[Federal Register: November 14, 1994]
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CONSUMER PRODUCT SAFETY COMMISSION
16 CFR Part 1700
Proposed Rule: Requirements for Child-Resistant Packaging;
Packages Containing 250 mg or More of Naproxen
AGENCY: Consumer Product Safety Commission.
ACTION: Proposed rule.
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SUMMARY: Under the Poison Prevention Packaging Act of 1970, the
Commission is proposing a rule to require child-resistant packaging for
naproxen preparations containing 250 mg or more of naproxen per
package. Naproxen is marketed as an anti-inflammatory drug. It is used
to treat various forms of arthritis, mild to moderate pain, and
menstrual pain. 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 naproxen.
DATES: Comments on the proposal should be submitted no later than
January 30, 1995.
ADDRESSES: Comments should be mailed to the Office of the Secretary,
Consumer Product Safety Commission, Washington, D.C. 20207, or
delivered to the Office of the Secretary, Consumer Product Safety
Commission, room 502, 4330 East-West Highway, Bethesda, Maryland 20814-
4408, telephone (301)504-0800.
FOR FURTHER INFORMATION CONTACT: Jacqueline Ferrante, Ph.D.,
Directorate for Health Sciences, Consumer Product Safety Commission,
Washington, D.C. 20207; telephone (301)504-0477 ext. 1199.
SUPPLEMENTARY INFORMATION:
A. Background
1. Relevant Statutes and Regulations
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 defined as 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. (It does not mean,
however, packaging which all such children cannot open, or obtain a
toxic or harmful amount from, within a reasonable time.) 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).
Effectiveness standards have been established under the PPPA for
special packaging (16 CFR 1700.15), as has a procedure to evaluate its
effectiveness (16 CFR 1700.20). Regulations have been issued requiring
special packaging for a number of household products (16 CFR 1700.14).
The findings that the Commission must make in order to issue a standard
requiring CR packaging for a product are discussed below in Section D
of this notice.
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 (1)
the manufacturer (or packer) also supplies the substance in CR packages
of a popular size and (2) the non-CR packages bear conspicuous labeling
stating: ``This package for households without young children.'' 15
U.S.C. 1473(a). If the package is too small to accommodate this label
statement, the package may bear a label stating: ``Package not child-
resistant.'' 16 CFR 1700.5(b). The right of the manufacturer or packer
to market a single size of the product in noncomplying packaging under
these conditions is termed the ``single-size exemption.''
The Commission may restrict the right to market a single size in
noncomplying packaging if the Commission finds that the substance is
not also being supplied in popular size packages that comply with the
standard. 15 U.S.C. 1473(c). In this case, the Commission may, after
giving the manufacturer or packer an opportunity to comply with the
purposes of the PPPA and an opportunity for a hearing, order that the
substance be packaged exclusively in CR packaging. To issue such an
order, the Commission must find that the exclusive use of special
packaging is necessary to accomplish the purposes of the PPPA.
2. Background of Naproxen
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID). This
class of compounds is used to treat various forms of arthritis, mild to
moderate pain, and menstrual pain.
Formerly, naproxen was a prescription drug that was required to be
in child-resistant packaging by the Commission's regulation of human
oral prescription drugs, 16 CFR 1700.14(a)(10). Initially, two Food and
Drug Administration (FDA) panels voted against the nonprescription
(``over-the-counter,'' or ``OTC'') sale of naproxen because of its slow
onset of action; potential for adverse gastrointestinal and renal
effects with high doses; and potential for misuse in children and the
elderly. American Druggist, March 1994, p. 45. The manufacturer then
agreed to reduce the recommended dose and include warning labels for
children and the elderly. Subsequently, FDA granted OTC status to the
sodium salt of naproxen by a letter dated January 11, 1994.
The OTC formulation of naproxen consists of naproxen sodium and is
equivalent to 200 mg of naproxen and 20 mg of sodium per tablet. The
recommended dose is 1 tablet every 8 to 12 hours. The maximum daily
dose is 3 tablets for patients between the ages of 12 and 65 and 2
tablets for those over 65. The drug is not recommended for children
under 12 years old except under the supervision of a doctor. However,
naproxen is used to treat juvenile arthritis in children over 2 years.
The patent for naproxen expired in 1993. The OTC naproxen product
approved by the FDA will be manufactured by the original patent holder
and marketed by another company as a joint venture. In accordance with
FDA's regulations, these two companies have requested sole marketing
rights for a period of 3 years.
Although these companies are voluntarily placing naproxen in child-
resistant packaging, a mandatory special packaging standard for
naproxen products would ensure that other companies that may come on
the market in the future use CR packaging. The post-OTC experience with
another NSAID, ibuprofen, supports this action. As discussed below, the
incidence of accidental ingestion of ibuprofen by children under 5
years old increased after it became available OTC and before special
packaging was required by the Commission. A mandatory standard 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 Naproxen
The Commission's Directorate for Health Sciences reviewed the
toxicity of naproxen. Side effects commonly associated with naproxen
and other NSAID's include dose-related gastrointestinal (GI)
complications such as constipation, heartburn, abdominal pain, nausea,
and diarrhea. Other adverse effects include headache, dizziness,
drowsiness, pruritus (itching), and tinnitus (ringing in the ears).
Naproxen may also cause liver and kidney toxicity, but these
effects are infrequent with routine therapeutic use. Kidney toxicity
has been documented in children following naproxen therapy. One report
describes a two-year-old male with juvenile arthritis who developed
acute renal failure and hyperkalemia (high blood potassium) following
treatment with 20 mg/kg/day of naproxen sodium for 1 month.
Acute overdosage of naproxen may result in mild, transient effects,
including drowsiness, GI disturbances, and prolonged clotting times.
Life-threatening effects are uncommon, but serious complications such
as seizures, apnea (cessation of breathing), metabolic acidosis
(reduced blood pH), and impaired kidney function have been documented.
The acute lethal dose of naproxen is unknown and the severity of
symptoms is not always dose-related.
The Commission's Directorate for Epidemiology reviewed data from
NEISS involving hospital emergency room treatment of children under 5
years old who ingested naproxen. There were nine reported cases from
1980 to 1989 and 23 reported cases from 1990 to 1993. The average
annual number of estimated cases during these time periods was 50 and
300, respectively. In 1982, one case resulted in the hospitalization of
a 2-year-old male.
AAPCC data from 1985 to 1992 were unavailable because naproxen
poisoning incidents were not categorized separately from other NSAID
incidents unless they resulted in death. However, this does not mean
that naproxen poisonings did not occur. The Commission's Directorate
for Health Sciences requested 1993 incident data from the AAPCC related
specifically to naproxen in children under 5 years old. Of the 1,413
naproxen ingestions reported, two resulted in outcomes characterized by
AAPCC as moderate''--i.e., pronounced and prolonged symptoms that
generally require treatment but are not life-threatening. In addition,
53 of the ingestions resulted in outcomes characterized by AAPCC as
minor''--i.e., symptoms present, but mild with rapid and complete
resolution. Forty-eight cases were documented as potentially toxic, but
the ultimate disposition was not reported. From 1985 to 1993, there
were no naproxen-related fatalities in children reported to the AAPCC.
Several cases of naproxen poisoning in children were reported
through the FDA's Adverse Reactions Reporting System (ARRS) and the
Worldwide Safety Surveillance and Reporting division of Syntex, the
manufacturer of naproxen. These include:
An 8-month-old girl died following daily treatment for fever and an
upper respiratory tract infection with 100 to 400 mg naproxen sodium
for 5 days. The autopsy showed serious effects on the liver and brain,
multiple GI ulcerations, and yeast colonization of the upper
respiratory tract.
A 2-year-old boy recovered after developing drowsiness, ataxia
(loss of voluntary muscle coordination), and a prolonged bleeding time
following ingestion of naproxen (up to 2 grams), hydrogen peroxide, and
eucalyptus oil. The ARRS listed naproxen as the suspect drug and
hydrogen peroxide as non-suspect. There was no comment relating to the
contribution of eucalyptus oil to the symptoms. Eucalyptus oil may
cause drowsiness and ataxia, but it does not affect bleeding time.
A 2-year-old girl suffered dyspepsia (indigestion) after ingesting
625 mg of naproxen. She recovered after her stomach was emptied.
Convulsions developed in a 5-year-old girl who accidently ingested
an unknown amount of naproxen sodium.
NEISS data for ingestions of ibuprofen, another popular NSAID that
began to be marketed OTC in 1984, show that there was a larger
estimated number of children under 5 years old treated in hospital
emergency rooms for each year from 1984-1992 than for each year from
1980-1983. In 1993, when the special packaging standard for ibuprofen
became effective, the estimated number of cases was lower than every
annual estimate from 1984-1992. Most cases of naproxen poisoning
described in the literature involve adults. These patients generally
developed GI side effects and several experienced seizures. The
incidence of side effects may differ in children and adults. Studies
involving children taking naproxen showed that, compared to adults, the
children's incidence of: (1) rash and prolonged bleeding times were
increased; (2) GI and central nervous system (CNS) reactions were
similar; and (3) other reactions decreased.
There is evidence that naproxen and other NSAID's have adverse
fetal effects when used during pregnancy. A 35-week-old newborn
delivered 8 hours after his mother ingested an overdose of 5 grams of
naproxen, developed severe hyponatremia (low blood sodium) and water
retention with indications of cerebral irritation and paralytic ileus.
It was tentatively diagnosed that naproxen adversely affected renal
function.
Complications were reported in three newborns after maternal
naproxen treatment to prevent premature labor. One newborn died, and
the autopsy showed a brain hemorrhage, multiple gastric ulcers,
extensive GI bleeding, and a cardiovascular birth defect that is a
known adverse effect of NSAID's.
A 7-day-old breast-fed infant boy developed symptoms associated
with naproxen toxicity after his mother was treated with 1 g naproxen
and 800 mg of antibiotic for 3 days.
C. Level for Regulation
The Commission proposes that special packaging be required for OTC
naproxen products containing 250 mg or more naproxen per package. This
level is based on (1) established guidelines for medical treatment
following ingestion of NSAID's and (2) a known toxic dose of naproxen,
reduced by a safety factor to account for biologic variability.
The precise toxic level of naproxen in humans is unknown. However,
guidelines established for pediatric NSAID overdose suggest medical
treatment for young children who ingest five times the maximum single
therapeutic dose. Therefore, the dose of naproxen requiring medical
intervention would be 5 mg/kg (the maximum single therapeutic dose)
times five, or 25 mg/kg. In a 10-kg child, this is equivalent to 250 mg
of naproxen, or one and one-quarter OTC tablets.
The same level results when calculated using a different approach.
When treatment information for poisonings is unavailable, the staff
typically uses a known toxic dose divided by a safety factor of 10 to
determine the level for regulation. Applying this factor to the 250 mg/
kg dose of naproxen that caused life-threatening acidosis in a 15-year-
old girl also results in a level of 25 mg/kg, or 250 mg in a 10-kg
child.
D. Statutory Considerations
1. Hazard to Children
As noted above, the toxicity data concerning children's ingestion
of naproxen sodium demonstrate that this compound can cause serious
illness and injury to children. Moreover, the preparations are readily
available to children. Although the current marketer of this compound
voluntarily uses CR packaging for this product, the Commission
concludes preliminarily 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 finds preliminarily that the degree and nature of the hazard
to children from ingesting naproxen is such that special packaging is
required to protect children from serious illness. The Commission bases
this preliminary 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 by section 3(a)(2) of the PPPA, 15 U.S.C.
1472(a)(2), to find that the special packaging is ``technically
feasible, practicable, and appropriate.'' Technical feasibility exists
when technology exists or readily can be 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. Appropriateness exists when packaging complying with the
standards will adequately protect the integrity of the substance and
not interfere with the intended storage or use.
The current marketers of OTC naproxen use packaging that not only
is child resistant, but also is easier for adult consumers (and
especially older adults) to open. Therefore, the Commission
preliminarily concludes that CR packaging for naproxen is technically
feasible, practicable, and appropriate.
3. Other Considerations
In establishing a special packaging standard, section 3(b) of the
PPPA, 15 U.S.C. 1472(b), requires the Commission to 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 items with respect to the
various determinations made in this notice, and finds no reason to
conclude that the rule is unreasonable.
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 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 preliminarily proposes an effective date of 180 days
from the date the final regulation is published in the Federal
Register. The Commission, however, would consider a shorter effective
date if the public interest warrants such a period. The public interest
might warrant a shorter effective date if, for example, naproxen were
going to be marketed in significant numbers in non-CR packaging for any
significant period before any Commission regulation requiring CR
packaging for this product became final. Accordingly, the Commission
solicits comment on the appropriateness of a 180-day or shorter
effective date. The 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., 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.
The purpose of the Regulatory Flexibility Act, as stated in section
2(b) (5 U.S.C. 602 note), is to require agencies, consistent with their
objectives, to fit the requirements of regulations to the scale of the
businesses, organizations, and governmental jurisdictions subject to
the regulations. 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 Economics has prepared a
preliminary economic assessment of a rule to require special packaging
for naproxen preparations with 250 mg or more of naproxen 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 naproxen are already using CR packaging and have requested
sole marketing rights for 3 years. Furthermore, the relatively low
costs of CR packages should not be an entry burden for future
marketers. Accordingly, for the reasons given above, the Commission
preliminarily concludes that the rule to require special packaging for
naproxen preparations having 250 mg or more of naproxen would not have
any significant economic effect on a substantial number of small
entities.
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 Poison
Prevention Packaging Act (PPPA) packaging requirements for naproxen
preparations.
The Commission's regulations at 16 CFR 1021.5(c)(3) state that
rules requiring special packaging for consumer products normally have
little or no potential for affecting the human environment. Preliminary
analysis of the potential impact of this proposed rule indicates that
CR packages for naproxen preparations would have no significant effects
on the environment. This is because the rule will not significantly
increase the number of CR packages in use and, in any event, the
manufacture, use, and disposal of the CR packages present the same
potential environmental effects as do the currently used packages.
Therefore, because the proposed 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)(24),
reading as follows (although unchanged, the introductory text of
paragraph (a) is included 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:
* * * * *
(24) Naproxen. Naproxen preparations for human use and containing
the equivalent of 250 mg or more of naproxen in a single package (i.e.,
retail unit) shall be packaged in accordance with the provisions of
Sec. 1700.15 (a), (b), and (c).
* * * * * *
Dated: November 7, 1994.
Sadye E. Dunn,
Secretary, Consumer Product Safety Commission.
List of Relevant Documents
(Note. This list of relevant documents will not be printed in
the Code of Federal Regulations.)
1. Vale, J.A. and Meredith, T.J., Acute poisoning due to non-
steroidal anti-inflammatory drugs: clinical features and management.
Medical Toxicology 1:12-31, 1986.
2. Memorandum from Terry Kissinger, Ph.D., EPHA, to Jacqueline
Ferrante, Ph.D., HSPS, Injury Data on Naproxen and Ibuprofen for the
1980-1993 Period,'' May 27, 1994.
3. Memorandum from Charles Wilbur, HSPS, to Jacqueline Ferrante,
Ph.D., HSPS, Technical Feasibility, Practicability, and
Appropriateness Determination for the Proposal to Require Child-
Resistant Packaging for OTC Preparations Containing Naproxen'' June
7, 1994.
4. 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,'' June 10, 1994.
5. Memorandum from Sandra Inkster, Ph.D., HSHE, to Jacqueline
Ferrante, Ph.D., HSPS, Review of Naproxen Toxicity,'' July 1, 1994.
6. Briefing memorandum from Jacqueline Ferrante, Ph.D., HSPS, to
the Commission, Proposed Special Packaging Standard for Naproxen,''
September 29, 1994.
[FR Doc. 94-27961 Filed 11-10-94; 8:45 am]
BILLING CODE 6355-01-P