[Federal Register Volume 61, Number 78 (Monday, April 22, 1996)]
[Proposed Rules]
[Pages 17807-17812]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-9734]




  Federal Register / Vol. 61, No. 78 / Monday, April 22, 1996 / 
Proposed Rules  

[[Page 17807]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201 and 331

[Docket No. 95N-0254]
RIN 0910-AA63


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
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 not take the product unless directed by a doctor 
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 not take the product unless directed by a doctor 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 not take the product unless directed by a doctor if the product 
contains more than 975 mg potassium in the labeled maximum daily dose. 
The agency is proposing that the calcium, magnesium, and potassium 
content be labeled in mg per dosage unit, rounded to the nearest whole 
number. FDA is issuing this notice of proposed rulemaking 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, an approved application, or no 
application.

DATES: Written comments by July 22, 1996. Written comments on the 
agency's economic impact determination by July 22, 1996. The agency is 
proposing that any final rule based on this proposal be effective 12 
months after the date of its publication in the Federal Register.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug 
Evaluation and Research (HFD-105), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2304.

SUPPLEMENTARY INFORMATION:

I. Background

A. Calcium

    In the advance notice of proposed rulemaking for OTC antacid drug 
products (38 FR 8714 at 8718, April 5, 1973), the Advisory Review Panel 
on OTC Antacid Drug Products (Antacid Panel) concluded that calcium 
carbonate is safe when taken in a dosage of not more than 160 
milliequivalents (mEq) of calcium (8 g calcium carbonate) per day. The 
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-
containing antacids.
    The maximum daily dose for calcium carbonate or calcium phosphate 
in Sec. 331.11(d) (21 CFR 331.11(d)) of the antacid monograph is 160 
mEq (e.g., 3.2 g calcium). This amount of calcium is contained in 8.0 g 
calcium carbonate, 18.7 g monobasic calcium phosphate, and 8.3 g 
tribasic calcium phosphate. The warning in Sec. 331.30(c)(1) (21 CFR 
331.30(c)(1)) states: ``Do not take more than (maximum recommended 
daily dosage
* * *) in a 24-hour period, or use the maximum dosage of this product 
for more than 2 weeks, except under the advice and supervision of a 
physician.''
    In the advance notice of proposed rulemaking for OTC digestive aid 
drug products (47 FR 454 at 469, January 5, 1982), the Advisory Review 
Panel on OTC Miscellaneous Internal Drug Products (Miscellaneous 
Internal Panel) stated that adverse reactions associated with calcium 
carbonate, including alkalosis, hypercalcemia, acid rebound, milk-
alkali syndrome, and constipation, usually occur with ingestion of 
larger than recommended doses and/or with chronic ingestion. The 
Miscellaneous Internal Panel stated that some antacids decrease the 
effectiveness of many other drugs. The Miscellaneous Internal Panel 
recommended the following labeling for drug products containing calcium 
carbonate: (1) ``If you are taking other drugs, consult your physician 
as this drug may interfere with their effectiveness,'' and (2) ``Do not 
take for longer than 2 weeks or in greater than recommended amounts, 
except on the advice of a physician.'' However, these warnings were 
never finalized because no calcium salt attained monograph status as an 
active ingredient for use as an OTC digestive aid drug product.

B. Magnesium

    In the advance notice of proposed rulemaking for OTC antacid drug 
products (38 FR 8714 at 8719), the Antacid Panel stated that in normal 
renal function it is difficult to reach excessive magnesium blood 
levels via the oral route, because magnesium enters and leaves the 
cells rapidly. However, the Antacid Panel stated that hypermagnesemia 
toxicity may occur in renal dysfunction and therefore a warning is 
necessary. The Antacid Panel concluded that for those products in which 
the maximal daily dose exceeds 50 mEq of magnesium, the labeling should 
state: ``Do not use this product if you have kidney disease except 
under the advice and supervision of a physician.''
    In the final monograph for OTC antacid drug products (39 FR 19862 
at 19868, June 6, 1974), the agency noted that at some of its early 
meetings the Antacid Panel initially considered 150 mEq per day of 
magnesium as the level for requiring a warning, but upon 
reconsideration reduced the amount to 50 mEq. The Antacid Panel gave 
several reasons for lowering this level: (1) The normal individual 
consumes from 20 to 40 mEq of magnesium per day and about one-third of 
that amount is absorbed into the body; (2) if a person is taking a 
magnesium-containing antacid, approximately 15 to 30 percent of that 
magnesium is absorbed, and (3) if a person does not have normal renal 
function, it is possible to have hypermagnesemia toxicity, i.e., the 
level of magnesium in the body may reach a toxic level.
    The final monograph for OTC antacid drug products includes a 
warning in Sec. 331.30(c)(4) for products containing more than 50 mEq 
of magnesium in the recommended daily dosage, which states: ``Do not 
use this product except under the advice and supervision of a physician 
if you have kidney disease.'' Although persons with normal renal 
function can easily tolerate more than 50 mEq of magnesium a day, the 
agency included this warning in the monograph because large doses of an 
antacid could present a serious problem for

[[Page 17808]]

individuals with reduced renal function.
    In the advance notice of proposed rulemaking for OTC laxative drug 
products (56 FR 12902 at 12905, March 21, 1975), the Advisory Review 
Panel on OTC Laxative, Antidiarrheal, Emetic, and Antiemetic Drug 
Products (Laxative Panel) stated that OTC laxative drug products 
containing more than 50 mEq (600 mg) magnesium in the maximum 
recommended daily dose should include a warning which states that 
people with kidney disease should not use the product except under the 
advice and supervision of a physician. In the Federal Register of 
January 15, 1985 (50 FR 2124 at 2153), the agency published a tentative 
final monograph for OTC laxative drug products that included the 
warning recommended by the Laxative Panel. This rulemaking has not been 
completed at this time.
    In the advance notice of proposed rulemaking for OTC digestive aid 
drug products (47 FR 454 at 471), the Miscellaneous Internal Panel 
stated that high serum magnesium levels may result from magnesium 
ingestion by persons with kidney damage. The Miscellaneous Internal 
Panel agreed with the Antacid Panel that a warning statement should be 
present on any magnesium hydroxide preparation (47 FR 470) and on any 
magnesium trisilicate preparation (47 FR 471) for which the maximal 
daily dose exceeds 50 mEq (600 mg) of magnesium. The Miscellaneous 
Internal Panel also stated that magnesium hydroxide has the potential 
for drug interactions with certain anticoagulants and antibiotics. 
Similarly, the Miscellaneous Internal Panel noted that magnesium 
trisilicate absorbs various alkaloids and antibiotics in vitro. 
However, this warning was never finalized because no magnesium salt 
attained monograph status as an active ingredient for use as an OTC 
digestive aid drug product.

C. Potassium

    In the advance notice of proposed rulemaking for OTC antacid drug 
products (38 FR 8714 at 8719), the Antacid Panel stated that 
hyperkalemia is rare for normal persons who can easily tolerate the 
potassium content of antacid drug products. The Antacid Panel 
concluded, however, that potassium can accumulate in the body of 
persons with impaired renal function and exert toxic effects. The 
Antacid Panel recommended the following warning for products containing 
more than 25 mEq (975 mg) potassium in the maximum recommended daily 
dose: ``Do not use this product if you have kidney disease except under 
the advice and supervision of a physician.'' This warning appears in 
Sec. 331.30(c)(6) of the antacid final monograph, slightly rephrased to 
read: ``Do not use this product except under the advice and supervision 
of a physician if you have kidney disease.''
    In the advance notice of proposed rulemaking (56 FR 12902 at 
12905), the Laxative Panel recommended that if a laxative product 
contains more than 25 mEq (975 mg) of potassium in the maximum 
recommended daily dose, the labeling should advise consumers with 
kidney disease not to use the product except under the advice and 
supervision of a physician. The agency is aware that some effervescent 
laxative drug products contain significant amounts of potassium as 
inactive ingredients. The Laxative Panel recommended that the inactive 
ingredients be listed (with or without the amounts) for OTC laxative 
drug products and that the availability of sodium, potassium, and 
magnesium in the maximum recommended daily dose be stated in the 
labeling. The Laxative Panel noted that certain inactive ingredients 
(including calcium hydroxide and potassium carbonate) are added to some 
laxative preparations to enhance their formulation or to contribute to 
the effervescent qualities.
    In the tentative final monograph for OTC laxative drug products (50 
FR 2124 at 2153), the agency agreed with the Laxative Panel's 
recommendation and proposed the following warning for those products 
containing more than 975 mg potassium in the maximum recommended daily 
dose: ``Do not use this product if you have kidney disease unless 
directed by a doctor.'' This rulemaking has not been completed at this 
time.

D. Rulemaking for Sodium Labeling of OTC Drug Products

    The agency has already addressed sodium labeling in a final rule 
published elsewhere in this issue of the Federal Register. That rule 
amends the general labeling provisions for OTC drug products to include 
sodium labeling and provides for across-the-board uniform sodium 
content and warning labeling for all OTC drug products intended for 
oral ingestion. New Sec. 201.64 requires sodium content labeling of all 
products containing 5 mg or more sodium per single recommended dose and 
requires that products containing more than 140 mg sodium per maximum 
recommended daily dose be labeled with a general warning that states: 
``Do not use this product if you are on a sodium-restricted diet unless 
directed by a doctor.'' Section 201.64 also provides for the voluntary 
use of certain descriptive terms (``sodium free,'' ``very low sodium,'' 
and ``low sodium''). These descriptive terms are the same terms used to 
describe sodium content in food labeling.
    Sodium content is expressed in mg per single dosage unit (e.g., 
tablet, teaspoonful), rounded-off to the nearest whole number, and 
includes the total amount of sodium regardless of the source (both 
active and inactive ingredients). OTC drug products ``intended for oral 
ingestion'' also include gum and lozenge dosage forms, but do not 
include dentifrices, mouthwashes, or mouth rinses. Because some OTC 
drug products not intended for oral administration can contain very 
high levels of sodium that may be absorbed from both active and 
inactive ingredients, the agency has asked for comments from interested 
individuals on whether the final rule should be amended to include 
sodium labeling for OTC rectal, vaginal, dentifrice, mouthwash, and 
mouth rinse drug products. The agency will address this subject in a 
future issue of the Federal Register.
    Two comments received to the tentative final monograph for OTC 
laxative drug products contended that sodium labeling of OTC laxative 
and other drug products should be consistent with FDA's food labeling 
terminology. The comments stated that food products already bear FDA 
terminology and the food terminology will become the dominant system. 
Thus, other mandatory FDA labeling systems should be made consistent 
with that system. The agency has used this approach in the final rule 
for sodium labeling of OTC drug products published elsewhere in this 
issue of the Federal Register.

E. Food Labeling Regulations

    FDA regulations for food products address calcium and magnesium 
labeling. Section 101.9 (21 CFR 101.9) requires the labeling of food 
products to declare the content, as a percent of the Reference Daily 
Intake (RDI), of calcium, iron, vitamin C, and vitamin E. Other 
vitamins and minerals for which a RDI has been established, including 
magnesium, may be listed voluntarily, unless they are added as a 
nutrient supplement or a claim is made about them, in which case they 
must be declared.
    Section 101.9(c)(5) provides for the voluntary declaration of 
potassium content in a labeled serving size. However, when a claim is 
made about potassium, the declaration is mandatory and is placed on the 
nutrition label

[[Page 17809]]

immediately following the sodium content. When the potassium content is 
less than 5 mg per serving, the content is expressed as zero.
    Vitamins and minerals, other than calcium, iron, vitamin C, and 
vitamin E, present at less than 2 percent of the RDI are not required 
to be declared in nutrition labeling but may be declared as zero or by 
use of an asterisk referring to a footnote that states, ``Contains less 
than 2% of the Daily Value of this (these) nutrient (nutrients)'' 
(Sec. 101.9(c)(8)(iii)). The RDI for calcium is 1,000 mg and for 
magnesium is 400 mg (Sec. 101.9(c)(8)(iv)). Thus, for foods containing 
less than 20 mg of calcium per serving, a declaration of zero is 
required on the nutrition label. For foods containing less than 8 mg of 
magnesium per serving, content declaration is not required (unless a 
claim is made about the nutrient) or may be declared as zero or as less 
than 2 percent of the Daily Value.
    The regulations in Sec. 101.36(b)(3) (21 CFR 101.36(b)(3)) for 
nutrition labeling of dietary supplements of vitamins and minerals 
require that potassium be declared except when present in quantitative 
amounts by weight that allow a declaration of zero.
    The regulations for health claims related to calcium and 
osteoporosis in Sec. 101.72(c)(2)(i)(E) (21 CFR 101.72(c)(2)(i)(E)) 
require the labeling of food products to state that a total dietary 
intake greater than 2,000 mg of calcium has no further known benefit to 
bone health. This requirement applies when the food or supplement 
contains more than 400 mg of calcium per reference amount. A recently 
published NIH Concensus Statement on optimal calcium intake states that 
up to a total intake of 2,000 mg per day appears to be safe in most 
individuals (``Optimal Calcium Intake,'' NIH Consensus Statement, 
12(4):1-31, June 6-8, 1994).

II. The Agency's Tentative Conclusions on Labeling of Orally 
Ingested OTC Drug Products Containing Calcium, Magnesium, and 
Potassium

A. Basis for Rulemaking -

    FDA 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. The agency believes certain 
labeling requirements are needed to alert persons with renal failure, 
kidney stones, or other conditions, and persons taking other 
medications who wish to monitor their intake of calcium, magnesium, and 
potassium. Consumers need to consider their intake from foods, dietary 
supplements, and drugs. Therefore, the agency is proposing 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).

B. Criteria for Content and Warning Labeling-

    In order to establish uniform content declarations and warnings 
relating to calcium, magnesium, and potassium for orally ingested OTC 
drug products and to establish content labeling similar to that used in 
food labeling, the agency is proposing to adopt: (1) 20 mg of calcium, 
8 mg of magnesium, and 5 mg of potassium as the amount per single 
recommended dose in an OTC drug product (which may involve one or more 
dosage units, e.g., tablets, teaspoonsful, etc.) that requires a 
content declaration; and (2) 3.2 g calcium, 600 mg magnesium, and 975 
mg potassium as the amounts present in the maximum labeled daily dose 
above which a warning is required. The agency is therefore proposing to 
amend the general drug labeling provisions in part 201 (21 CFR part 
201) to include these labeling requirements for OTC drug products 
intended for oral ingestion.
    The proposed levels for requiring content labeling are similar to 
those used in food labeling. In contrast, the proposed levels for 
requiring warnings are based on recommendations of FDA advisory review 
panels in the early 1970's. The agency acknowledges that there may be 
more recent scientific information to consider in setting requirements 
for OTC drug product labeling. The agency specifically encourages 
comment and data on this aspect of the proposal.

C. Basis for Amount Requiring Content Labeling

1. Calcium and Magnesium Content-
    As stated in section I.E. of this document, a serving of food 
containing 20 mg or more of calcium requires a content declaration, and 
a serving of food containing 8 mg or more of magnesium (if added as a 
supplement or if a claim is made) requires a content declaration in the 
nutrition labeling of foods. Thus, the agency is using 20 mg calcium 
and 8 mg magnesium per single recommended dose as the amounts at which 
OTC drug products should include content labeling for these 
ingredients.
2. Potassium Content
    As noted in section I.E. of this document, potassium labeling for 
foods is optional unless a claim is made about the potassium content; 
but, if declared, it is expressed in mg per serving for those foods 
containing 5 mg or more. In Sec. 201.64(a) of the final rule for sodium 
labeling of OTC drug products, the agency required a declaration of the 
sodium content for all OTC drugs intended for oral ingestion if the 
sodium content per single recommended dose is 5 mg or more. The agency 
believes it is not necessary to declare potassium amounts below 5 mg 
per dose. However, the agency believes it is appropriate to declare the 
potassium content if the product contains 5 mg or more per single 
recommended dose.

D. Basis for Amount Requiring Warning Statements

    The agency believes that for uniformity in labeling, warnings 
should be required across-the-board for calcium, magnesium, and 
potassium for those OTC drug products intended for oral ingestion 
containing a certain concentration of these ingredients.
1. Calcium Warning
    Based on the current requirements in the monograph for OTC antacid 
drug products and the recommendations of the Miscellaneous Internal 
Panel (see section I.A. of this document), the agency is proposing to 
require the following warning for all OTC drug products containing more 
than 3.2 g calcium (equivalent to 8 g calcium carbonate) per labeled 
maximum daily dose: ``Do not use this product if you have kidney stones 
or if you are on a calcium-restricted diet unless directed by a 
doctor.'' The NIH Consensus Statement on optimal calcium intake 
suggests that a 2,000 mg total daily intake is safe, but it does not 
give a definitive conclusion as to what level is unsafe. When the 3,200 
mg daily dosage level, proposed as the level requiring a warning, is 
added to the 1,000 mg recommended daily intake that may be included in 
a person's diet, the resulting 4,200 mg daily intake is considerably 
higher than the 2,000 mg level found to be safe in the NIH consensus 
statement. The agency invites comments on whether the proposed 3.2 g 
level requiring a warning should be lowered.
2. Magnesium Warning
    The agency is proposing to require the following warning for all 
OTC drug products that contain more than 600 mg magnesium per labeled 
maximum daily dose: ``Do not use this product if you have kidney 
disease or if you are on a

[[Page 17810]]

magnesium-restricted diet unless directed by a doctor.'' This warning 
is similar to the warning in Sec. 331.30(c)(4) of the final monograph 
for OTC antacid drug products.
3. Potassium Warning
    The agency is proposing to require the following warning for all 
OTC drug products that contain more than 975 mg potassium per maximum 
recommended dose: ``Do not use this product if you have kidney disease 
or if you are on a potassium-restricted diet unless directed by a 
doctor.'' This warning is similar to the warning in Sec. 331.30(c)(6) 
of the final monograph for OTC antacid drug products.

E. Units of Measure-

    The agency believes the units of measure, where possible, should be 
similar for foods and drugs. The unit of measure in declaring the 
content of these components in foods is mg or g per serving of food. 
While a serving of food is not the same as a dosage of a drug, the 
agency believes it is logical to declare the content in mg per dosage 
unit of the drug and to require a content declaration if the ingredient 
per dose (which could be contained in one or more active or inactive 
ingredients and in one or more dosage units) is equal to the amount in 
a serving of food that requires a declaration in the nutrition 
labeling. This is similar to the agency's approach in the final rule 
for sodium labeling of OTC drug products. Section 201.64(b) states: 
``The sodium content shall be expressed in milligrams per dosage unit 
and shall include the total amount of sodium regardless of the source, 
i.e., from both active and inactive ingredients.''

F. Rounding to Whole Number

    While the food labeling regulations allow for the content 
declaration of certain ingredients (e.g., sodium and potassium) to be 
labeled as ``zero'' up to a certain level (5 mg per serving) 
(Sec. 101.9(c)(8)(i) and (c)(8)(ii)), the agency believes these 
ingredients in drugs should not be labeled as zero content except when 
the content is zero (based on rounding to the nearest whole number, as 
in the regulation for sodium labeling of OTC drug products). As 
discussed in the sodium labeling final rule, most OTC drug products are 
manufactured and the concentration of ingredients can be strictly 
controlled. Thus, the concentration of specific ingredients is expected 
to be less variable in OTC drug products than in foods. For consistency 
in labeling, the agency believes the labeling of these ingredients 
should be expressed in mg per dosage unit rounded to the nearest whole 
number for those products containing less than 1 g. For those products 
containing 1 g or more per dosage unit, the content labeling may be 
rounded to the nearest tenth of a g.

G. Implementation of Labeling Requirements

    The agency encourages manufacturers to comply voluntarily with the 
provisions of this proposed rule despite the fact that revisions in the 
requirements may occur in the final rule in response to submitted 
comments. Should any manufacturer choose to adopt the labeling 
described in this proposed rule, and should any revisions occur in the 
final rule, the agency will permit the use of existing stocks of labels 
for those products labeled according to the proposed rule for a period 
of 1 year following publication of the final rule.
    Should this proposed amendment to part 201 relating to calcium, 
magnesium, and potassium content and warning labeling of all OTC drug 
products intended for oral ingestion be published as a final rule, then 
the existing requirements relating to magnesium labeling in 
Sec. 331.30(c)(4) and potassium labeling in Sec. 331.30(c)(5) of the 
final monograph for OTC antacid drug products and the proposed labeling 
requirements for magnesium and potassium being considered in other 
ongoing OTC drug rulemakings will be deleted. The agency advises that 
on or after 12 months after publication of a final rule any OTC drug 
product subject to this rule that does not meet these labeling 
requirements and that is initially introduced or initially delivered 
for introduction into interstate commerce will be misbranded under 
sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321(n) and 352(a) and (f)).

III. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
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). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the proposed 
rule is not a significant regulatory action as defined by the Executive 
Order and, thus, is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Should this proposed rule become a final rule, one-
time label modification costs associated with changing product labels 
would be incurred by some manufacturers. FDA estimates those costs to 
total less than $500,000 for the entire industry. This projected cost 
is based on estimates of the number of products that will be affected 
by the proposed rule, the number of distinct label changes that will be 
required, and the cost of printing new labels.
    OTC antacid drug products are the primary products having a 
significant number of orally administered active ingredients containing 
calcium, magnesium, and potassium. The monograph for those products has 
been in effect since 1974 and these products currently bear magnesium 
and potassium warning labeling. For these products, the labeling change 
would involve a slight change in wording, resulting only in a minor 
cost to have a labeling revision printed. For those products containing 
calcium, a new warning would be required in product labeling. In almost 
all cases, this revision would be routinely done at the next labeling 
printing so that minimal costs should be incurred. Manufacturers will 
have up to 12 months after publication of a final rule in the Federal 
Register to revise their product labeling. It is anticipated that most 
antacid drug products would undergo a label printing within a 12-month 
period. Products containing magnesium and potassium would need only 
minor revisions, and products containing calcium would need to add some 
new labeling.
    Other OTC drug products (i.e., antidiarrheals, laxatives, and 
internal analgesics) having one or a few calcium, magnesium, and 
potassium-containing active ingredients that would be affected by 
mandatory calcium, magnesium, and potassium labeling currently are not 
required to bear the labeling recommended in this proposed rule. These 
products would need to have new labels printed to incorporate the 
labeling requirements of this rulemaking. These products will also need 
to have new labeling printed in the future when the final monographs 
for OTC antidiarrheal, laxative, and internal analgesic drug products 
are published. This again involves one-time label modification costs. 
For products that will be undergoing such labeling

[[Page 17811]]

changes, the incremental costs attributable to this rule for calcium, 
magnesium, and potassium labeling would be negligible. A limited number 
of OTC antidiarrheal, laxative, and internal analgesic drug products 
contain calcium, magnesium, and potassium-containing active 
ingredients.
    Accordingly, the agency certifies that the proposed rule will not 
have a significant economic impact on a substantial number of small 
entities. Therefore, under the Regulatory Flexibility Act, no further 
analysis is required.
    The agency invites public comment regarding any substantial or 
significant economic impact that this rulemaking would have on OTC drug 
products intended for oral ingestion. Types of impact may include, but 
are not limited to, costs associated with relabeling, repackaging, or 
reformulating. Comments regarding the impact of this rulemaking on OTC 
drug products should be --accompanied by appropriate documentation. A 
period of 90 days from the date of publication of this proposed 
rulemaking in the Federal Register will be provided for comments on 
this subject to be developed and submitted. The agency will evaluate 
any comments and supporting data that are received and will reassess 
the economic impact of this rulemaking in the preamble to the final 
rule.

IV. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the labeling requirements proposed 
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 proposed warning statements are 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 is product formulation information that manufacturers have on hand 
as part of their usual and customary business practice.

V. Environmental Impact

    The agency has determined under 21 CFR 25.24(c)(6) 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.

VI. Request for Comments

    Interested persons may, on or before July 22, 1996, submit to the 
Dockets Management Branch (address above) written comments regarding 
this proposal. Written comments on the agency's economic impact 
determination may be submitted on or before July 22, 1996. Three copies 
of all comments are to be submitted, except that individuals may submit 
one copy. Comments are to be identified with the docket number found in 
brackets in the heading of this document and may be accompanied by a 
supporting memorandum or brief. Received comments may be seen in the 
office above between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 331

    Labeling, Over-the-counter drugs.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, it is 
proposed that title 21 of the Code of Federal Regulations be amended in 
parts 201 and 331 as follows:

PART 201--LABELING

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

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 508, 
510, 512, 530-542, 701, 704, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 358, 
360, 360b, 360gg-360ss, 371, 374, 379e); secs. 215, 301, 351, 361 of 
the Public Health Service Act (42 U.S.C. 216, 241, 262, 264).

    2. New Sec. 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 
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 less than 1 gram, milligrams should be used. The 
calcium content shall be rounded-off to the nearest whole number in 
milligrams (or tenth of a gram if over 1 gram) and shall be listed on a 
separate line after the heading ``Calcium Content'' as the last 
sentence in the ingredients section.
    (c) The labeling of OTC drug products intended for oral ingestion 
shall contain the following warning 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: ``Do not use this product if you have 
kidney stones or if you are on a calcium-restricted diet unless 
directed by a doctor.''
    (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 
(date 1 year after publication of the final rule), is misbranded under 
sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and 
Cosmetic Act.
    3. New Sec. 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 
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 less than 1 gram, milligrams should be used. The 
magnesium content shall be rounded-off to the nearest whole number in 
milligrams (or tenth of a gram if over 1 gram) and shall be listed on a 
separate line after the heading ``Magnesium Content'' as the last 
sentence in the ingredients section.
    (c) The labeling of OTC drug products intended for oral ingestion 
shall contain the following warning 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: ``Do not use this product if

[[Page 17812]]

you have kidney disease or if you are on a magnesium-restricted diet 
unless directed by a doctor.''
    (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 
(date 1 year after publication of the final rule), is misbranded under 
sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and 
Cosmetic Act.
    4. New Sec. 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 
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 less than 1 gram, miligrams should be used. The 
potassium content shall be rounded-off to the nearest whole number in 
milligrams (or tenth of a gram if over 1 gram) and shall be listed on a 
separate line after the heading ``Potassium Content'' as the last 
statement in the ingredients section.
    (c) The labeling of OTC drug products intended for oral ingestion 
shall contain the following warning 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: ``Do not use this product if you 
have kidney disease or if you are on a potassium-restricted diet unless 
directed by a doctor.''
    (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 
(date 1 year after publication of the final rule), is misbranded under 
sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and 
Cosmetic Act.

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

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

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 
355, 360, 371).


Sec. 331.30  [Amended]

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

    Dated: March 30, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-9734 Filed 4-19-96; 8:45 am]
BILLING CODE 4160-01-F