[Federal Register: January 15, 1997 (Volume 62, Number 10)]
[Rules and Regulations]
[Page 2217-2250]
[[Page 2217]]
_______________________________________________________________________
Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Parts 101, 111, and 310
Iron-Containing Supplements and Drugs: Label Warning Statements and
Unit-Dose Packaging Requirements; Final Rule
[[Page 2218]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 101, 111, and 310
[Docket Nos. 91P-0186 and 93P-0306]
Iron-Containing Supplements and Drugs: Label Warning Statements
and Unit-Dose Packaging Requirements
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing regulations
to require label warning statements on products taken in solid oral
dosage form to supplement the dietary intake of iron or to provide iron
for therapeutic purposes, and unit dose packaging for iron-containing
products that contain 30 milligrams (mg) or more of iron per dosage
unit. FDA is taking these actions because of the large number of acute
iron poisonings, including deaths, in children less than 6 years of age
attributable to accidental overdoses of iron-containing products. FDA
is temporarily exempting one form of elemental iron, carbonyl iron,
from the packaging requirements of this final rule. The temporary
exemption will automatically expire 1 year from the effective date of
this final rule. If, during the temporary exemption period, FDA
receives animal data that establish that carbonyl iron is significantly
less toxic than at least one commonly used iron salt, FDA will consider
permanently exempting carbonyl iron from the packaging requirements of
this final rule.
DATES: The regulation is effective July 15, 1997. For compliance dates
see Secs. 111.50(b)(1) and (b)(2) and 310.518(b)(1) and (b)(2).
FOR FURTHER INFORMATION CONTACT: Linda S. Kahl, Center for Food Safety
and Applied Nutrition (HFS-206), Food and Drug Administration, 200 C
St. SW., Washington, DC 20204, 202-418-3101.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of October 6, 1994 (59 FR 51030), FDA
published a proposed rule (the iron proposal) to require label warning
statements for products taken in solid oral dosage form to supplement
the dietary intake of iron or to provide iron for therapeutic purposes.
The proposal did not cover liquid or powder forms of iron and did not
bear in any way on conventional foods containing naturally occurring or
added iron. FDA also proposed regulations to require unit-dose
packaging\1\ for iron-containing products\2\ that contain 30 mg or more
of iron per dosage unit.\3\
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\1\ For the purposes of this document ``unit-dose packaging''
means a method of packaging a product into a nonreusable container
designed to hold a single dosage intended for administration
directly from that container, irrespective of whether the
recommended dose is one or more than one of these units.
\2\ Throughout this document, the term ``iron-containing
products'' refers to solid oral dosage forms of both dietary
supplement and drug products.
\3\ In this document, the term ``dosage unit'' is used to denote
the individual physical units of the iron-containing product such as
tablets, capsules, caplets, or other physical forms, irrespective of
whether one or more than one of these physical units comprises the
recommended dose.
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FDA proposed these regulations because of the acute iron
poisonings, including deaths, in children less than 6 years of age
attributable to accidental overdoses of iron-containing products. The
intent of these proposed regulations was to reduce the risk of
accidental iron poisonings of young children by utilizing FDA's
authority in conjunction with the existing requirements of the U.S.
Consumer Product Safety Commission (CPSC) for child-resistant packaging
for household substances. Since the publication of the iron proposal,
FDA has obtained information from the American Association of Poison
Control Centers (AAPCC) that indicates that accidental overdose of
iron-containing products continues to be a problem in young children
(Refs. 1 and 2). In 1994, at least 3,210 children under 5 years of age
were treated in emergency rooms for exposure to iron-containing
products, and two children are known to have died following such
accidental overdose.
The iron proposal responded to citizen petitions submitted by AAPCC
(the AAPCC petition) (Docket No. 91P-0186/CP1) (Ref. 3); the Attorneys
General of 34 States, Commonwealths, and Territories (the AG petition)
(Docket No. 93P-0306/CP1) (Ref. 4); and the Nonprescription Drug
Manufacturers Association (the NDMA petition) (Docket No. 93P-0306/CP2)
(Ref. 5). These petitions requested that FDA take action to ensure that
products containing iron or iron salts do not pose a health hazard to
young children and infants.
In the Federal Register of February 16, 1995 (60 FR 8989), in
response to the Dietary Supplement Health and Education Act of 1994
(DSHEA), FDA published a supplemental proposed rule reflecting a shift
in the agency's authority to establish regulations for dietary
supplements.
The agency received over 100 responses to the iron proposal and the
supplemental proposal with one or more comments each from dietary
supplement, drug, and packaging trade associations; consumers; Federal
and State Government agencies; State attorneys general; poison control
centers; the international community; health care providers; and
dietary supplement and drug manufacturers and packers. Comments on the
proposed requirement for a warning statement on iron-containing
products were generally supportive, although many comments disagreed
with the specifics of the agency's proposed text and requirements for
prominence and placement. Several comments stated that firms already
are including a voluntary warning statement on the label of iron-
containing products. Comments on the proposed requirement for unit-dose
packaging for iron-containing products that contain more than 30 mg of
iron per dosage unit were divided on whether the proposed requirement
was needed to ensure the safety of these products, and several comments
challenged FDA's authority to establish such regulations.
II. Warning Statement for Iron-Containing Products
A. The Proposed Warning Statements
FDA proposed to require label warning statements on iron-containing
dietary supplements and drug products. FDA tentatively concluded that
the warning statements should incorporate elements from both the AG
petition and the NDMA petition, as well as other elements that are
designed to ensure that the statements perform their function.
FDA proposed two warning statements--one statement for use on iron-
containing products packaged in unit-dose packaging and a slightly
different statement for use on iron-containing products packaged in
other than unit-dose packaging, e.g., a container with a child-
resistant closure (CRC).
The proposed warning statement for use on iron-containing products
packaged in unit-dose packaging reads as follows:
WARNING--Keep away from children. Keep in original package until
each use. Contains iron, which can harm or cause death to a child.
If a child accidentally swallows this product, call a doctor or
poison control center immediately.
The proposed warning statement for use on iron-containing products
packaged in other than unit-dose packaging reads as follows:
[[Page 2219]]
WARNING--Close tightly and keep away from children. Contains
iron, which can harm or cause death to a child. If a child
accidentally swallows this product, call a doctor or poison control
center immediately.
Each of these proposed warning statements included a handling
instruction (e.g., ``Close tightly and keep away from children''), an
informational statement (``Contains iron, which can harm or cause death
to a child''), a provisional statement (``If a child accidentally
swallows this product''), and an instructional statement (``Call a
doctor or poison control center immediately'').
B. Focus Group Findings
In order to determine the effectiveness of the proposed warning
statements in alerting consumers to the danger that an accidental
overdose of iron poses to young children, FDA contracted with Macro
International, Inc., to test several different potential warning
messages for iron-containing products in a total of eight focus groups.
A notice of the availability of the focus group report was published in
the Federal Register of May 23, 1995 (60 FR 27321). The notice invited
the public to comment on this report. This focus group research
supported the agency's tentative conclusion, explained in the iron
proposal, that many adults are not aware of the danger that an
accidental overdose of iron poses to young children.
In the focus groups, all participants were presented with an
information piece detailing the danger that an accidental overdose of
iron poses to young children. The information piece contained
statistics that showed that accidental overdoses of iron-containing
products are a leading cause of poisoning deaths in children under the
age of 6, that illness can result from the ingestion of as little as
250 mg of iron in a child weighing 10 kilograms (kg) or less (22 pounds
(lb) or less) and that ingestion of 600 mg of iron has been reported to
be fatal to children weighing 10 kg or less. Half of the eight groups
(``pre-evaluation groups'') received the information piece before they
evaluated the warning messages, and the other half (``postevaluation
groups'') received the information piece after they evaluated the
warning messages. Participants in the postevaluation groups initially
heard only a brief statement about the need for a standardized warning
statement on iron-containing products and heard nothing about the
nature of the hazard posed by an accidental overdose of iron-containing
products or about the number of children who had died. The
postevaluation groups subsequently were given the opportunity to
reevaluate the warning messages after hearing the longer, more detailed
information piece.
Participants in the postevaluation groups found warning messages
such as ``iron can harm or cause death to a child'' to be unnecessarily
severe, to the point that they considered the messages to be bizarre
and unbelievable. The postevaluation groups tended to like a short
generic message that did not identify a specific hazard. In contrast,
participants in the pre-evaluation groups were more accepting of
stronger statements of the hazard and tended to prefer statements that
used the terms ``death'' or ``fatal''--the same statements that the
postevaluation groups thought were unacceptably severe. When
participants in the postevaluation groups were given information on the
nature and magnitude of the hazard subsequent to their evaluation of
the various statements, they evaluated the messages in the same way as
did the pre-evaluation groups. Finally, when asked for their own
suggestions, groups were virtually unanimous in recommending that the
general public be better informed about the dangers of iron-containing
products to young children.
Most participants in the research expressed the opinion that a good
warning statement includes at least three elements: (1) A handling
instruction that the product should be kept out of the reach of or away
from children; (2) an informational statement that the product contains
iron, and that excess or large doses of iron can harm or cause death to
a child; and (3) an instructional statement to call a doctor or poison
control center immediately in case of overdose. Participants' choices
reflected their desire for a concise and unambiguous message with some
degree of quantification about the amount of iron that must be ingested
to be dangerous. Participants differed over the exact contents and
order of the wording for a warning message but agreed that, regardless
of what is eventually contained in the message, it should be worded as
succinctly and efficiently as possible.
The focus group research also provided information on the language
of the handling instruction in the warning statement. The focus group
participants did not recognize a strong connection between the
informational statement and the specific handling instruction that they
were asked to evaluate and were not very positive toward statements
such as ``Keep in original container'' and ``Close tightly.'' They were
generally confused about how to interpret ``Keep in original package
until each use'' with respect to blister-packaged products.
Participants did not know whether the statement meant that they should
keep the product in its original box or in its blister package. The
``Close tightly'' language was seen as too obvious, intended for
products without child-resistant caps or related to product freshness.
The consumer research thus suggests that information about the
nature and magnitude of the danger that accidental overdose of iron-
containing products poses to young children is essential to the
consumer's understanding of the warning statement. It also suggests
that the first sentence of a warning statement is likely to influence a
consumer's decision as to whether to continue reading the rest of the
statement, and that package-specific handling instructions are more
likely to confuse consumers than provide a measure of safety. Finally,
it evidences that consumers will handle these products appropriately
(i.e., by keeping the products in the original package or by keeping a
bottle tightly closed) if they are provided with information on the
nature and magnitude of the hazard.
C. Comments on the Utility and Scope of the Proposed Warning Statements
Several comments suggested that the warning statement should appear
on all iron-containing dietary supplement and drug products rather than
only on solid dosage forms. One comment from a State department of
health services advised the agency that in September, 1993, a 5-year
old child was hospitalized for a serious, though nonfatal, iron
poisoning. The iron involved was in the form of a syrup prescribed for
the victim. The comment stated that the department of health services
did not know how many other children may have suffered injury as the
result of ingesting liquid iron supplements.
The agency appreciates receiving the information about the
accidental ingestion of a liquid iron-containing product. In the iron
proposal, the agency stated that it was not aware of incidents of
poisoning being caused by iron-containing products in liquid or powder
form, and thus, it did not propose to cover liquid or powder forms of
iron-containing products. The agency stated, however, that it would
consider what regulatory action is appropriate to take with regard to
iron-containing products in liquid or powder form if it becomes aware
of information indicating that these products have caused or can cause
poisonings in children.
[[Page 2220]]
The report of a single case in which a child was hospitalized for a
serious, but not fatal, iron poisoning does not justify a change in the
agency's tentative view concerning the need for a Federal regulation
mandating labeling for liquid forms of iron-containing products. A
Federal regulation is appropriate and necessary to protect the public
health when safe use of a product cannot be ensured absent such a
regulation. No regulation, however, will guarantee zero risk from
products regulated by FDA. The existence of a single case report of a
serious poisoning does not establish that illness or injury is likely
to continue to occur. Rather, this single case report creates some
ambiguity. It is not clear based on this report whether poisoning from
liquid iron-containing products is an accident of low frequency or one
that bears careful monitoring. Therefore, in this final rule, the
agency is not including iron-containing products in liquid or powder
form within the coverage of the labeling requirement. However, the
agency would consider extending the coverage of the labeling and
packaging requirements if it receives persuasive information that shows
that accidental pediatric ingestion of liquid or powder iron-containing
products is a problem, and that a warning statement or some special
packaging requirement is necessary to ensure safe use of products that
contain either of these forms of iron.
One comment questioned the usefulness of a warning statement
because children cannot read. One comment stated that dietary
supplement bottles are small, and there is other information competing
for attention. Another comment stated that consumers have become
accustomed to warning statements, implying that warning statements have
become so common that their usefulness is diluted. A comment from a
dietary supplement manufacturer stated that a warning statement on all
products is not necessary and noted that the firm puts warning
statements on products most likely to be attractive to children.
FDA does not agree that a warning statement is not useful because
children cannot read. The warning statement is intended to be read by
adults so that the adults will understand the nature and magnitude of
the problem and the importance of keeping the product out of reach of
children. FDA agrees that some dietary supplement and drug bottles are
small, and that there is other information competing for attention.
Nonetheless, the public health significance of accidental iron overdose
compels that manufacturers overcome limitations in package size, if any
there be. Therefore, FDA expects that industry will make appropriate
revisions to labels on small product containers to provide appropriate
space for the warning statement.
FDA does not agree that a warning statement on iron-containing
products would be diluted because consumers have become accustomed to
such statements. The focus group research shows that consumers want a
strong warning on these products, and that consumers will heed the
warning if provided with information describing the nature and
magnitude of the hazard. FDA disagrees that a warning statement on all
products is unnecessary or only useful on products that are attractive
to children because the seriousness of the consequences of accidental
overdose compel that all products bear the warning. Thus, FDA finds no
merit in these comments.
D. Comments on the Text of the Proposed Warning Statement
FDA received a number of comments requesting modification of the
wording of the proposed warning statements. The comments objected to
the proposed warning statement in three main respects: (1) Failure to
include the concept of ``overdose;'' (2) use of the term ``death;'' and
(3) use of the phrase ``keep away from children.'' In response to these
comments, FDA is revising the text of the wording statement. Table 1 of
this document provides a side-by-side comparison of the text of the
warning statement in the proposed and final rules.
Table 1--Comparison of the Text of the Warning Statement in the Proposed
and Final Rules \1\
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Element of the Statement Text of the Warning Text of the Warning
----------------------------- Statement in the Statement in the
Proposal Final Rule
-------------------------------------------
Warning Warning
------------------------------------------------------------------------
Informational statement..... Contains iron, which Accidental overdose
can harm or cause of iron-containing
death to a child. products is a
leading cause of
fatal poisoning in
children under 6.
Handling instruction........ Keep away from
children. Keep in
original package
until each use.\2\.
[or]
Close tightly and Keep this product
keep away from out of reach of
children.\3\. children.
Provisional statement....... If a child In case of
accidentally accidental overdose
swallows this * * *.
product * * *.
Instructional statement..... * * * call a doctor * * * call a doctor
or poison control or poison control
center immediately. center immediately.
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\1\ The order of the statements in this table is the order of the
statements as they appear in the final regulation.
\2\ For use on unit-dose packages.
\3\ For use on non-unit packages.
1. Informational Statement
Several comments requested that the wording of the warning
statement be changed to refer to ``large doses'' of iron or ``excessive
consumption'' of iron. These comments maintained that the proposed
wording of the warning statements implies that iron is toxic at any
level of intake, even though iron is only dangerous when consumed in
excess. Other comments stated that the warning statements as proposed
may frighten and discourage appropriate use of iron-containing
products. Several comments stated that the essence of the message
should be that ``an overdose of iron could be harmful'' because this
would be more consistent with FDA's stated objective for the warning
statement, which is to ensure that products containing iron or iron
salts do not pose a health hazard to young children and infants.
Another comment cited Sec. 330.1(g) (21 CFR 330.1(g)) as an example of
a regulation that uses the term ``overdose.''
One comment stated that the proposed warning statements appear to
be too general and are misleading to the consumer as to the actual
danger. This comment stated that it would be sufficient to mention that
the products could have the negative effects only in cases of overdose.
FDA has reevaluated the proposed wording of the warning statements
in
[[Page 2221]]
response to these comments and concludes that the proposed wording
implies that iron is inherently toxic and does not inform consumers
about the actual nature of the hazard, i.e., an accidental overdose of
an iron-containing product. Iron itself is an essential nutrient and is
not harmful or fatal unless consumed in large quantities, as may occur
in accidental overdoses. Therefore, a statement informing the consumer
of the dangers of an accidental overdose is a more appropriate
informational statement than those in the proposed warning statements.
The findings of the focus group research support this conclusion.
The focus group participants' preferences reflect a desire for some
degree of quantification about the amount of iron that must be ingested
to be dangerous. The term ``overdose'' conveys a degree of
quantification that makes it unlikely that consumers will mistakenly
infer that usual or prescribed dosages of iron-containing products are
dangerous. For these reasons, the agency is revising the informational
statement to clarify that the hazard is from an accidental overdose of
an iron-containing product.
Several comments requested that the agency not use the term
``death'' in the warning statement because it is unduly alarming and
too harsh and may cause avoidance of iron supplementation by patient
populations already at risk for low iron intake. One comment stated
that ``death'' may frighten or inflame. Another comment stated that use
of the word ``death'' is a departure from most FDA warnings and from
warnings recommended in the citizen petitions.
Some comments suggested replacing the term ``death'' with the
phrase ``harmful or fatal'' because this phrase conveys the danger of
excessive iron while not unduly alarming the general population. A few
comments noted that ``fatal'' is the term in the NDMA voluntary warning
in use on many product labels. One comment cited the agency's
regulations in 21 CFR 101.17(b)(1) (warnings for foods in self-
pressurized containers with hydrocarbon and halocarbon propellants), 21
CFR 201.314 (warning statement on over-the-counter (OTC) drugs
containing salicylates), and 21 CFR 201.319(b) (warning labels on OTC
drugs containing water soluble gums) as precedent for use of the word
``fatal.''
FDA has reevaluated the use of the word ``death'' in this warning
statement in light of these comments. FDA sees no reason to maintain
the term ``death'' if, as the comments contend, it will unduly alarm
consumers, because the term ``fatal'' means ``cause death'' (Webster's
New Riverside University Dictionary, 2d ed., 1988). Therefore, FDA is
revising the informational statement to remove the term ``death'' and
add the term ``fatal.''
As a result of the changes that the agency is making in response to
this and the preceding comment, the revised informational statement
reads: ``Accidental overdose of iron-containing products is a leading
cause of fatal poisoning in children under 6.''
The comments that requested that FDA clarify that the hazard was
associated with an accidental overdose of iron-containing products,
rather than consumption of iron-containing products under intended
conditions of use, made clear that information about the nature and the
magnitude of the danger that accidental overdose of iron-containing
products poses to young children is essential to consumer understanding
of the warning statement. This concept was reiterated by the consumers
who participated in FDA's focus group research. Although participants
in the consumer research were divided over the order of the elements
(informational, handling, provisional, and instructional statements) of
the warning statement, the consumer research supported a conclusion
that the first sentence of a warning statement is likely to influence a
consumer's decision as to whether to continue reading the rest of the
statement. Therefore, in this final rule FDA is changing the sequence
of the sentences in the warning statement so that the informational
statement, which states the nature and magnitude of the danger that
accidental overdose of iron-containing products poses to young
children, precedes the handling instruction.
2. Handling Statement
FDA proposed two different handling instructions based on whether
the iron-containing product was in a unit-dose package or a non-unit-
dose package. FDA has reevaluated the need for, and utility of,
different warning statements depending on the type of packaging. As
already discussed, one of the findings of the focus group research was
that package-specific handling instructions are more likely to confuse
consumers than provide a measure of safety. Moreover, FDA believes that
consumers will handle these products appropriately (i.e., by keeping
the product in the original package or by keeping a bottle tightly
closed) if they are provided with the information on the nature and
magnitude of the hazard. Therefore, in this final rule the agency is
removing the proposed package specific element of the handling
instruction, which necessitated a different warning statement for
products in unit-dose packaging than for products in other than unit-
dose packaging. FDA is revising proposed Sec. 101.17(e)(1) and proposed
Sec. 310.518(b) (now Sec. 310.518(c)) (21 CFR 310.518(c))) to provide a
single required warning statement for all iron-containing supplement
and drug products in solid oral dosage form regardless of the type of
packaging.
A few comments objected to the phrase ``Keep away from children''
and suggested as an alternative the use of the phrase ``Keep out of
reach of children.'' These comments argued that it would be confusing
and inappropriate to say ``Keep away * * *'' on iron-containing
products intended for children, and that the term ``Keep out of reach *
* *'' is a targeted, well understood statement that clearly conveys the
message that children should not be given free access to the product.
FDA has reevaluated the proposed language of the handling statement
``Keep away from children'' and agrees that this statement may imply
that the product is inherently toxic to children. Thus, the statement
would be confusing to consumers when used on a bottle of tablets used
by children. The statement ``Keep out of the reach of children'' states
the proper handling of the product without implying that the product is
inherently toxic under intended conditions of use. Therefore, FDA is
revising the proposed text of the handling instruction to read ``Keep
this product out of reach of children'' rather than ``Keep away from
children.''
Some comments suggested that FDA should require two types of
warning statements based on the level of iron in each dosage unit of
the product. These comments suggested that products containing higher
doses of iron (such as products that contain 30 mg or more of iron) be
required to bear a warning statement, such as the industry voluntary
warning statement, and that products containing lower doses of iron
(such as multivitamin products) be required to bear a more general
warning, such as: ``WARNING: Keep out of reach of children. In case of
accidental overdose, contact a physician or Poison Control Center
immediately.'' The comments asserted that products containing higher
levels of iron are associated with a greater risk than multivitamin-
mineral products. In contrast, most participants in the agency's
consumer research felt that a single warning message should be used on
all iron-containing products regardless of the iron dose.
[[Page 2222]]
Iron-containing products cause injury, including serious injury and
death, when children gain uncontrolled access to them. As discussed in
the iron proposal (59 FR 51030 at 51036), children's vitamins were the
type of product ingested in the majority (45 of 80 or 56 percent) of
the cases of nonfatal pediatric iron ingestion reported to the CPSC
from 1986 to 1993. Further, the amount of iron that may produce
symptoms of iron poisoning (i.e., 25 mg/kg of iron) for a 10 kg child
would be provided by as few as 25 tablets containing 10 mg of iron each
or approximately 14 tablets containing 18 mg of iron each (59 FR 50130
at 51041). Ten and eighteen mg of iron are the amounts typically
contained in children's and adult multivitamin supplements with iron,
respectively.
Ingestion of as little as 650 mg of iron has resulted in death
(Ref. 6). This amount of iron would be supplied by 65 tablets
containing 10 mg of iron or 37 tablets containing 18 mg of iron.
Based on these data, FDA concludes that the potential for poisoning
exists with all iron-containing products in solid oral dosage form,
regardless of the iron content, and that label warning statements are
necessary on all these products. Therefore, the agency is making no
changes in the warning statements in response to these comments.
3. Provisional Statement
As already discussed, several comments maintained that the proposed
wording of the warning statements implies that iron is toxic at any
level of intake, even though iron is only dangerous when consumed in
excess.
The proposed provisional statement: ``If a child accidentally
swallows this product, * * *'' implies that iron, rather than an
overdose of iron, causes the harm. Therefore, FDA is revising the
provisional statement to read: ``In case of accidental overdose, * *
*'' to convey that it is an accidental overdose of iron that requires
attention, rather than an accidental swallowing of any amount of iron.
4. Instructional Statement
Several comments supported FDA's instructional statement to ``call
a doctor or poison control center immediately.'' These comments
concurred with FDA that medical personnel are best equipped to
determine the significance of the dose a child has ingested, and that,
thus, the label should include this instruction.
One comment challenged FDA's proposed instructional statement to
``call a doctor'' and suggested that the instructional statement
provided in the voluntary industry warning to ``seek professional
assistance'' was more appropriate because it was already understood and
accepted when used on OTC products. The comment expressed the opinion
that use of the term ``call a doctor'' would limit the assistance
options for consumers by suggesting that only a doctor could help them.
The comment pointed out that consumers in FDA's focus groups did not
express a strong opinion either in favor of, or in opposition to, the
substitution of the phrase ``call a doctor'' for the common phrase used
on OTC products to ``seek professional assistance.''
FDA realizes that a professional health care provider other than a
doctor could provide assistance to a consumer in the event of
accidental overdose. FDA disagrees, however, that the word
``professional'' accurately conveys the meaning ``medical.'' The
information that the instructional statement must convey is that
consumers should seek medical assistance in the event of accidental
overdose. FDA sees no reason to replace the phrase ``call a doctor''
with the phrase ``seek medical assistance'' because consumers will
understand that ``call a doctor'' implies that they should seek medical
assistance, regardless of whether their customary health care provider
is a doctor or other medical professional, and because ``call a
doctor'' is a more succinct phrase than ``seek medical assistance.''
Therefore, FDA is retaining unchanged the proposed instructional
statement that describes the appropriate action to take when a child
accidentally consumes multiple tablets (``call a doctor or poison
control center immediately'').
5. Comments on the Consumer Research
FDA received only a few comments on the agency's consumer research.
These comments maintained that the consumer research showed that the
agency's proposed warning statement was ineffective.
FDA agrees that the consumer research showed that the proposed
wording of the warning statement was ineffective because the proposed
warning statement did not provide adequate information about the nature
and magnitude of the hazard and did not provide such information before
the handling, provisional, and instructional elements of the warning
statement. However, the revised language of the warning statement (see
Table 1 and discussion below) adequately responds to all the concerns
raised by the comments and the consumer research.
6. Revised Text of the Warning Statement
Based on the findings of the agency's focus group research, the
comments on those findings, and the comments on the proposal, FDA is:
(1) Revising the proposed warning statement by changing the sequence of
the sentences so that the informational statement precedes the handling
instruction; (2) modifying the informational statement so that it
better describes the nature of the hazard; (3) eliminating the two
different handling instructions based on whether the iron-containing
product is in a unit-dose package or a non-unit-dose package; (4)
modifying the handling instruction informing the consumer that children
should not have free access to the product; and (5) including a
reference to overdose in the provisional statement regarding the
instruction on appropriate action in instances where a child
accidentally consumes multiple tablets. FDA is taking this action to
provide consumers with clear and appropriate information on the nature
and magnitude of the hazard and to clarify that the hazard is not
associated with use of iron-containing products under normal
conditions. The revised warning statement reads:
WARNING: Accidental overdose of iron-containing products is a
leading cause of fatal poisoning in children under 6. Keep this
product out of reach of children. In case of accidental overdose,
call a doctor or poison control center immediately.
7. Other Comments on the Text of the Warning Statement
Several comments suggested that FDA adopt the language of the
industry voluntary warning and stated that it is not apparent that
FDA's proposed warning statements provide an additional consumer
benefit over the voluntary NDMA warning statement. One comment
expressed the opinion that FDA's consumer research supported the
positions taken by NDMA regarding labeling of products containing iron
and did not support the warning statements proposed by FDA. The NDMA
voluntary warning statement reads as follows:
WARNING: Close tightly and keep out of reach of children.
Contains iron, which can be harmful or fatal to children in large
doses. In case of accidental overdose, seek professional assistance
or contact a Poison Control Center immediately.
FDA has reviewed the language of the suggested NDMA voluntary
warning statement in light of the focus group research. FDA agrees that
none of the versions of warning statements tested in
[[Page 2223]]
the focus groups performed any better than the industry voluntary
warning statement. However, none of the messages that were tested,
including the industry voluntary warning, performed satisfactorily. The
focus groups perceived the industry voluntary warning statement to be a
standard kind of warning about product toxicity. Because such warnings
are seen frequently on many different kinds of products and provide
little new or useful information, they fail to command much consumer
attention (Ref. 7). The consumer research did not show that the
industry voluntary warning statement effectively conveys to consumers
the nature of the hazard to young children presented by careless
handling and storage of iron-containing products.
The agency's modified warning statement remedies the deficiencies
identified by the consumer research in the tested warning statements,
including the NDMA voluntary warning statement, in two ways. First, the
agency's modified informational statement stresses the nature and
magnitude of the hazard as one of accidental overdose. Second, by
placing the informational statement before the handling instruction,
the modified informational statement will command consumer attention.
In contrast, the key concept of overdose appears at the end of the
informational statement of the NDMA voluntary warning statement:
``Contains iron, which can be harmful or fatal to children in large
doses,'' which diminishes its impact. In addition, the NDMA voluntary
warning statement places the informational statement after the handling
instruction: ``Close tightly and keep out of reach of children,'' where
it will not command as much consumer attention. FDA therefore is not
revising Secs. 101.17 and 310.518 to codify the language of the NDMA
voluntary warning statement.
Several comments provided variations of the agency's proposed
warning statement or the voluntary NDMA warning statement or their own
versions of a suitable warning statement. Examples of these proposed
variations include:
WARNING: Keep all containers of iron-containing products away
from children at all times. Reclose the child resistant cap
completely every time after use. Keep in original package until each
use. Iron-containing products can harm or cause death to a child.
Should you suspect a child has accidentally swallowed an iron-
containing product call a doctor or Poison Control Center
immediately.
WARNING: Keep out of reach of children. Contains iron which can
harm or be fatal to a child in large doses. In case of accidental
overdose, seek professional assistance or contact a poison control
center immediately.
FDA is not accepting any of these suggested statements. All of them
share one or more fundamental problems with FDA's original proposed
statement and the industry warning. Specifically, all of these warning
statements begin with a handling instruction rather than an information
statement. Some fail to incorporate the concept that it is an overdose
of product that is harmful and would therefore lead to the
misconception that iron is inherently harmful. Because all of the
suggested warnings contain one or more fundamental problems, FDA has
rejected these suggested variations.
One comment requested that FDA strengthen the language of the
warning so that it is clearly understood that iron may kill.
FDA has considered this comment and determined that the new
informational statement that it has developed (i.e., ``Accidental
overdose of iron-containing products is a leading cause of fatal
poisonings in children under 6.'') clearly articulates and strengthens
the wording compared to the wording in the proposal. Therefore, FDA
concludes that the concern expressed by this comment is fully
addressed.
A comment from 13 State Attorneys General stated that if the term
``warning'' and the treatment-oriented information (i.e., the
instructional statement) are included on the label in a prominent
manner, then it is not necessary to include a reference to the harm
that can come from ingestion of large doses or reference to the
specific consequences. Other comments stressed the importance of the
term ``WARNING'' and the importance of providing the instructional
reference to contact a poison control center.
FDA agrees that the term ``WARNING'' and the instructional
statement advising that a doctor or poison control center be contacted
are necessary to alert the consumer to the potential consequences of
use of the product and the need to take immediate action. The agency
disagrees, however, that the informational statement is not necessary
when the term ``WARNING'' and the instructional statement are present.
An informational statement provides consumers with the information they
need to readily understand the serious consequences that may result if
the warning is not heeded. Therefore, FDA is taking no action in
response to these comments.
One comment raised the concern that the proposed warning statement
ignores other potential toxicities, such as that caused by an overdose
of vitamin A, and suggested replacing the proposed iron-specific
warning statement with a general cautionary statement in bold print.
The suggested wording of this general cautionary statement was ``KEEP
OUT OF REACH OF CHILDREN. IN CASE OF ACCIDENTAL OVERDOSE, CONTACT A
PHYSICIAN OR POISON CONTROL CENTER IMMEDIATELY.''
The agency is not adopting the suggestion to replace the iron-
specific warning statement with a general warning statement. The agency
has a longstanding policy of limiting the use of warning statements so
that such statements do not become so common that they are ignored. The
label warning statement required on solid oral dosage forms of iron-
containing products is a response to an immediate public health hazard
of large proportions, the deaths and injuries of children who
accidentally consumed large doses of these products. Therefore, the
warning statement is specifically worded to alert consumers to the
presence of iron and to the danger that accidental overdose of iron
poses to young children.
One comment requested that the label warning statement specifically
state that all medicines should be stored in original containers.
As already discussed, FDA has concluded, based on the results of
consumer focus groups, that such specific handling instructions are
more likely to confuse consumers than to provide an additional measure
of safety. Participants in the focus groups were confused about how to
interpret ``Keep in original package until use'' with respect to
blister-packaged products. They did not know whether the statement
meant that they should keep the product in its original box or in its
blister package. Therefore, the agency is taking no action in response
to this comment.
One comment questioned the need for a specific warning message
where general messages already state that supplements and drugs should
be kept out of reach of children, or the packaging itself is child-
safe. This comment added that, given these facts, a specific warning
message would appear to be more trade-restrictive than necessary.
Dietary supplements marketed in the United States are not required
to bear a general warning statement on the label. Drug product labels
are required to bear warnings that are adequate to protect consumers.
As stated in the response to a previous comment, general warning
statements fail to describe the nature of the specific and immediate
hazard of
[[Page 2224]]
accidental iron overdose in young children. Therefore, FDA has
determined that the warning statement specified in this final rule
responds to the known safety concerns associated with solid dosage form
of iron-containing products. The warning statement will apply to both
domestically produced and imported iron-containing products.
In the Agreement on Technical Barriers to Trade from the Uruguay
Round of the multilateral trade negotiations, ``technical regulation''
is defined as a:
Document which lays down product characteristics or their
related processes and production methods, including the applicable
administrative provisions, with which compliance is mandatory. It
may also include or deal exclusively with terminology, symbols,
packaging, marking or labeling requirements as they apply to a
product, process or production method.
Article 2.2 under Technical Regulations and Standards states: ``* *
* technical regulations shall not be more trade-restrictive than
necessary to fulfil a legitimate objective, taking account of risks
non-fulfillment would create. Such legitimate objectives are, inter
alia * * * protection of human health or safety.''
The warning statement for iron-containing products is necessary to
protect the public health by helping to prevent accidental poisoning of
young children. Therefore, the agency concludes that the warning
statement is neither trade restrictive nor a trade barrier.
One comment from a physician recommended placing a ``Mr. Yuk''
sticker or emblem on each bottle of iron-containing tablets because
this label device is recognized by children as an indication of poison.
FDA disagrees with this comment. The ``Mr. Yuk'' sticker alerts
children that the product is not safe to eat. Iron-containing products,
when consumed in appropriate quantities, are safe to eat. Placing a
``Mr. Yuk'' emblem on a product such as a bottle of children's vitamins
would mean that the label would present an inconsistent message that
could confuse children about what is safe to eat and what is not.
Therefore, FDA is not taking the action suggested in this comment.
A few comments requested that the warning statement be accompanied
by a pictograph to readily depict the hazard and to ensure that it will
be readily understood by illiterate or non-English-speaking consumers.
FDA recognizes that a pictograph can be useful to convey some
information to consumers. However, no data were submitted to show that
the message could not be communicated without a pictograph. Given this
fact, FDA finds no basis to require the use of a pictograph. However,
FDA would have no objection if manufacturers, in conjunction with the
required message, used a pictograph (such as a slash line through a
picture of a child with an open mouth reaching for something) in
addition to the required warning statement.
One comment requested that FDA reconsider its position and include
the physical consequences and symptoms that may result from an iron
overdose on the product package or container. This comment stated that
adults will readily understand consequences and take effective action
to eliminate the risk of an accidental child poisoning based on this
information.
In the iron proposal (59 FR 51030 at 51044), FDA stated that it
feared that setting out this information could lead parents to conclude
erroneously that the child is not in danger because he or she does not
exhibit one of the listed symptoms. No information was submitted in
this comment that would cause the agency to reach a different
conclusion. Listing of symptoms is irrelevant because they may not be
exhibited by a child, and the most important information is that an
overdose may be fatal. Moreover, as discussed above, FDA has revised
the warning statement to include an informational sentence describing
the nature of the hazard and providing adults with information to
motivate them to eliminate the risk. Therefore, FDA is taking no action
in response to this comment.
One comment requested that FDA require that the labeling of all
iron-containing products display the exact name of the iron ingredient
instead of the equivalent amount of iron present in the product. The
comment added that this information is extremely important to the
medical professionals and emergency personnel who treat iron
poisonings.
No action is necessary in response to this comment because this
information is already required on the label of food products
containing iron under 21 CFR 101.4(b), which requires that the ``name
of an ingredient must be a specific name and not a collective (generic)
name.'' For dietary supplements containing iron, the ingredient list
must include the source of the iron (e.g., ferrous sulfate). In
addition, the amount of iron must also be provided in the nutrition
labeling.
For drug products containing iron, section 502(e) of the Federal
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 352(e)) and 21 CFR
201.10 require a label statement of a drug's established name and the
established name and quantity of the product's active ingredients.
E. Appearance of the Warning Statement on the Label of Iron-Containing
Products
FDA proposed in Secs. 101.17(e)(2) and 310.518(b)(3) to require
that the warning statement:
* * * appear prominently and conspicuously on the immediate
container labeling in such a way that the warning is intact until
all of the dosage units to which it applies are used. In cases where
the immediate container is not the retail package, the warning
statement shall also appear prominently and conspicuously on the
principal display panel of the retail package. In addition, the
warning statement shall appear on any labeling that contains
warnings.
1. Comments on Requiring the Warning Statement to Appear Prominently
and Conspicuously on the Immediate Container Labeling
Several comments on the labeling aspects of the proposed rule
opposed or questioned the agency's tentative conclusion that the
warning statement should be placed on the principal display panel (the
PDP) in order to be prominent and conspicuous. Many of these comments
noted that warnings on consumer products are generally located together
on the side or back panel, and that consumers are accustomed to finding
warning information in these places. One comment argued that placing
the warning statement on the PDP negates the purpose of the information
panel (the IP) because the traditional location for warning statements
is the IP, and consumers may overlook a warning statement that is not
in the expected location.
One of the comments elaborated upon warning placement by noting
that warnings for self-pressurized containers and self-pressurized
containers with halocarbons, hydrocarbon propellants, or
chlorofluorocarbon propellants are not mandated to appear on the PDP
(Sec. 101.17 (a), (b), and (c)). The regulations for foods containing
aspartame also do not require that the warning statement for
phenylketonurics appear on the PDP (21 CFR 172.804(e)(2)).
Most of the participants in the focus groups believed that the
warning statement should go on the back of the product rather than the
front of the product. The participants reasoned that the front of the
product was used for marketing purposes, and consumers
[[Page 2225]]
were used to looking at the back of the product for warnings. The focus
groups also felt that the ``clutter'' on the front of the product label
might dilute the warning message. Similarly, several comments pointed
out that the placement of the warning statement on the PDP would
overcrowd an already space-limited PDP and result in a diluted warning
message, especially if a smaller type size was used.
The agency recognizes that the PDP space is often very limited, and
that warnings plus other required information could crowd the PDP.
Therefore, in deciding how to provide for placement of the warning, the
agency reflected on two basic questions: (1) What is the intent of this
regulation? and (2) Can the intent be met by placing the warning
statement on a panel other than the PDP?
The agency's purpose in this rulemaking is to inform consumers of
the dangers to small children from an accidental overdose of a product
that contains iron. Because of the serious, life-threatening
consequences of such an overdose, FDA tentatively concluded that
warning statements are most likely to be read when they are placed on
the PDP. This tentative conclusion followed the precedent established
in the regulations requiring warning statements on the PDP of protein
products (Sec. 101.17(d)), whose incorrect use can also result in dire
health consequences.
However, after evaluating the above comments and the results of the
focus groups, the agency agrees that the warning statement does not
need to be placed on the PDP to be effective in informing consumers of
the hazard associated with overdose. The intent of the regulation can
be met by placing the warning statement on the IP. The IP is the
traditional location for warning statements. Information on the IP is
readily accessible to consumers, particularly when it is presented in
accordance with graphical requirements that enhance its prominence (see
discussion below). Therefore, in this final rule the agency is revising
proposed Secs. 101.17(e) and 310.518(b) (now Sec. 310.518(c)) to
require that the warning statement be placed on the IP of the immediate
container label.
Several of the comments remarked that the proposal did not require
that the warning statement be placed on the PDP of the immediate
container if the immediate container was not the retail package.
In the iron proposal (proposed Secs. 101.17(e)(2) and
310.518(b)(3)), the agency proposed to require that: (1) The warning
statement appear on the immediate container labeling; (2) it appear in
such a way that the warning is intact until all of the dosage units to
which it applies are used; and (3) if the immediate container is not
the retail package, the warning statement must appear on the PDP of the
retail package. FDA proposed these requirements as a single regulation
that would apply to products in unit-dose packaging, in which the
immediate container labeling does not have a PDP, as well as products
in other than unit-dose packaging, in which the immediate container
label does have a PDP. The comments that deduced that the proposed
regulation did not require that the warning statement be placed on the
PDP of the immediate container label if the immediate container was not
the retail package indicate that the language of that single regulation
did not clearly articulate the agency's intent, i.e., that the warning
statement be on both the PDP of the retail package and the immediate
container label, if there is one.
Therefore, FDA is revising Secs. 101.17(e) and 310.518(b) (now
Sec. 310.518(c)) to clarify where the warning statement must be placed.
Specifically, FDA is splitting the applicable provisions into several
subparagraphs, which are described below. In addition, the agency has
revised the regulations, as already discussed, to require that the
warning statement appear on the IP rather than on the PDP.
In this final rule, Secs. 101.17(e)(2)(i) and 310.518(c)(2)(i)
require that the warning statement for iron-containing dietary
supplements and drugs appear ``on the information panel of the
immediate container label.'' Sections 101.17(e)(2)(ii) and
310.518(c)(2)(ii) provide that if iron-containing supplements and drugs
are packaged in unit-dose packaging, and if the immediate container
bears labeling,\4\ but not a label, the warning statement must appear
``on the immediate container labeling.'' Sections 101.17(e)(3) and
310.518(c)(3) require that, where the immediate container is not the
retail package, the warning statement for all iron-containing dietary
supplements and drugs (i.e., regardless of the manner in which the
product is packaged) appear ``prominently and conspicuously on the
information panel of the retail package label.''
---------------------------------------------------------------------------
\4\ FDA recognizes that the package liner of a unit-dose package
that bears no printed material is not labeling and would not need to
bear the warning statement. Given the importance of the warning, FDA
hopes that this fact will not cause manufacturers to cease putting
printed material on the package liner.
---------------------------------------------------------------------------
These requirements are necessary to ensure that the warning
statement is seen by adults with responsibility for proper storage of
the product. The placement of the warning statement on the retail
package label will make it likely that the warning statement will be
seen at the time the product is purchased to inform the purchaser of
the product's potential to cause poisoning and of the need to store the
product properly when it is brought into the house. However, under
customary conditions of use, the retail container is frequently
disposed of, and individuals other than the purchaser may use the
product. Therefore, FDA is providing that the immediate container also
bear the warning if it bears any labeling at all.
In this final rule, Secs. 101.17(e)(4) and 310.518(c)(4) provide
that the warning statement shall also appear on any labeling that
contains warnings. These requirements are unchanged from the proposal,
but they have been moved to a separate subparagraph as part of the
overall reorganization of Secs. 101.17(e)(2) and 310.518(c)(2).
2. Comments on Prominence Through Graphical Requirements
Several comments discussed the use of graphic requirements to set
the warning statement apart from the rest of the label information. One
comment pointed out that a warning statement can be made prominent and
conspicuous by graphics such as surrounding the warning statement with
a box, printing the warning statement in capital letters, printing the
warning statement in bold typeface, and using contrasting graphics.
Several comments recommended that the agency set requirements for
graphics and discussed the need for type size specifications. Another
comment suggested that FDA let the manufacturers determine the elements
of prominence and conspicuousness needed to call attention to the
warning statement. One comment cited the saccharin warning requirements
as an example of a warning statement with specific contrasting graphic
requirements.
Most of the participants in the focus groups agreed that the
warning statement should be in a boxed area to separate it from other
information and to call attention to the warning. Many participants
also felt that printing the warning statement in a color that contrasts
with the predominant color of the packaging was eye-catching. Other
graphical options considered by the focus groups included using
contrasting
[[Page 2226]]
print and background, different sizes of print, and bolding of the
message.
In the iron proposal, FDA tentatively concluded that graphical
requirements were not necessary to ensure that a warning statement
placed on the PDP is prominent and conspicuous, because no data were
supplied by the petitioners to support the use of graphics in the
warning statement, and because the protein products regulation that the
agency used as a precedent did not mandate specific graphical
requirements. However, as discussed above, in this final rule the
agency is moving the location of the warning statement from the PDP to
the IP. The agency agrees that use of certain graphical requirements is
an effective approach to ensuring that the warning statement is
prominent and conspicuous. Moreover, a warning statement that appears
on the IP, rather than on the PDP, needs graphical enhancements to
ensure that it is prominent and conspicuous because the IP generally is
more crowded than the PDP.
Based on the comments and the results of the consumer research, the
agency agrees that a box enclosing the warning statement will set the
warning statement apart from the rest of the label. FDA has used this
mechanism with the nutrition label in response to the directive in the
Nutrition Labeling and Education Act of 1990 (the 1990 amendments) that
the label be readily observable (Pub. L. 101-535, section 2(b)(1)(A) of
the 1990 amendments). Therefore, the agency is requiring, in
Secs. 101.17(e)(5) and 310.518(c)(5), that the warning statement for
iron-containing products be separated from other information by a box.
Manufacturers may use other graphics, in addition to the box, if they
choose to do so.
Three comments suggested that the cap or the PDP of the product
bear a symbol or statement informing consumers that a new warning has
been placed on the IP. For example, a prominent flag or a short
statement saying ``See Iron Warning'' or ``See New Warning'' could be
printed prominently on the PDP.
FDA has decided not to require a flag or statement alerting
consumers to the new warning label. The comments and the results of the
consumer research have convinced the agency that consumers are already
in the habit of looking at the IP for important information such as
warnings, and the box around the warning statement will draw attention
to it.
3. Comments on the Placement of the Warning Statement on Unit-Dose
Packaging.
To reinforce the message of the warning after the product is in the
home, FDA proposed (proposed Secs. 101.17(e)(2) and 310.518(b)(3) (now
Sec. 310.518(c)(3))) to require that the mandatory warning statement
appear on the immediate container labeling in such a way that it is
intact until all of the dosage units to which it applies are used. This
provision would have effectively required that unit-dose packaged
products bear the warning either directly on each individual cavity of
the unit-dose packaging or on some section of the unit-dose packaging
in such a way that separating an individual cavity would not destroy
the warning label.
FDA received several comments on this proposed requirement.
Comments stated that the proposal was unclear as to whether the warning
could appear along the full length of a strip of unit-dose packaging,
or whether it must appear in its entirety on each unit dose (e.g., on
each tablet in a blister pack). Several comments stated it would be
physically impossible to place the entire lengthy warning proposed by
FDA on each unit dose and still meet the minimum type size requirements
of 21 CFR 101.2(c) or the requirements of 21 CFR 101.15(a)(6) that the
labeling be prominent and conspicuous. One comment stated that the
label space available for each cavity of a multipack blister type unit-
dose package is usually less than 1/2 inch by 1/2 inch and if, as
proposed, a firm is required to print the entire warning statement, the
print size would be so small that it would require magnification to
read.
Several comments suggested that the individual units of a unit-dose
package be permitted to bear an abbreviated warning statement that
alerts consumers to the hazard and preventive measures, such as: (1)
``WARNING--Contains Iron. Keep Away From Children;'' and (2) ``WARNING:
Keep in Original Package Until Each Use. Keep Away from Children.'' One
comment also suggested that it would be helpful to manufacturers if FDA
specified that the abbreviated warning could be printed on a strip or
tab either above or below the individual cavities.
FDA is requiring that the warning must appear on the immediate
container of the product because, as discussed in the proposal in this
proceeding, reports of 2,000 poisonings in children over approximately
7 years provides strong evidence that many adults are not aware of the
potential for serious harm posed by iron-containing products. The
agency understands that printing the entire warning statement on each
unit dose of an iron-containing product, while necessary to ensure that
the warning statement remains intact until all of the individual dosage
units to which it applied are used, would present problems in making
the warning ``prominent and conspicuous.'' FDA disagrees, however, that
placing an abbreviated warning statement on each cavity of a unit-dose
package would be effective in alerting consumers to the risk that iron-
containing products poses to young children because, as discussed
above, FDA has concluded that an informational statement that clearly
communicates the nature and magnitude of the hazard is essential for
the warning statement to be effective. Therefore, the agency has
reconsidered how to achieve the intent of the proposed regulations
without requiring that the warning statement remain intact until all of
the dosage units to which it applies are used.
FDA notes that, if for example, the full warning statement were
placed on any side of a package (i.e., above, below, or on either side
of individual cavities) of iron-containing products in unit-dose
packaging that contains multiple, individual unit-dose packages that
are connected without physical delineations (e.g. perforations) between
the individual unit-dose packages, would allow the warning to remain
intact until all of the dosage units to which it applies are used.
Similarly, for iron-containing products in any unit-dose packaging
(i.e., with or without physical delineations between the individual
unit-dose packages), multiple copies of the warning statement across
the immediate container label would increase the likelihood that at
least one complete warning statement will remain intact until most of
the individual units have been used. Although this second option could
not ensure that the warning statement would remain intact until all of
the dosage units to which it applies have been used, it is clear that
options such as this can approach, if not fully achieve, the desired
outcome of the proposed regulations.
Therefore, in this final rule, FDA is revising
Sec. 101.17(e)(2)(ii) to read:
If a product is packaged in unit-dose packaging, and the
immediate container bears labeling, the statements required by
paragraph (e)(1) of this section shall appear prominently and
conspicuously on the immediate container labeling in a way that
maximizes the likelihood that the warning is intact until all of the
dosage units to which it applies are used.
[[Page 2227]]
FDA also is revising Sec. 310.518(c)(2)(i) to include a parallel
requirement. The revised wording of these regulations makes clear that
the manufacturer bears the responsibility to show diligence in
designing labeling that will meet the agency's goal of informing
consumers of the dangers to small children from an accidental overdose
of a product that contains iron but provides the manufacturer with
flexibility in determining how it will do so.
4. Comments Specific to Prescription Drug Products
One comment suggested that the warning statement on prescription
drug products, if placed on a label, should contain a message to the
pharmacist not to cover the warning with the prescription label so that
the warning remains visible to the consumer.
FDA believes that the comment raises an important point. However,
the agency expects that pharmacists will be aware that warnings should
not be covered by anything, not by a price tag, a pharmacy label, or
anything else. Therefore, FDA is taking no action in response to this
comment.
III. Packaging of Iron-Containing Products
FDA also proposed to require unit-dose packaging of iron-containing
drugs and dietary supplements with potencies of 30 mg or more of iron
per dosage unit. FDA tentatively concluded that unit-dose packaging of
such products would contribute in a significant way, over and above the
protection provided by warning statements and CRP's, to reduce
children's access to potentially fatal doses of iron.
A. FDA's Legal Authority to Establish Packaging Requirements for Iron-
Containing Products
Several comments questioned FDA's legal authority to establish
regulations requiring packaging of dietary supplements and drugs. The
comments argued that Congress never authorized, and never intended, FDA
to have such authority under the act. Moreover, these comments
contended that even if FDA previously had such authority, Congress
transferred this authority from the Secretary of Health, Education, and
Welfare (HEW) (now Health and Human Services) to the CPSC under the
Poison Prevention Packaging Act (PPPA) (15 U.S.C. 1471 et seq.) when
that agency was created.
These comments argued that the language of both the PPPA and the
act are clear in expressing Congress' intent that FDA was not granted
authority over the packaging of foods or drugs to prevent childhood
poisonings. These comments contended that through passage of the
Consumer Product Safety Act (Pub. L. 92-573) (CPSA), Congress intended
that CPSC have exclusive jurisdiction over packaging to limit child
access to poisonous substances. These comments noted that in enacting
the CPSA, Congress transferred from the Secretary of HEW to CPSC
certain functions under the Federal Hazardous Substance Act (HSA) (15
U.S.C. 1261 et seq.) and the PPPA. In addition, in enacting the CPSA,
Congress transferred the administrative and enforcement functions of
the PPPA from the Secretary of HEW to CPSC (15 U.S.C. 2079).
FDA disagrees with the comments' interpretation of the provisions
of the laws in question. As discussed in the iron proposal and the
supplementary proposal, FDA's authority to require unit-dose packaging
of iron-containing dietary supplements and drugs derives directly from
sections 402(a)(4) and (g) and 501(a)(2)(A) and (a)(2)(B) of the act
(21 U.S.C. 342(a)(4) and (g) and 21 U.S.C. 351(a)(2)(A) and (a)(2)(B)).
The existence of other laws to which foods and drugs are subject does
not limit FDA's authority to fulfill its responsibility under the act
to help ensure that foods, including dietary supplements, and drugs are
not injurious to health.
FDA disagrees with the comments that asserted that the agency has
no authority over how food is packaged. This claim is belied by the act
itself. Section 409 of the act (21 U.S.C. 348), although not applicable
to this rulemaking, gives FDA authority to prescribe the conditions
under which a food additive may be safely used, including packaging
requirements deemed necessary to ensure the safety of such use (section
409(c)(1)(A) of the act). Section 721(b)(3) of the act (21 U.S.C.
379e(b)(3)) provides similar authority for color additives.
More relevant to this rulemaking, sections 402(a)(4) and
501(a)(2)(A) of the act provide that a food or a drug is adulterated if
it has been packed under insanitary conditions whereby it may have been
rendered injurious to health. Section 402(a)(4) has been read broadly
(see United States v. Nova Scotia Food Products, Corp., 568 F.2d 240,
247 (2d Cir. 1977)) as a grant of authority to ensure that foods are
not packed in a manner, including process, package design, and
packaging materials, that creates the possibility that the foods will
cause harm under their reasonably foreseeable conditions of use. For
example, parts 108, 113, and 114 (21 CFR parts 108, 113, and 114)
address the steps necessary to ensure that the packaging of low acid
and acidified foods does not permit the outgrowth of botulism, whose
presence in the food would render the food injurious to health. Part
110 (21 CFR part 110) defines current good manufacturing practice
(CGMP) for food generally, and in Sec. 110.80(b)(13) requires that
packaging be done in a manner that protects the food against
contamination and that ensures that safe and suitable packaging
materials are used (see also Sec. 110.5(a)(2)). These provisions
provide authority for the agency to require the use of packaging that
is designed to help ensure that dietary supplements that contain 30 mg
or more of iron per dosage unit are not rendered injurious to health.
FDA is aware of no reason why section 501(a)(2)(A) of the act, which
contains virtually the same words as section 402(a)(4) of the act,
should not be read equally as broadly.
Section 501(a)(2)(B) of the act provides that a drug is adulterated
if the methods used in, or the facilities or controls used for, its
manufacture, processing, packing, or holding do not conform to, or are
not operated in conformity with, CGMP to ensure that such drug meets
the requirements of the act as to safety and has the identity and
strength, and meets the quality and purity characteristics which it
purports or is represented to have. The agency has determined that,
under section 501(a)(2)(B) of the act, manufacturers are responsible
for preventing certain foreseeable misuse of a drug product. A drug
product may be safe and effective as manufactured, but used in an
unsafe and ineffective manner. As discussed earlier, data demonstrate
that the current manner of holding products that contain 30 mg or more
of iron per dosage unit until their use by the intended consumer fails
to ensure that the products will be safe (see 59 FR 51030 at 51033).
Large numbers of children are ingesting such products and suffering
serious injuries and death. Because unit-dose packaging technology is
available and can reduce the danger of iron poisoning, CGMP dictates
that such packaging be used for products containing more than 30 mg of
iron per dosage unit.
FDA concludes that unit-dose packaging will significantly reduce
the likelihood of serious injuries to young children. FDA finds that
this will be the case because unit-dose packaging will limit the number
of unit doses that a child may consume once it gains access to the
product, not because unit-dose packaging will make it any more
[[Page 2228]]
difficult to open the package.\5\ The fewer the number of tablets or
capsules the child consumes, the smaller the dose of iron the child
will ingest. The smaller the dose, the lower the risk that the child
will suffer serious injury. Thus, FDA's unit-dose packaging requirement
will significantly limit the likelihood that iron products containing
30 mg or more of iron per dosage unit may be injurious to health
because the requirement that the child open each package unit will
limit the amount of iron that the child can consume (see 59 FR 51030 at
51049). No comments provided any information to the contrary.
---------------------------------------------------------------------------
\5\ Given CPSC's child resistance requirements, FDA's action
will have no effect on how difficult it is to open the package.
---------------------------------------------------------------------------
The CPSA, HSA, and PPPA do not prevent FDA from acting. Foods and
drugs are neither consumer products (see 15 U.S.C. 2052(a)(1)(H) and
(a)(1)(I)) nor hazardous substances (see 15 U.S.C. 1261(f)(2)). Thus,
the CPSA and HSA are not relevant to this rulemaking. FDA's action is
also not precluded by the PPPA because FDA is not establishing a
special packaging performance standard for products that contain 30 mg
or more of iron per dosage unit. As explained above, nothing in FDA's
regulation is designed to define or modify what constitutes child-
resistance for iron-containing products. In this rulemaking, FDA is
defining the requirements of CGMP for these products to help ensure
that they are not packed under conditions whereby they may be rendered
injurious to health (sections 402(a)(4), 402(g)(2), and 501(a)(2) of
the act). Such action is fully within FDA's authority under the act.
Therefore, FDA finds no merit to these comments.
Several comments argued that section 402(f) of the act makes clear
that FDA has the burden of demonstrating that any particular dietary
supplement is adulterated or unsafe under the conditions of use
recommended or suggested in the labeling, or in the absence of such
labeling, under ordinary conditions of use. These comments contended
that FDA cannot merely assert that a dietary supplement is no longer
safe because of the form of packaging in which it is sold. Moreover,
these comments contended that FDA must find, for each product, that
under the recommended conditions of use, the product presents a
significant or unreasonable risk of illness or injury.
FDA disagrees with these comments. The DSHEA, which added section
402(f) to the act, did not exempt dietary supplements that are foods
(that is, e.g., that are not intended to prevent, cure, treat, or
mitigate a disease) from the food provisions of the act (see section
201(ff) of the act (21 U.S.C. 321(ff))). Under the act as amended by
the DSHEA, a dietary supplement that is a food is adulterated if it is
prepared, packed, or held under insanitary conditions whereby it may
have become contaminated with filth, or whereby it may have been
rendered injurious to health (section 402(a)(4) of the act). This
situation is the one that FDA is addressing in this rulemaking.
Moreover, section 402(g)(2) of the act specifically authorizes FDA to
adopt good manufacturing practice regulations for dietary supplements.
FDA is relying on this provision of the act, as well as sections
402(a)(4) and 701(a) of the act (21 U.S.C. 371(a)), in adopting the
unit-dose packaging requirement for dietary supplements that are foods
that contain 30 mg or more of iron per dosage unit.
The agency received a comment from the CPSC requesting that FDA
amend its proposed regulations to clarify that iron-containing products
conforming to FDA's regulation are subject to compliance with certain
regulations issued by the CPSC.
In light of the desire of both the CPSC and FDA to ensure that
manufacturers of iron-containing products comply with both CPSC's
regulations for child-resistant special packaging and FDA's CGMP
regulations for iron-containing products, in this final rule FDA is
revising proposed Secs. 111.50 (21 CFR 111.50) and 310.518(a) to make
clear that products subject to these regulations are also subject to 16
CFR parts 1700, 1701, and 1702.
B. Effectiveness of Unit-Dose Packaging
The agency received a number of comments bearing on the
effectiveness of unit-dose packaging to limit pediatric access to
products. The majority of these comments expressed support for FDA's
tentative conclusion that unit-dose packaging will effectively limit
pediatric access to products. A few comments challenged this tentative
conclusion. None of these comments provided data to support their
views.
One comment expressed the view that unit-dose packaging would not
be effective because such packaging is subject to compromise. Another
comment contended that the child-resistant effectiveness of child-
resistant unit-dose packaging is not absolute (i.e., because the CPSC
specification is based on the number of units that a child is able to
access in a period of time) in contrast to the effectiveness of CRC
type packaging (i.e., in which the CPSC regulations specify that
opening the closure within a period of time constitutes failure of the
system).
FDA recognizes that unit-dose packaging, like all packaging, can be
compromised, and that packaging in and of itself cannot make a product
safe. However, based on information available to the agency (Refs. 8
and 9) and as discussed in the iron proposal (59 FR 51030 at 51049),
unit-dose packaging, even conventional unit-dose packaging, limits
pediatric access to multiple dosage units of product. Moreover, the
effectiveness of unit-dose packaging to limit pediatric access to
product is not dependent on proper reclosure of the packaging. In
contrast, the effectiveness of closure type packaging to limit
pediatric access is dependent on proper reclosure of the container. If
the closure is compromised (i.e., opened, improperly reclosed, or
damaged), all of the contents of the package are readily available for
ingestion. FDA's concern is limiting the possibility that the product
will be injurious to health. Unit-dose packaging, even conventional
unit-dose packaging, will help to accomplish this end by limiting the
amount of iron that a child can consume in a short period of time.
Therefore, FDA finds that the comments provide no basis for modifying
its approach to the problem of acute iron poisoning in young children.
C. Access to Products by Certain Persons
The agency received several comments bearing on the potential
difficulty that some elderly and handicapped persons may have in
gaining access to products in unit-dose packaging. For example, one
comment noted that unit-dose packaging may limit access to products by
persons with rheumatoid arthritis. Two comments expressed their view
that unit-dose packaging is inconvenient. Another comment expressed the
view that for adults with limited dexterity, conventional unit-dose
packaging is not difficult to open. None of these comments provided any
data or information to support their views.
A comment from CPSC noted the difficulty in assessing the extent to
which elderly or handicapped persons may be hampered in accessing
product packaged in conventional unit-dose packaging, because there are
no ``accessibility'' standards for conventional unit-dose packaging. In
their comment, CPSC provided a report of their study examining the
accessibility of child-resistant and conventional unit-dose packaging
with seniors, aged 60 to 75 years old. CPSC
[[Page 2229]]
reported that all four child-resistant unit-dose package types passed
the senior accessibility test criteria. Moreover, all 100 seniors
tested were able to open the conventional unit-dose packaging.
In the iron proposal and the supplemental proposal, FDA anticipated
the practical effect of the combination of new Secs. 111.50 and
310.518(a) and CPSC's child-resistant packaging regulations for iron-
containing drugs and dietary supplements, 16 CFR 1700.14(a)(12) and
(a)(13), respectively. Manufacturers and distributors of drugs and
dietary supplements containing 30 mg or more of iron per dosage unit
and containing 250 mg or more of total iron per package will have two
options. One option will be to package their product in child-resistant
unit-dose packaging (e.g., child-resistant blisters, child-resistant
pouches, or other child-resistant packaging that accomplishes the
objective of making a single dosage unit available at a time). A second
option will be to package their product in conventional unit-dose
packaging through exercising their right to an exemption to CPSC's
special packaging regulations as required by the PPPA.
FDA notes that since publication of the iron proposal, CPSC has
amended its regulations in 16 CFR part 1700 (60 FR 37710, July 21,
1995) for testing the child-resistant effectiveness of packaging to
require a senior adult use effectiveness of not less than 90 percent
for a senior adult test panel consisting of 100 adults aged 50 to 70
years old. The intent of these amendments is to increase the use of
child-resistant packaging by making it easier for adults to use them
properly.
It is not FDA's intent to circumvent the aim of the PPPA to allow
access by elderly and handicapped persons who may be unable to use
household substances packaged in child-resistant packaging. However, in
the absence of information to the contrary, FDA has no basis to
conclude that iron-containing products packaged in conventional unit-
dose packaging will unduly limit elderly or handicapped persons' access
to such products. Therefore, FDA concludes that unit-dose packaging
does not limit access to product by elderly or handicapped persons.
D. False Sense of Security
Two comments expressed their view that unit-dose packaging should
not be required for products containing 30 mg or more of iron per
dosage unit because such a requirement will provide a false sense of
security and will not limit pediatric access to product.
FDA recognizes that no single approach is adequate to ensure the
safe use of iron-containing products. However, a combination of
educational programs, label warning statements, and packaging measures
can reasonably be expected to be effective in reducing significantly
the incidence of poisonings. As discussed in the iron proposal, FDA is
sponsoring educational efforts to better inform health care providers
and consumers of the risks presented by iron-containing products, and
FDA is requiring label warning statements to provide information to
consumers about the hazards to young children presented by iron-
containing products. These two approaches will effectively alert health
care providers and consumers to the hazards presented by iron-
containing products. Moreover, contrary to the comments' contention
that these measures, including unit-dose packaging, will provide a
false sense of security, these measures more likely will support a
heightened sense of concern. Persons informed of the pediatric hazard
presented by iron-containing products will take extra measures to
ensure that the products are handled appropriately, including ensuring
that the unit-dose packaging is not compromised in any way. Therefore,
FDA finds no merit in these comments.
E. CRC is Adequate
One comment expressed the view that CRC packaging is adequate for
limiting pediatric access to a toxic amount of iron.
As discussed in the iron proposal, based on information available
to the agency, misuse of CRC type packaging is one contributing factor
to pediatric iron poisonings. For example, in 21 of the 26 pediatric
iron poisoning deaths in which the type of packaging was reported, the
product was packaged in CRC type packaging (Ref. 10). In the absence of
information indicating that misuse of closure type packaging will no
longer occur and in light of the potentially fatal consequences when a
young child gains access to a lethal amount of iron, FDA is not
persuaded that CRC type packaging is adequate to ensure that these
products are packaged under conditions that are not injurious to
health.
Another comment expressed the view that: ``FDA's current effort to
go beyond the CPSC requirement for child-resistant closures with
respect to iron-containing supplements should be viewed as an anomaly
and not as a failure of the CRC system.''
The agency disagrees with the view that this rulemaking is an
anomaly. Rather, FDA considers that this rulemaking is a special
measure in response to a special circumstance, i.e., the large number
of acute iron poisonings, including death in children less than 6 years
of age, attributable to accidental overdoses of iron-containing
products. FDA will continue to exercise its legal authority to fulfill
its legislative mandate to ensure that foods, including dietary
supplements, and drugs are not injurious to health.
Nonetheless, FDA agrees that this rulemaking should not be viewed
as a failure of the CRC system. The agency notes that it is
establishing additional packaging requirements only for products that
contain 30 mg or more of iron per dosage unit because of the
irreversible and potentially fatal consequences presented by these
higher dose iron-containing products rather than because of a view that
the CRC system has failed in any way.
F. Difficulty in Making Child-Resistant Unit-Dose Packaging
One comment stated that it is more difficult to make a child-
resistant unit-dose package that is accessible and acceptable to adults
than to make a conventional unit-dose package. The comment further
noted that this difficulty was the reason why so few highly toxic
products in the market were packaged in a unit-dose package.
FDA is not establishing packaging performance standards, child-
resistant or otherwise, for iron-containing products in this
rulemaking. Such standards are the responsibility of the CPSC. Rather,
FDA is establishing these packaging requirements as a matter of good
manufacturing practice to ensure that dietary supplements and drugs
that contain 30 mg or more of iron per dosage unit are not packed under
conditions whereby they may be rendered injurious to health. Therefore,
FDA finds that the comment is not relevant to this rulemaking.
G. Alternative Approaches
Two comments recommended that all iron-containing drugs and dietary
supplements be packaged in child-resistant unit-dose packaging to
ensure that they are inaccessible to young children.
As discussed in the proposal, information available to FDA
demonstrates that the iron-containing products presenting the greatest
hazard to young children are those that contain 30 mg or more iron per
dosage unit. As discussed above, FDA has concluded, based on the
available evidence, that label warning statements and educational
efforts are adequate to
[[Page 2230]]
address the problems with products containing less than 30 mg of iron
per dosage unit, and that label warning statements, educational
efforts, and unit-dose packaging are necessary to ensure that products
containing 30 mg or more of iron per dosage unit are packaged under
conditions that are not injurious to health. Therefore, the agency is
rejecting this recommendation.
One comment recommended that, rather than requiring unit-dose
packaging of products containing 30 mg or more of iron per dosage unit,
FDA should limit the total number of dosage units allowed per package
based on the amount of iron that is toxic. No specific upper limit on
the total iron to be allowed per container was provided in this
comment.
FDA notes that CPSC has taken an approach similar to that suggested
by the comment by requiring child-resistant special packaging if the
packaging contains more than 250 mg of total iron. In the iron
proposal, FDA discussed the amount of ingested iron that is lethal to
young children (i.e., to a 10 kg child) and noted that an acute
ingestion of 25 mg/kg of iron may produce symptoms of poisoning, 60 mg/
kg of iron may develop into clinically significant iron poisoning, and
250 mg/kg of iron may well be lethal for a young child. Because the
comment did not specify an upper limit on the total iron to be allowed
in the container, FDA will address the comment based on an upper limit
of 250 mg of iron (i.e., the amount of iron that may produce symptoms
of poisoning).
If FDA were to limit the total number of dosage units in a
container based on 250 mg of iron, then a manufacturer would be able to
provide up to 8 dosage units of a product containing 30 mg of iron per
dosage unit (240 mg of total iron), or 3 dosage units of a product
containing 65 mg of iron per dosage unit (195 mg of total iron), per
container to meet this requirement. Because CPSC's child-resistant
special packaging requirement has a threshold of 250 mg of total iron,
such products could be packaged in conventional packaging and still be
in compliance with CPSC's child-resistant special packaging
regulations.
Packaging eight or fewer dosage units in closure-type packaging is
impractical and actually is approaching a requirement of a ``unit-dose
bottle.'' Moreover, iron-containing products frequently contain 90 to
100 dosage units per bottle, and consumers who currently purchase iron-
containing products in such quantities would be likely to continue this
practice, thereby purchasing 12 bottles of an iron-containing product
that contains 30 mg of iron per dosage unit or 30 bottles of an iron-
containing product that contains 65 mg of iron per dosage unit. Because
all of the vials perform the same function, consumers are likely to
store them in one place. The existence of multiple vials, particularly
if the products are packaged with conventional-type closures, means
that a child who discovers and gains access to one vial is likely to
gain access to multiple vials. Further, to minimize the space needed
for storage, consumers who bring multiple vials into the home may
choose to repackage the product into as few bottles as possible,
thereby defeating the intent of the regulations. Therefore, FDA
concludes that limiting the total number of dosage units per container
based on the total amount of iron per container will not contribute in
a significant way to achieving the agency's goal of limiting pediatric
access to a toxic amount of iron by ensuring that iron-containing
products are packaged in a manner that will not render the product
injurious to health.
The agency received two comments recommending that opaque packaging
material be required for unit-dose packaging to provide additional
safeguards to limit pediatric access to product. These comments noted
that opaque packaging is required for child-resistant unit-dose
packaging in New Zealand and throughout the European Community.
FDA recognizes that opaque packaging is one approach that may
reduce pediatric access to product. However, the comments did not
provide the agency with sufficient information to enable FDA to
conclude that opaque unit-dose packaging is necessary to ensure that
iron-containing products are packaged under conditions that are not
injurious to health. Given this fact, FDA finds no basis to require the
use of opaque packaging at this time. However, FDA would have no
objection if manufacturers used opaque unit-dose packaging.
One comment recommended that the proposed regulation be modified to
provide flexibility to permit manufacturers to try alternative
packaging designs that achieve the same effect of limiting pediatric
access to multiple doses of iron-containing products.
In establishing unit-dose packaging requirements for iron-
containing products that contain 30 mg or more of iron per dosage unit,
one of the agency's goals is to avoid restrictive requirements that
unnecessarily limit technological advances that accomplish the
objective of reducing pediatric access to potentially lethal amounts of
iron. Under new Secs. 111.50 and 310.518, the term ``unit-dose
packaging'' means any type of packaging that achieves the goal of
allowing access to one dosage unit at a time. The agency wants to
clarify that, for the purpose of this rulemaking, several types of
packaging can satisfy the definition of ``unit-dose-packaging,''
including blister-type packaging, pouches, and dispensers that deliver
one dosage unit at a time. Moreover, the agency anticipates that future
advances in package design will result in other types of packaging that
will also meet this definition. Therefore, because the regulations as
proposed provide for flexibility in the type of packaging used to
achieve unit-dose, FDA is taking no action in response to this comment.
One comment asked whether the agency intends to eliminate the
practice of packaging iron-containing drug products that are sold by
prescription in dispensing size bottles for use by pharmacists. These
bottles contain up to 1,000 tablets each. The comment stated that few
pharmacists are capable of dispensing these products in unit-dose
packaging and added that unit-dose packaging is not necessary for
products obtained by prescription. The latter point was made by a
second comment as well.
FDA does intend that change be effected in the dispensing and
packaging practices of some iron-containing products, including iron-
containing drug products sold by prescription. Some of the iron-
containing drug products that have caused injury to children have been
sold by prescription, and the agency is concerned that their being sold
by prescription has not caused adults to ensure that they are kept
inaccessible to children. Consequently, the agency believes that unit-
dose packaging is necessary for iron-containing prescription drug
products that contain 30 mg or more of iron per dosage unit. Therefore,
the requirement of this final rule to package iron-containing products
that contain 30 mg or more of iron per dosage unit in unit-dose
packaging will result, as an unintended consequence, in an elimination
of the practice of packaging such iron-containing prescription drug
products in dispensing size bottles for use by pharmacists.
One comment recommended that FDA revise the proposal to specify
that all iron-containing tablets sold over-the-counter be sold with
CRC's. The comment suggested that packaging for iron-containing drug
products sold by prescription not be changed because
[[Page 2231]]
pharmacies will repackage the contents. The agency understands this
latter suggestion to mean that packaging for products sold by
prescription should not be subject to regulation since pharmacists will
repackage tablets into pharmacy vials.
FDA has not revised the regulations in response to this comment.
The distinction between unit-dose packaging and CRC is essential to the
rule. As explained above, decisions about child-resistant packaging are
the province of CPSC. FDA is requiring unit-dose packaging for products
that provide 30 mg or more of iron per dosage unit to ensure that these
products are not rendered injurious to health. Serious injuries,
including death, are attributable to accidental overdose of products
containing this amount of iron per unit. FDA's conclusion, reached on
the basis of this rulemaking, is that unit-dose packaging will limit
the number of dosage units to which a child will gain access and
thereby significantly limit the risk of injury. As noted above, to
limit the risk of serious injury and death, the agency intends that
such iron-containing drug products sold by prescription will also be
packaged in unit-dose packaging.
One comment suggested that FDA review its specifications for unit-
dose packaging in a public forum that would include packaging suppliers
and associations to determine whether CRC might enhance safety more
than unit-dose packaging.
The agency declines to accept this suggestion. As stated
previously, FDA is not setting specifications for unit-dose packaging
or for CRC's. Such specifications are the responsibility of the CPSC.
FDA has the responsibility to ensure that products are packed under
conditions that will not render them injurious to health. Young
children are gaining access to toxic and potentially fatal amounts of
iron from iron-containing products packaged in CRC type packaging. It
is for this reason that FDA has determined that unit-dose packaging of
products containing 30 mg or more of iron per dosage unit is necessary
to ensure that iron containing products are packaged under conditions
that will not render them injurious to health.
One comment requested that FDA review its implementation plan with
industry and with individual suppliers of unit-dose packaging to
discuss issues relevant to materials and machinery, including adequate
supply of packaging, cost, validation, stability, and compliance.
FDA declines this request because the agency's analysis of costs
and benefits (see section VI. of this document) takes into account
these aspects of compliance with the rule. Based on comments received
from the packaging industry, the analysis has found that: (1) There is
an adequate supply of packaging, and (2) not all firms will need to
purchase packaging equipment because adequate capacity exists within
the contract packaging industry. The analysis also takes into account
other costs of complying with the requirements of this rule, such as
administrative costs, storage and transportation costs, stability
testing, and label redesign costs.
One comment stated that the proposal failed to address certain
regulatory concerns including the impact of the rule on product
submissions currently under review by the Center for Drug Evaluation
and Research (CDER) and whether new product submissions will be
required by this rule.
There currently are no submissions under review by CDER for iron-
containing drug products. If future submissions are made to CDER for
such products, FDA expects that they will reflect any change in the
stability of the products that may be caused by a change to unit-dose
packaging. The rule does not, however, in and of itself, establish
separate submission requirements for iron-containing drug products.
IV. Formulation and Appearance of Iron-Containing Products
The AG petition recommended that FDA prohibit the manufacture and
sale of adult formulations of iron-containing products that look like
candy or contain a sweet outer coating. The AAPCC petition asked FDA to
urge the industry to voluntarily reformulate iron-containing products
containing 30 mg or more of iron per dosage unit to be in less
attractive dosage units, specifically avoiding resemblance to popular
candies. NDMA asked FDA to reject the recommendation of the AG petition
because any provision for ``no candy-like appearance'' would not be
practical and would be difficult to administer because of the
subjective nature of assessing candy-like appearance. In the proposal,
FDA requested comments on whether use of ``candy'' and ``colorful''
coatings on iron-containing products is hazardous to infants and young
children because of the apparent attractiveness of the products. FDA
stated that the agency would consider action in this regard if the
information received presented an objective basis for additional steps
that FDA could take to limit the appeal of iron-containing products to
young children.
FDA received several comments on the appearance of iron-containing
products. Most of these comments expressed an opinion that the
resemblance of certain iron-containing products, including products
formulated specifically for use by children, to candy or to cartoon
characters contributed to the problem of children ingesting large
quantities of these products. One comment argued that experience
demonstrated that children are attracted to bright, shiny, colorful
objects, and that, although children will swallow most objects, they
will continue to seek out objects that taste good. This comment stated
that changing the sweet coating would be an additional safeguard to
ensure that children do not ingest large quantities of these
supplements. Another comment asserted that a candy-like appearance and
taste both needlessly attract an unsuspecting child and encourage
ingestion of large quantities of these products by a child who may be
unlikely to chew through the sugar coat.
Another comment, from a State department of health, reported that
investigation of 5 of 17 deaths revealed evidence that children chewed
or sucked on the iron tablets. A comment from a State consumer
protection board expressed the opinion that hazardous products with a
look-alike appearance to food products that are safe to consume present
conflicting messages that can confuse children about what is safe to
eat, and what is not. Some comments noted that current recommendations
from industry trade organizations include a recommendation that
products containing 30 mg or more of iron per dosage unit should not be
manufactured to have a sweet, candy-like outer coating.
In the proposal, FDA stated its tentative view that it may not be
possible to objectively measure the candy-like appearance of iron-
containing products. None of the comments provided a basis for FDA to
change this tentative view. Therefore, FDA is not adopting any
requirements relating to the formulation or appearance of iron-
containing products.
V. Forms of Iron That May Be Less Toxic
A. Introduction
Three basic types of elemental iron powders are marketed for use in
foods: Reduced iron, electrolytic iron, and carbonyl iron. The terms
``reduced,'' ``electrolytic,'' and ``carbonyl'' refer to the production
process by which the iron is manufactured rather than the
[[Page 2232]]
composition of the product. In the iron proposal, FDA specifically
requested comments on the appropriateness of elemental iron as a source
of iron in drugs and dietary supplements. FDA stated that the agency
would consider exempting iron-containing products that incorporate
elemental iron from any regulations that result from the rulemaking
instituted by the iron proposal if the information received was
persuasive in establishing that the use of elemental iron would
substantially decrease the risk of pediatric poisoning while allowing
for effective dietary iron supplementation.
B. Public Workshop
In the Federal Register of March 21, 1995 (60 FR 14918), FDA
published a notice announcing a public workshop on the acute toxicity
of elemental forms of iron relative to that of iron salts. The purpose
of the workshop was to solicit scientific data and information about
the acute toxicity of elemental forms of iron with regard to whether
such forms are sufficiently safe in dietary supplement and drug
products to warrant exemption from the special packaging and labeling
requirements that FDA had proposed for products containing iron salts.
Specifically, the notice stated that the purposes of the workshop
were to: (1) Identify data that objectively describe the acute toxicity
of elemental iron; (2) identify the market uses of elemental iron and
any adverse reaction reporting systems or processes used by
manufacturers and vendors; (3) identify any data on acute, accidental
exposure of children or adults to products containing elemental iron;
(4) discuss a possible conceptual framework for evaluation of the
effects of elemental forms of iron upon acute exposure; and (5) discuss
the validity and limitations of acute toxicity data in experimental
animals in predicting the risk in young children.
The notice also stated that specific topics that may be relevant
and on which discussion was invited included: (1) Physiological factors
that influence toxicity of elemental forms of iron, in comparison with
those for iron salts; (2) the quality, results, and relevance of animal
studies on acute toxicity of elemental iron and iron salts; (3) the
quality and results of human studies for evaluating the effects of
elemental iron; (4) factors influencing the validity of extrapolation
of experimental animal data on acute toxicity of various forms of iron
for predicting the risk in young children; and (5) current uses of
elemental iron in dietary supplements and drugs and the data available
for predicting the risk in young children.
The workshop was held on April 20, 1995, in Rockville, MD.
Statements were made by representatives of several manufacturers of
iron-containing products, a trade association, a physician, and a law
firm representing a manufacturer of iron-containing products. Most of
the participants who made oral presentations at the public meeting also
submitted written comments containing details of the information
discussed at the meeting.
The data and information submitted to FDA in response to the
agency's request for data in the notice announcing the public workshop,
as well as the data and information submitted to FDA in comments to the
iron proposal and the supplementary proposal, are discussed below. Most
of the data and information submitted to FDA addressed a single form of
elemental iron, namely, carbonyl iron. However, one comment provided
data and information on polysaccharide iron complex (PIC), a nonionic
iron complex synthesized by the neutralization of a ferric chloride
carbohydrate solution. Both forms of iron will be considered below.
C. Market Uses of Elemental Iron
FDA received one comment from a manufacturer who claimed to be the
sole producer of carbonyl iron in the United States and who stated that
the firm had introduced a pharmaceutical/food grade of carbonyl iron
into the marketplace in 1988. The comment provided information on the
manufacturers of multivitamins and stand-alone iron supplements who
have purchased carbonyl iron for use in those products, brand names of
products containing carbonyl iron, the potency (expressed in mg of
iron) of the various products, and the distributors who sold the
products. The manufacturer stated that carbonyl iron had been used in
more than 2 billion tablets marketed by 15 manufacturers in 35 brands
of iron-containing dietary supplement and drug products.
Another comment from an industry trade association stated that
there are between 1,300 and 3,000 products containing iron, including
carbonyl iron, on the market.
The agency received one comment from a manufacturer of PIC, which
is approximately 46 percent iron by weight and is sold in solid oral
dosage forms in both dietary supplement and drug products in doses
ranging from 18 mg of iron to 150 mg of iron. The comment provided
information on the brand names of ten products containing PIC in solid
oral dosage form and the potency (expressed in mg of iron) of the
various products. The comment stated that approximately 255.8 million
brand-name tablets or capsules containing PIC had been produced during
the period 1993 to 1994.
FDA appreciates receiving this information, which demonstrates that
certain forms of elemental iron are used as ingredients in a range of
iron-containing products that are marketed for use by children and
adults. This information provides a context for evaluating the impact
of an agency decision to exempt any form of elemental iron from any or
all of the requirements of this final rule. At this time, it appears
that between 1 percent and 3 percent of iron-containing products on the
market contain carbonyl iron, and that between 0.3 percent and 0.8
percent of iron-containing products on the market contain PIC.
D. Comments on the Acute Toxicity in Animals of Elemental Iron Compared
to That of Iron Salts
A comment from a professor of nutrition at a research university
stated that there are apparently distinct advantages to the use of
carbonyl iron as an alternative to the use of iron salts because of
decreased toxicity at the doses that young children are likely to
ingest. Another comment from a hematologist urged that carbonyl iron be
exempted because of its low acute toxicity. Neither comment, however,
supplied any data to support these statements.
Several comments asserted that administering iron as carbonyl iron
for the prevention and treatment of iron deficiency provides a greater
margin of safety than administering iron as iron salts. One comment
conceded that available data are limited but stated that while the
estimated lethal dose (LD) of ferrous sulfate in rats was 200 to 300 mg
of iron (Fe) (expressed in terms of iron content) per kg body
weight,\6\ the LD of carbonyl iron in rats and guinea pigs was 50,000
to 60,000 mg Fe/kg body weight or more\7\ (Ref. 11). This comment
concluded that these studies in experimental animals suggested that
carbonyl iron has a 100-to 200-fold
[[Page 2233]]
greater safety margin than ferrous sulfate.
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\6\ The comment did not provide a literature citation for these
data. The comment also did not specify whether the data reflected
LD<INF>50 values (i.e., the dose that is fatal to 50 percent of the
animals) or LD<INF>100 values (i.e., the dose that is fatal to 100
percent of the animals).
\7\ The data cited are LD<INF>100 values. The comment also noted
that the LD<INF>0 value (i.e., the dose at which all animals
survive) for rats and guinea pigs was 10,000 to 15,000 mg Fe/kg body
weight.
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Another comment from a manufacturer of carbonyl iron included a
report, commissioned by that manufacturer, on the toxicity of carbonyl
iron powder. This report acknowledged that little data were provided to
directly compare the toxicity of carbonyl iron with ionic forms of
iron.
FDA has reviewed the animal toxicity data cited in the comments and
other available animal toxicity data (Refs. 11 through 16). Most of the
reported data were expressed as LD<INF>50 values (i.e., the dose that
is fatal to 50 percent of the animals in the study), although some data
were expressed as no-adverse-effect-level (NOAEL) values. For clarity
and convenience, the LD<INF>50 data are summarized in Tables 2 through
4. However, in most cases the data reported in these tables do not
reflect studies in which the toxicity of one form of iron was directly
(i.e., concurrently) compared to that of other forms of iron.
Table 2.--Magnitude of Differences in Studies Reporting Median Lethal
Dose (LD<INF>50) Levels: Carbonyl Iron Versus Iron Salts \1\
------------------------------------------------------------------------
LD<INF>50 (mg Fe/kg body weight)
Species -------------------------------------- Approximate fold
Carbonyl iron Iron salt difference
------------------------------------------------------------------------
Rat 30,000 298 to 1,00030 to 90
(ferrous
sulfate)
580 to >2,300 13 to 50
(ferrous
fumarate)
Guinea pig 20,000 300 to 350 57 to 67
(ferrous
sulfate)
263 to 350 57 to 76
(ferrous
gluconate)
350 (ferric 57
ammonium
citrate)
2,000 (ferrous 10
carbonate)
Dog >25,000 160 (ferrous 156
sulfate)
------------------------------------------------------------------------
\1\ Data summarized from published literature (Refs. 11 through 16).
Table 3.--Magnuitude of Differences in ST Reporting Median Lethal Dose
(LD<INF>50) Levels: Differences Among Various Iron Salts \1\
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