[Federal Register Volume 59, Number 218 (Monday, November 14, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-27961]


[[Page Unknown]]

[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