Final Rule: Requirements for Child-Resistant Packaging; Packages Containing 250 mg or More of Naproxen

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;

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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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