[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]
BILLING CODE 6355-01-P