[Federal Register Volume 60, Number 145 (Friday, July 28, 1995)]
[Rules and Regulations]
[Pages 38671-38675]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-18504]
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CONSUMER PRODUCT SAFETY COMMISSION
16 CFR Part 1700
Final Rule: Requirements for Child-Resistant Packaging; Packages
Containing 250 mg or More of Naproxen
AGENCY: Consumer Product Safety Commission.
ACTION: Final rule.
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SUMMARY: The Commission is issuing a rule to require child-resistant
packaging for naproxen preparations containing 250 mg or more of
naproxen per retail 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 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. The Commission takes this action under the
authority of the Poison Prevention Packaging Act of 1970.
DATES: The rule will become effective on February 6, 1996, and applies
to naproxen preparations packaged on or after that date.
FOR FURTHER INFORMATION CONTACT: Michael Bogumill, Division of
Regulatory Management, Consumer Product Safety Commission, Washington,
DC 20207; telephone (301) 504-0400 ext. 1368.
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).
2. 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. As discussed below, the Commission
is aware of many reports of poisoning incidents involving naproxen in
children under 5 years old.
Until recently, naproxen was a prescription drug that was required
to be in child-resistant packaging by the
[[Page 38672]]
Commission's regulation of human oral prescription drugs, 16 CFR
1700.14(a)(10). By a letter dated January 11, 1994, the Food and Drug
Administration (``FDA'') granted nonprescription (``over-the-counter,''
or ``OTC'') status to the sodium salt of naproxen.
The patent for naproxen expired in 1993. The OTC naproxen product
approved by the FDA is currently 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 sole
marketing rights until January 11, 1997. Currently, the companies are
voluntarily placing naproxen in CR packaging.
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.(5) 1
\1\ Numbers in parentheses refer to documents at the end of this
notice.
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Although the current marketers are voluntarily placing naproxen in
child-resistant packaging, a mandatory special packaging standard for
naproxen products would ensure that other companies that may market
such products in the future would use CR packaging. As discussed below,
an increased incidence of accidental ingestions by children under 5
involving ibuprofen (another NSAID) after it became available OTC,
supports this action. 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.
3. The Proposed Rule
On November 14, 1994, the Commission issued a proposed rule that
would require CR packaging for OTC drugs containing the equivalent of
250 mg or more of naproxen. 59 FR 56445. As discussed below, the
Commission received 4 comments in response to the proposed rule. All
were in favor of issuing the rule.
The Commission also received a request to extend the comment period
from Syntex Corporation (``Syntex''), one of the companies involved in
the joint venture for temporary exclusive marketing rights for
naproxen. Syntex stated that it needed additional time to prepare a
response to the proposed rule since it had recently been acquired by
Roche. The Commission granted the request for an extension of time. 60
FR 2716 (January 11, 1995). However, the Commission did not
subsequently receive any comments from Syntex.
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).(5)
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.(5)
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.(5)
The Commission's Directorate for Epidemiology reviewed data from
the National Electronic Injury Surveillance System (``NEISS'')
involving hospital emergency room treatment of children under 5 years
old who ingested naproxen. NEISS is a probability sample based on
hospital emergency rooms nationwide. There were nine reported cases
from 1980 to 1989 and 26 reported cases from 1990 to 1994. The average
annual number of estimated cases during these time periods was 50 and
260, respectively. In 1982, one case resulted in the hospitalization of
a 2-year-old male. In 1994, the Commission had reports of three
emergency room cases, each involving a 2-year-old child who was
examined or treated and released following ingestion of naproxen.(7)
The Commission's Directorate for Health Sciences requested 1993
incident data from the American Association of Poison Control Centers
(``AAPCC'') related specifically to naproxen in children under 5 years
old. (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.) Of the 1,413 naproxen
ingestions reported for 1993, 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.(5)
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 who died
following daily treatment for fever and an upper respiratory tract
infection with 100 to 400 mg naproxen sodium for 5 days; a 2-year-old
boy who 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; a 2-year-old girl who suffered dyspepsia (indigestion)
after ingesting 625 mg of naproxen; and a 5-year-old girl who developed
convulsions after she accidently ingested an unknown amount of naproxen
sodium.(5)
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 1984-1994 after ibuprofen was
granted OTC status, than for each year from 1980-1983.(7)
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: rash and
prolonged bleeding times were
[[Page 38673]]
increased; GI and central nervous system (CNS) reactions were similar;
and other reactions decreased.(5)
The relevant literature shows that naproxen and other NSAID's have
adverse fetal effects when used during pregnancy. A 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.(5)
C. Level for Regulation
The Commission is issuing a rule that requires special packaging
for OTC naproxen products containing the equivalent of 250 mg or more
naproxen per retail package. This level is based on established
guidelines for medical treatment following ingestion of NSAID's. It is
also based on a known toxic dose of naproxen, reduced by a safety
factor to account for biologic variability. (5 and 10)
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. (5 and 10)
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. (5 and 10)
The Commission emphasizes that the 250 mg level applies to the
total amount of the product sold at retail in a single package,
regardless of whether the contents of the package are loose or also
packaged in non child-resistant envelopes or strip packages. In
administering the PPPA regulations for acetaminophen, iron-containing
preparations and ibuprofen, the Commission has encountered instances in
which product manufacturers package one or two tablets in individual
envelopes for sale to consumers seeking medication for immediate use.
Because each envelope is an individual retail unit and contains less
than the amount of ibuprofen or acetaminophen subject to regulation,
the envelopes need not be child-resistant.
However, the Commission has also encountered instances in which
repackagers have packaged multiple non child-resistant envelopes of
acetaminophen, iron, or ibuprofen in outer blister packs or clamshell
packages that contain a total quantity of these products in excess of
the regulatory minimum, but that are also not child-resistant. We note
that the regulatory minimum contained in a ``single package'' refers to
the total contents of the retail package, not the contents of each
individual envelope. To avoid future confusion on this issue, this
regulation refers to the contents of the ``retail package'' to clarify
that whether a product requires child-resistant packaging is based on
the total amount of naproxen packaged for sale at retail.
D. Comments on the Proposed Rule
The Commission received four comments responding to the proposed
rule. These came from the American Society of Health-System
Pharmacists, the National Association of Pediatric Nurse Associates and
Practitioners, and two groups of university students. All agreed that
the Commission should require CR packaging for naproxen. In addition,
the students argued for an effective date shorter than the 180-day
period proposed by the Commission. One group of students advocated a
90-day effective date. The argument for the shorter date was that the
companies with exclusive marketing rights are voluntarily using CR
packaging now.
The Commission does not agree that a shorter effective date is
necessary. In general, the PPPA requires at least 180 days before a
regulation takes effect. 15 U.S.C. 1471n. As explained in section F
below, the Commission does not believe that a shorter period is
justified in this case.
E. 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.(5) The Commission 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 finds 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
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. (9)
The current marketers of OTC naproxen use packaging that not only
is child resistant, but also is easier for adult consumers to open.
Therefore, the Commission concludes that CR packaging for naproxen is
technically feasible, practicable, and appropriate.
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;
[[Page 38674]]
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.
F. 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 does not believe that a shorter effective date is
necessary to protect the public interest. Naproxen is currently sold in
CR packaging by the companies that have exclusive marketing rights
until January 11, 1997. The Commission does not have any indication
that significant quantities of naproxen will be marketed in non-CR
packaging before a 180 day effective date, with the possible exception
of 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. The final rule will apply to products that are
packaged on or after the effective date.
G. 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.
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.
For the proposed rule, the Commission's Directorate for Economics
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 concluded
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 sole marketing rights for 3 years. Furthermore, the relatively low
costs of CR packages should not be an entry burden for future
marketers. The Commission received no comments on its preliminary
analysis and is not aware of any changes that would affect the
Commission's previous conclusion. Thus, the Commission 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. (8)
H. 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 PPPA
requirements for naproxen 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). In connection
with the proposed rule, the Commission determined that CR packages for
naproxen preparations would have no significant effects on the
environment. The Commission is unaware of any developments to change
this preliminary assessment. Therefore, because the rule would have no
adverse effect on the environment, neither an environmental assessment
nor an environmental impact statement is required. (8)
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, 16 CFR part 1700 is amended 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 republishing paragraph (a)
introductory text and adding new paragraph (a)(25), to read as follows:
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) Naproxen. Naproxen preparations for human use and containing
the equivalent of 250 mg or more of naproxen in a single retail package
shall be packaged in accordance with the provisions of Sec. 1700.15
(a), (b), and (c).
Dated: July 24, 1995.
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,'' September 28, 1994.
5. Memorandum from Sandra Inkster, Ph.D., HSHE, to Jacqueline
Ferrante, Ph.D., HSPS, ``Review of Naproxen Toxicity,'' July 17,
1994.
6. Briefing memorandum from Jacqueline Ferrante, Ph.D., HSPS, to
the Commission, ``Proposed Special Packaging Standard for
Naproxen,'' September 29, 1994.
7. Memorandum from Terry Kissinger, Ph.D., EPHA, to Jacqueline
Ferrante, Ph.D., HSPS, ``Update of Injury Data Involving Naproxen
and Ibuprofen,'' May 4, 1995.
8. Memorandum from Marcia P. Robins, ECSS, to Jacqueline
Ferrante, Ph.D., HSPS, ``Final Regulatory Flexibility Act Analysis:
Child-Resistant Packaging for OTC Packages Containing 250 mg or more
of Naproxen,'' June 12, 1995.
9. Memorandum from Charles Wilbur, HSPS, to Jacqueline Ferrante,
Ph.D., HSPS, ``Technical Feasibility, Practicability, and
Appropriateness Determination for the Final Rule to Require Child-
Resistant Packaging for OTC Preparations Containing Naproxen,'' May
4, 1995.
[[Page 38675]]
10. Briefing memorandum from Jacqueline Ferrante, Ph.D., HSPS,
to the Commission, ``Final Special Packaging Standard for
Naproxen,'' June 29, 1995.
[FR Doc. 95-18504 Filed 7-27-95; 8:45 am]
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