[Federal Register Volume 61, Number 225 (Wednesday, November 20, 1996)]
[Proposed Rules]
[Pages 59043-59046]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-29691]
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CONSUMER PRODUCT SAFETY COMMISSION
16 CFR Part 1700
Proposed Rule: Requirements for Child-Resistant Packaging;
Packages Containing More Than 50 mg of Ketoprofen
AGENCY: Consumer Product Safety Commission.
ACTION: Proposed rule.
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SUMMARY: The Commission is proposing a rule to require child-resistant
packaging for ketoprofen preparations containing more than 50 mg of
ketoprofen per retail package. Ketoprofen is a nonsteroidal anti-
inflammatory drug and is used to relieve minor aches and pains and to
reduce fever. The Commission has preliminarily determined that child-
resistant packaging is necessary to protect children under 5 years of
age from serious personal injury and serious illness resulting from
ingesting ketoprofen. The Commission takes this action under the
authority of the Poison Prevention Packaging Act of 1970.
DATES: Comments on the proposal should be submitted no later than
February 3, 1997.
ADDRESSES: Comments should be mailed to the Office of the Secretary,
Consumer Product Safety Commission, Washington, DC 20207, or delivered
to the Office of the Secretary, Consumer Product Safety Commission,
Room 502,
[[Page 59044]]
4330 East-West Highway, Bethesda, Maryland 20814-4408, telephone (301)
504-0800.
FOR FURTHER INFORMATION CONTACT: Jacqueline Ferrante, Ph.D., Division
of Poison Control and Scientific Coordination, Directorate for Health
Sciences, Consumer Product Safety Commission, Washington, DC 20207;
telephone (301) 504-0477 ext. 1199.
SUPPLEMENTARY INFORMATION:
A. Background
1. Relevant Statutory and Regulatory Provisions
The Poison Prevention Packaging Act of 1970 (``PPPA''), 15 U.S.C.
1471-1476, authorizes the Commission to establish standards for the
``special packaging'' of any household substance if (1) the degree or
nature of the hazard to children in the availability of such substance,
by reason of its packaging, is such that special packaging is required
to protect children from serious personal injury or serious illness
resulting from handling, using, or ingesting such substance and (2) the
special packaging is technically feasible, practicable, and appropriate
for such substance.
Special packaging, also referred to as ``child-resistant (CR)
packaging,'' is packaging that (1) is designed or constructed to be
significantly difficult for children under 5 years of age to open or
obtain a toxic or harmful amount of the substance contained therein
within a reasonable time and (2) is not difficult for ``normal adults''
to use properly. 15 U.S.C. 1471(4). Household substances for which the
Commission may require CR packaging include (among other categories)
foods, drugs, or cosmetics as these terms are defined in the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321). 15 U.S.C. 1471(2)(B). The
Commission has performance requirements for special packaging. 16 CFR
1700.15, 1700.20.
Section 4(a) of the PPPA, 15 U.S.C. 1473(a), allows the
manufacturer or packer to package a nonprescription product subject to
special packaging standards in one size of non-CR packaging only if the
manufacturer (or packer) also supplies the substance in CR packages of
a popular size, and the non-CR packages bear conspicuous labeling
stating: ``This package for households without young children.'' 15
U.S.C. 1473(a), 16 CFR 1700.5.
2. Ketoprofen
Ketoprofen is a nonsteroidal anti-inflammatory drug (``NSAID'').
This class of compounds also includes ibuprofen and naproxen.
Ketoprofen is used to relieve minor aches and pains such as those
associated with colds, toothaches, menstrual cramps, and muscular
aches. It is also used to reduce fever.[2] 1
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\1\ Numbers in brackets refer to documents listed at the end of
this notice.
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For the past ten years, ketoprofen has been a prescription drug.
Like all prescription drugs, it was required to be in child-resistant
packaging by the Commission's regulation of human oral prescription
drugs, 16 CFR 1700.14(a)(10). The U.S. patent on ketoprofen expired in
1993. On October 6, 1995, the Food and Drug Administration (``FDA'')
granted nonprescription (``over-the-counter,'' or ``OTC'') status to
ketoprofen. [2]
The OTC formulations, ketoprofen and ketoprofen tartrazine, contain
12.5 milligrams (mg) of ketoprofen per dose. The recommended dose is 1
tablet every 4 to 6 hours. The maximum daily dose is 6 tablets. The
drug is not recommended for children under 16 years old except under
the supervision of a doctor. OTC ketoprofen should not be used (1) with
any other analgesic or anti-pyretic, (2) for more than 3 days for
fever, (3) for more than 10 days for pain, or (4) during the last
trimester of pregnancy unless directed by a physician. [2]
3. Special Packaging
The current marketers are voluntarily placing ketoprofen in child-
resistant packaging. However, a mandatory special packaging standard
for ketoprofen products would ensure that other companies that may
market such products in the future would use CR packaging.
Two other NSAIDs that previously became available OTC are ibuprofen
and naproxen. After ibuprofen was introduced OTC, there was an
increased incidence of accidental ingestions of the drug by children
under 5. [2]
In part to avoid a similar experience with naproxen, in 1995, the
Commission then issued a rule requiring CR packaging for naproxen
preparations containing 250 mg or more per retail package. 60 FR 38671.
The rule became effective February 6, 1996. Similar reasoning applies
to ketoprofen.
A mandatory standard for ketoprofen would also enable the
Commission to ensure that the packaging used meets the performance
requirements of the PPPA test protocol at 16 CFR 1700.15, 1700.20.
B. Toxicity of Ketoprofen
The Commission's Directorate for Epidemiology and Health Sciences
reviewed the toxicity of ketoprofen. Side effects commonly associated
with ketoprofen, as with other NSAID's, are gastrointestinal (GI)
complications. These include nausea, vomiting, diarrhea, constipation,
heartburn, and abdominal pain. Other common adverse effects include
headache, dizziness, visual disturbances, rash, and hypersensitivity
reactions.[2]
Ketoprofen may also cause more severe adverse GI effects, such as
gastric or duodenal ulcer with bleeding or perforation; intestinal
ulcers; ulcerative stomatitis or colitis; gingival ulcer; perforation
and hemorrhage of the esophagus, stomach, small or large intestine;
hematemesis; and rectal bleeding. Renal injuries also may result from
chronic use of ketoprofen.[2]
The staff reviewed the relevant medical literature which cites
several cases of severe adverse reactions to ketoprofen administration.
In one case, a 61 year old woman suffered acute renal failure after
taking 400 mg of ketoprofen daily for 10 days. She recovered after
peritoneal dialysis. In addition, the literature reports one case of
pancreatitis after 12 days of ketoprofen therapy and two cases of
ketoprofen induced hepatitis. Other cases reported in the literature
involved co-ingestion of other substances.[2]
The FDA maintains a data base known as the Adverse Events Reporting
System (``AERS'') for reports of adverse reactions detected after
marketing a drug or biological product. Drug manufacturers are required
to report to the FDA any known adverse effects associated with their
products, but only an estimated 1% of all adverse reactions are
actually reported. Also, reports may reflect effects from an underlying
disease process or a reaction to multiple drugs. Of the 903 ketoprofen-
associated cases reported to the FDA between 1986 and October 1995, the
most common adverse reactions were abdominal pain (122), diarrhea (87),
nausea (82), GI hemorrhage (70), rash (55), indigestion (39), labored
breathing (34), allergic reaction (30), dizziness (30), and hives
(30).[2]
Among the ketoprofen cases in the AERS database are 51 more serious
reactions, i.e., hospitalizations, reactions resulting in permanent
disability, or deaths. Five of these involved children under 16 years
of age. Three 15 year old children required hospitalization for severe
renal injury, and one 15 year old suffered a life-threatening GI
hemorrhage and perforation. These events followed 10-18 days of therapy
with daily doses of 200-225 mg ketoprofen. A 10 year old also required
hospitalization for severe
[[Page 59045]]
vision abnormalities after 15 days of treatment with 150 mg
ketoprofen.[2]
The medical literature reports 2 overdoses, both involving other
substances as well. In one case, a 12 year old girl ingested an unknown
amount of ketoprofen plus 12 hydrocodone/acetaminophen tablets. She
developed tonic-clonic seizures with loss of consciousness and
metabolic acidosis. The symptoms resolved within 2 hours and she
recovered fully. In the other incident, an adult ingested 12 capsules
of sustained release ketoprofen 200 mg (total=2.4 grams) with 375
milliliters (12.5 ounces) of vodka. Only mild effects resulted since
the victim vomited within 1 hour of the ingestion.[2]
The AERS database reports no pediatric ketoprofen overdoses, but
there were some incidents involving adults. One intentional overdose of
1,000 mg ketoprofen resulted in moderate to severe kidney injury
(kidney pain, bloody urine, increase creatinine levels). Ingestion of
500 mg of ketoprofen plus an unknown amount of ciprofloxacin produced
death in a 50 year old woman. The symptoms which included GI
hemorrhage, thrombocytopenia, coagulation disorders, and decreased
prothrombin, were most likely related to ketoprofen.[2]
The AERS system also reports two neonatal poisoning cases in which
the mothers took ketoprofen at some point in their pregnancy. One
infant died shortly after birth from acute renal failure. In the second
case (which involved multiple medications) twins developed acute renal
failure shortly after birth. One twin died and the other recovered but
was neurologically impaired.[2]
The staff reviewed accidental ingestion data for children under age
5. The American Association of Poison Control Center (``AAPCC'')
collects incident data through its Toxic Exposure Surveillance System
(``TESS'') which covers incidents from 1985 to 1994. Poisoning
incidents involving ketoprofen are not recorded separately from other
NSAIDs unless they were fatal. No deaths involving ketoprofen were
reported during this period.[2]
CPSC's data base, the National Electronic Injury Surveillance
System (``NEISS'') monitors emergency room visits to selected hospitals
throughout the United States. Review of NEISS data from 1988 to June
1996 shows three cases involving ketoprofen and children under 5 years
old. All three incidents occurred in 1996. None were fatal or required
hospitalization.[2]
C. Level for Regulation
The Commission is proposing a rule that requires special packaging
for OTC ketoprofen products containing more than 50 mg ketoprofen per
retail package. This level is based on established guidelines for
medical treatment following pediatric ingestion of NSAID's.[5] These
guidelines suggest medical treatment for young children who ingest five
times the maximum single therapeutic dose. For ketoprofen, the maximum
single therapeutic dose is 75 mg or 1.08 mg/kg assuming an average
adult weight of 70 kg. The dose of ketoprofen requiring medical
intervention would be five times 1.08 mg/kg, which in a 10-kg child
would be more than 50 mg of ketoprofen, or four OTC tablets.[2]
D. Statutory Considerations
1. Hazard to Children
As noted above, the toxicity data concerning children's ingestion
of ketoprofen demonstrate that this compound can cause serious illness
and injury to children. Moreover, the preparations are readily
available to children. The Commission preliminarily concludes that a
regulation is needed to ensure that products subject to the regulation
will be placed in CR packaging by any new manufacturers. In addition,
the regulation will enable the Commission to enforce the CR packaging
requirement and ensure that effective CR packaging is used.
Pursuant to section 3(a) of the PPPA, 15 U.S.C. 1472(a), the
Commission preliminarily finds that the degree and nature of the hazard
to children from ingesting ketoprofen is such that special packaging is
required to protect children from serious illness. The Commission bases
this finding on the toxic nature of these products, described above,
and their accessibility to children in the home.
2. Technical Feasibility, Practicability, and Appropriateness
In issuing a standard for special packaging under the PPPA, the
Commission is required to find that the special packaging is
``technically feasible, practicable, and appropriate.'' 15 U.S.C.
1472(a)(2). Technical feasibility may be found when technology exists
or can be readily developed and implemented by the effective date to
produce packaging that conforms to the standards. Practicability means
that special packaging complying with the standards can utilize modern
mass production and assembly line techniques. Packaging is appropriate
when complying packaging will adequately protect the integrity of the
substance and not interfere with its intended storage or use.[4]
The current marketers of OTC ketoprofen voluntarily use packaging
that is child resistant. Similar designs have been shown to meet the
revised testing protocol for senior adult use effectiveness. Therefore,
the Commission concludes that CR packaging for ketoprofen is
technically feasible, practicable, and appropriate.[3]
3. Other Considerations
In establishing a special packaging standard under the PPPA, the
Commission must consider the following:
a. The reasonableness of the standard;
b. Available scientific, medical, and engineering data concerning
special packaging and concerning childhood accidental ingestions,
illness, and injury caused by household substances;
c. The manufacturing practices of industries affected by the PPPA;
and
d. The nature and use of the household substance. 15 U.S.C.
1472(b).
The Commission has considered these factors with respect to the
various determinations made in this notice, and preliminarily finds no
reason to conclude that the rule is unreasonable or otherwise
inappropriate.
E. Effective Date
The PPPA provides that no regulation shall take effect sooner than
180 days or later than one year from the date such final regulation is
issued, except that, for good cause, the Commission may establish an
earlier effective date if it determines an earlier date to be in the
public interest. 15 U.S.C. 1471n.
The Commission does not believe that a shorter effective date is
necessary to protect the public interest. The companies that are
currently marketing ketoprofen are voluntarily using CR packaging. The
Commission does not have any indication that significant quantities of
ketoprofen will be marketed in non-CR packaging before a 180 day
effective date, except for a single size non-CR package as allowed
under the PPPA. Thus, the Commission finds that a 180 day effective
date is consistent with the public interest and proposes that a final
rule would take effect 180 days after publication of the final rule. A
final rule would apply to products that are packaged on or after the
effective date.
F. Regulatory Flexibility Act Certification
When an agency undertakes a rulemaking proceeding, the Regulatory
Flexibility Act, 5 U.S.C. 601 et seq.,
[[Page 59046]]
generally requires the agency to prepare proposed and final regulatory
flexibility analyses describing the impact of the rule on small
businesses and other small entities. Section 605 of the Act provides
that an agency is not required to prepare a regulatory flexibility
analysis if the head of an agency certifies that the rule will not have
a significant economic impact on a substantial number of small
entities.
The Commission's Directorate for Economic Analysis prepared a
preliminary assessment of the impact of a rule to require special
packaging for ketoprofen preparations with more than 50 mg ketoprofen
in a single package. Based on this assessment, the Commission concludes
that such a requirement would not have a significant impact on a
substantial number of small businesses or other small entities because
the current marketers of ketoprofen are using CR packaging.
Furthermore, the relatively low costs of CR packages should not be an
entry burden for future marketers.
G. Environmental Considerations
Pursuant to the National Environmental Policy Act, and in
accordance with the Council on Environmental Quality regulations and
CPSC procedures for environmental review, the Commission has assessed
the possible environmental effects associated with the proposed PPPA
requirements for ketoprofen preparations.
The Commission's regulations state that rules requiring special
packaging for consumer products normally have little or no potential
for affecting the human environment. 16 CFR 1021.5(c)(3). Therefore,
because the rule would have no adverse effect on the environment,
neither an environmental assessment nor an environmental impact
statement is required.
List of Subjects in 16 CFR Part 1700
Consumer protection, Drugs, Infants and children, Packaging and
containers, Poison prevention, Toxic substances.
For the reasons given above, the Commission proposes to amend 16
CFR part 1700 as follows:
PART 1700--[AMENDED]
1. The authority citation for part 1700 continues to read as
follows:
Authority: Pub. L. 91-601, secs. 1-9, 84 Stat. 1670-74, 15
U.S.C. 1471-76. Secs 1700.1 and 1700.14 also issued under Pub. L.
92-573, sec. 30(a), 88 Stat. 1231. 15 U.S.C. 2079(a).
2. Section 1700.14 is amended by adding new paragraph (a)(25),
reading as follows (although unchanged, the introductory text of
paragraph (a) is republished below for context):
Sec. 1700.14 Substances requiring special packaging.
(a) Substances. The Commission has determined that the degree or
nature of the hazard to children in the availability of the following
substances, by reason of their packaging, is such that special
packaging is required to protect children from serious personal injury
or serious illness resulting from handling, using, or ingesting such
substances, and the special packaging herein required is technically
feasible, practicable, and appropriate for these substances:
* * * * *
(25) Ketoprofen. Ketoprofen preparations for human use and
containing more than 50 mg of ketoprofen in a single retail package
shall be packaged in accordance with the provisions of Sec. 1700.15
(a), (b), and (c).
* * * * *
Dated: November 15, 1996.
Sadye E. Dunn,
Secretary, Consumer Product Safety Commission.
List of Relevant Documents
1. Briefing memorandum from Jacqueline Ferrante, Ph.D., HSPS, to
the Commission, ``Proposed Rule to Require Child-Resistant Packaging
for Ketoprofen,'' October 15, 1996.
2. Memorandum from Susan C. Aitken, Ph.D., HSHE, to Jacqueline
Ferrante, Ph.D., HSPS, ``Toxicity of Ketoprofen,'' August 19, 1996.
3. Memorandum from Marcia P. Robins, ECSS, to Jacqueline
Ferrante, Ph.D., HSPS, ``Preliminary Assessment of Economic and
Environmental Effects of a Proposal to Require Child-Resistant
Packaging for OTC Pharmaceuticals Containing Ketoprofen,'' August
19, 1996.
4. Memorandum from Charles Wilbur, HSPS, to Jacqueline Ferrante,
Ph.D., HSPS, ``Technical Feasibility, Practicability, and
Appropriateness Determination for the Proposed Rule to Require
Child-Resistant Packaging for OTC Products Containing Ketoprofen,''
August 20, 1996.
5. Vale, J.S. and Meredith, T.J. Acute Poisoning Due to Non-
steroidal Anti-inflammatory Drugs: Clinical Features and Management.
Med. Toxicol. 1:12-31, 1986.
[FR Doc. 96-29691 Filed 11-19-96; 8:45 am]
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