FR Doc 04-6480

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