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

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]

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