estimate the number of products 
that will be affected by this final rule. However, FDA agrees with one 
comment that states that thousands of OTC drug products are likely to 
be affected.
    FDA's DLS identifies a large number of products that contain 
calcium, magnesium, and potassium as active ingredients. For example, 
the DLS identifies 129 manufacturers, 319 marketers, and 744 products 
containing a number of calcium salts (acetate, carbonate, citrate, 
lactate, oxide, phosphate, polycarbophil, and sulfate). The DLS 
identifies 202 manufacturers, 613 marketers, and 1,553 products 
containing magnesium (aluminosilicates, carbonate, chloride, citrate, 
glycinate, hydroxide, magaldrate, oxide, phosphate, phosphate dibasic, 
salicylate, sulfate, and trisilicate). The DLS identifies 84 
manufacturers, 149 marketers, and 445 products containing potassium 
(bicarbonate, carbonate, phosphate, phosphate dibasic or tribasic, 
salicylate, and tartrate). There are also a number of other less 
frequently used calcium, magnesium, and potassium salts included in the 
DLS. Some of these products contain more than one of these salts. Thus, 
the number of manufacturers and marketers affected by this final rule 
is less than the totals (415 manufacturers and 1,081 marketers) of the 
numbers stated herein. However, the total number of products (2,742) 
provides an estimate of the number of products that may need analyses. 
In addition, a number of these products are likely to have more than 
one stockkeeping unit (SKU) (individual products, packages, and sizes) 
that requires relabeling. For example, one private label manufacturer 
informed FDA that it has 91 products that would be affected by this 
final rule (that would need product analyses done), but these 91 
products represent 4,000 SKUs that would require relabeling. (Note--
these figures also included products containing sodium.) Another 
manufacturer informed FDA that it had 42 formulations affected by the 
calcium, magnesium, potassium, and sodium

[[Page 13732]]

labeling requirements, but did not mention the number of SKUs affected. 
Based on these numbers, FDA estimates that 10,000 SKUs may need 
labeling revisions.
    FDA is aware of varying cost estimates for conducting an individual 
cation analysis for an individual lot of a specific formulation. These 
estimates range from $150 for private label products to between $300 
and $400 for nationally branded products. If more than one cation is 
tested at the same time, there would likely be a slight cost savings 
($400 for four cations (including sodium if sodium is also done) for 
one product), but not a significant savings because a separate sample 
analysis would need to be done for each cation. FDA has also been 
informed that some manufacturers plan to perform tests on three lots of 
each specific formulation; thus, the cost per formulation would be $450 
to $1,200 per cation, and $1,200 to $3,600 if the analysis had to be 
done for all three cations (calcium, magnesium, and potassium). For 
certain cations, the need for analysis would be clear from the batch 
formulation. However, in some cases, manufacturers might have to test 
for all three cations to obtain baseline data.
    To estimate the cost of product analysis, FDA weighted the cost of 
product testing to reflect the difference in testing costs reported by 
private label and branded product manufacturers. FDA estimates that 
branded products account for about 20 percent of all OTC drug products, 
and private label products account for the remaining 80 percent. The 
weighted cost of product testing for one cation, assuming that all 
product manufacturers will conduct tests on three lots, is $570 (($150 
x .8 x 3)+($350 x .2 x 3)). Most manufacturers will know by their 
product formulations how many cations they will need to test. To 
estimate testing cost, FDA assumes that 50 percent of the products will 
require testing for 2 or 3 cations (midpoint of 2.5 used for estimation 
purposes). Assuming 3,000 products may need to be tested, the total 
cost of this requirement is $3.0 million (($570 x 1,500)+($570 x 2.5 x 
1,500)).
    All products containing over the threshold amounts of the cations 
will be required to be relabeled. Estimates of relabeling costs for the 
type of changes required by this rule vary greatly and range from $500 
to $15,000 per SKU, depending on whether the products are nationally 
branded or private label. Because of the large number of products 
affected by this rule, FDA used the same weighted average cost to 
relabel (i.e., $3,600 per SKU) that was estimated for the final rule 
for the standardized format and content labeling requirements of OTC 
drug products (64 FR 13254 at 13279 to 13281). If 10,000 SKUs need to 
be relabeled, therefore, the one-time costs will be $36 million. The 
cost of this rule may be mitigated to the extent that manufacturers can 
coordinate the testing and relabeling required by this final rule with 
that of the OTC drug sodium content labeling rule, published elsewhere 
in this issue of the Federal Register, and to the extent that the 
relabeling can be coordinated with the general OTC drug products 
labeling rule (64 FR 13254).
    In addition to the above costs, some manufacturers may incur one-
time and annually recurring costs if they need to increase the label 
and/or package size of some SKUs because of the additional information 
required by this final rule. FDA had estimated that about 6,400 of the 
almost 100,000 marketed OTC drug SKUs may require increased label and/
or package sizes to comply with the final labeling rule (64 FR 13254). 
As about one-half of these 6,400 SKUs were for products subject to this 
final rule, much of the costs for increasing label and/or package sizes 
may have already been accounted for in the impact analysis of that 
broader rule. FDA estimates that the additional few lines of labeling 
required by this final rule could compel an additional 3 percent of the 
approximately 10,000 affected SKUs to increase their label and/or 
package size. These costs were not accounted for in the prior rule.
    Because of the large number of products affected by this final 
rule, FDA assumes that the average cost per SKU to increase label and/
or package size would be essentially the same as FDA previously 
estimated in its analysis of the standardized format and content 
labeling requirements for OTC drug products. The model used to estimate 
the cost to change label/package sizes for the standardized format and 
content labeling requirements rule was developed by the Eastern 
Research Group, Inc. (ERG), a private economics consulting firm under 
contract to FDA (Ref. 2). ERG assigned probabilities to several options 
for package changes, including adding a carton (if not already 
present), adding a fifth panel, increasing the size of the packaging, 
or switching to a nonstandard form of labeling such as peel-back or 
accordion labels. Where applicable, the costs for changing a container 
size included container inventory loss, adjustment of the packaging 
line, and stability testing. Based on this model, FDA had estimated 
that the cost to increase label/package sizes to comply with the 
standardized format and content labeling requirements for OTC drug 
products in Sec.  201.66 was $38.1 million for 6,313 SKUs, with an 
annual recurring cost of $11.5 million. Consequently, the average per 
SKU one-time cost was $6,038, and the average per SKU recurring cost 
was $1,820. Under the same assumptions, this final rule would impose 
additional one-time costs for increasing label/package sizes of $1.8 
million (0.03 x 10,000 x $6,038) with annual recurring costs of $0.5 
million (0.03 x 10,000 x $1,820). Thus, FDA estimates the overall costs 
of this final rule to be $40.8 million in one-time costs (i.e., $36 
million to relabel, $3 million for testing, and $1.8 million to 
increase label/package sizes) and $0.5 million in annual recurring 
costs.
    This final rule will not require any new reporting and 
recordkeeping activities. Therefore, no additional professional skills 
are needed. There are no other Federal rules that conflict with this 
final rule.
    This final rule may have a significant economic impact on some 
small entities. It will affect the information content of all OTC drug 
products that contain above the threshold amounts of calcium, 
magnesium, and potassium. Firms that manufacture or relabel these OTC 
drug products will need to change the labeling for each affected 
product. FDA estimates that there are at least 400 firms that 
manufacture OTC drug products. Based on the Small Business 
Administration's determination that a small firm in this industry has 
fewer than 750 employees, roughly 70 percent of the firms are 
considered small.
    The economic impact on any particular small firm is very difficult 
to measure because it will vary with the number of products affected, 
the number of SKUs per product, the ability to coordinate these label 
changes with those required for other purposes, the number of cation 
tests that must be performed, and the size of the required labeling 
compared to the space available on existing packaging. For example, 
assuming average industry costs, a small firm that would need to change 
labels for 5 products with 3 SKUs each, for a total of 15 SKUs, could 
experience a one-time cost from $50,000 to $120,000, plus some annually 
recurring costs. If only one cation test were required for each product 
and the labeling fit on existing packaging, the one-time cost to comply 
with the rule would be about $57,000 and there would be no annually 
recurring costs. However, if the products required tests for all three 
cations and one SKU from each product required a larger label/package 
size, the cost to comply would increase to

[[Page 13733]]

$92,750 with an annual recurring cost of approximately $9,100. A small 
private label manufacturer with the same product line and 10 customers 
for each SKU would face costs of $562,500 and $848,650, with $91,000 in 
annually recurring costs, respectively. These costs would be largely 
offset, however, to the extent that OTC drug manufacturers can 
coordinate these label changes with those already required by the final 
rule for the labeling requirements of OTC drug products (64 FR 13254), 
the sodium labeling rule, and any voluntary market-driven label changes 
that would be completed within the permitted compliance period.
    FDA has taken the following steps to minimize the impact on small 
entities: (1) Providing sufficient time for implementation to enable 
entities to use up existing labeling stock and (2) coordinating the 
labeling revisions in this final rule with the revisions required by 
the final rule for sodium content labeling. FDA believes that these 
actions provide substantial flexibility and reductions in cost for 
small entities.
    FDA considered but rejected the following several labeling 
alternatives: (1) A shorter or longer implementation period, and (2) an 
exemption from coverage for small entities. While FDA believes that 
consumers would benefit from having this new labeling in place as soon 
as possible, we also acknowledge that a shorter implementation period 
could significantly increase the compliance costs and these costs could 
be passed through to consumers. A longer time period for this rule may 
cost more if firms would have to undertake two successive labeling 
revisions. In addition, a longer time period would unnecessarily delay 
the benefit of the new labeling to consumers who self-medicate with 
these OTC drug products. FDA rejected an exemption for small entities 
because the new labeling information 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 final regulatory flexibility 
analysis, as required under the Regulatory Flexibility Act.

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)). The calcium, magnesium, and 
potassium content per dosage unit for active ingredients is product 
formulation information that many manufacturers should have on hand as 
part of their usual and customary business practice. Some manufacturers 
may need to do content analysis for inactive ingredients.

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, FDA concludes 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, Nonprescription Drug 
Manufacturers Association, January 14, 1997, coded LET3, Docket No. 
95N-0254, Division of Dockets Management.
    2. Eastern Research Group, Inc., ``Cost Impacts of the Over-the-
Counter Pharmaceutical Labeling Rule,'' in OTC vol. 28 FR, Docket 
No. 96N-0420, Division of Dockets Management.

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 331

    Labeling, Over-the-counter drugs.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act, and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
201 and 331 are 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 201.66 is amended by revising paragraph (c)(7)(i) to read as 
follows:


Sec.  201.66  Format and content requirements for over-the-counter 
(OTC) drug product labeling.

* * * * *
    (c) * * *
    (7) * * *
    (i) Required information about certain ingredients in OTC drug 
products (e.g., sodium in Sec.  201.64(b), calcium in Sec.  201.70(b), 
magnesium in Sec.  201.71(b), and potassium in Sec.  201.72(b)) shall 
appear as follows: ``each (insert appropriate dosage unit) contains:'' 
[in bold type (insert name(s) of ingredient(s) (in alphabetical order) 
and the quantity of each ingredient). This information shall be the 
first statement under this heading.
* * * * *

0
3. Section 201.70 is added to subpart C to read as follows:


Sec.  201.70  Calcium labeling.

    (a) The labeling of over-the-counter (OTC) drug products intended 
for oral ingestion shall contain the calcium content per dosage unit 
(e.g., tablet, teaspoonful) if the calcium content of a single maximum 
recommended dose of the product (which may be one or more dosage units) 
is 20 milligrams or more. OTC drug products intended for oral ingestion 
include gum and lozenge dosage forms, but do not include dentifrices, 
mouthwashes, or mouth rinses.
    (b) The calcium content shall be expressed in milligrams or grams 
per dosage unit and shall include the total amount of calcium 
regardless of the source, i.e., from both active and inactive 
ingredients. If the dosage unit contains less than 1 gram of calcium, 
milligrams should be used. The calcium

[[Page 13734]]

content per dosage unit shall be rounded-off to the nearest 5 
milligrams (or nearest tenth of a gram if over 1 gram). The calcium 
content per dosage unit shall follow the heading ``Other information'' 
as stated in Sec.  201.66(c)(7).
    (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 calcium present in the labeled maximum daily dose of the 
product is more than 3.2 grams: ``Ask a doctor before use if you have 
[in bold type] [bullet]\1\ kidney stones [bullet] a calcium-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) Any product subject to this paragraph that is not labeled as 
required by this paragraph 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) September 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.

0
4. Section 201.71 is added to subpart C to read as follows:


Sec.  201.71  Magnesium labeling.

    (a) The labeling of over-the-counter (OTC) drug products intended 
for oral ingestion shall contain the magnesium content per dosage unit 
(e.g., tablet, teaspoonful) if the magnesium content of a single 
maximum recommended dose of the product (which may be one or more 
dosage units) is 8 milligrams or more. OTC drug products intended for 
oral ingestion include gum and lozenge dosage forms, but do not include 
dentifrices, mouthwashes, or mouth rinses.
    (b) The magnesium content shall be expressed in milligrams or grams 
per dosage unit and shall include the total amount of magnesium 
regardless of the source, i.e., from both active and inactive 
ingredients. If the dosage unit contains less than 1 gram of magnesium, 
milligrams should be used. The magnesium content shall be rounded-off 
to the nearest 5 milligrams (or nearest tenth of a gram if over 1 
gram). The magnesium content per dosage unit shall follow the heading 
``Other information'' as stated in Sec.  201.66(c)(7).
    (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 magnesium present in the labeled maximum daily dose of the 
product is more than 600 milligrams: ``Ask a doctor before use if you 
have [in bold type] [bullet]\1\ kidney disease [bullet] a magnesium-
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 magnesium or 
potassium-restricted diet.
---------------------------------------------------------------------------

    \1\ See Sec.  201.66(b)(4) of this chapter for definition of 
bullet symbol.
---------------------------------------------------------------------------

    (d) Any product subject to this paragraph that is not labeled as 
required by this paragraph 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) September 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.

0
5. Section 201.72 is added to subpart C to read as follows:


Sec.  201.72  Potassium labeling.

    (a) The labeling of over-the-counter (OTC) drug products intended 
for oral ingestion shall contain the potassium content per dosage unit 
(e.g., tablet, teaspoonful) if the potassium 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 
dentifrices, mouthwashes, or mouth rinses.
    (b) The potassium content shall be expressed in milligrams or grams 
per dosage unit and shall include the total amount of potassium 
regardless of the source, i.e., from both active and inactive 
ingredients. If the dosage unit contains less than 1 gram of potassium, 
milligrams should be used. The potassium content shall be rounded-off 
to the nearest 5 milligrams (or nearest tenth of a gram if over 1 
gram). The potassium content per dosage unit shall follow the heading 
``Other information'' as stated in Sec.  201.66(c)(7).
    (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 potassium present in the labeled maximum daily dose of the 
product is more than 975 milligrams: ``Ask a doctor before use if you 
have [in bold type] [bullet]\1\ kidney disease [bullet] a potassium-
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 magnesium or 
potassium-restricted diet.
---------------------------------------------------------------------------

    \1\ See Sec.  201.66(b)(4) of this chapter for definition of 
bullet symbol.
---------------------------------------------------------------------------

    (d) Any product subject to this paragraph that is not labeled as 
required by this paragraph 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) September 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.

PART 331--ANTACID PRODUCTS FOR OVER-THE-COUNTER (OTC) HUMAN USE

0
6. The authority citation for 21 CFR part 331 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.


Sec.  331.30  [Amended]

0
7. Section 331.30 Labeling of antacid products is amended by removing 
paragraphs (c)(4) and (c)(5) and redesignating paragraph (c)(6) as 
paragraph (c)(4).


[[Page 13735]]


    Dated: March 15, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-6480 Filed 3-23-04; 8:45 am]

BILLING CODE 4160-01-S