Proposed Rule: Requirements for Child-Resistant Packaging; Packages Containing More Than 50 mg of Ketoprofen

CONSUMER PRODUCT SAFETY COMMISSION

16 CFR Part 1700

Proposed Rule: Requirements for Child-Resistant Packaging;

Packages Containing More Than 50 mg of Ketoprofen

AGENCY: Consumer Product Safety Commission.

ACTION: Proposed rule.

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SUMMARY: The Commission is proposing a rule to require child-resistant

packaging for ketoprofen preparations containing more than 50 mg of

ketoprofen per retail package. Ketoprofen is a nonsteroidal anti-

inflammatory drug and is used to relieve minor aches and pains and to

reduce fever. 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 ketoprofen. The Commission takes this action under the

authority of the Poison Prevention Packaging Act of 1970.

DATES: Comments on the proposal should be submitted no later than

February 3, 1997.

ADDRESSES: Comments should be mailed to the Office of the Secretary,

Consumer Product Safety Commission, Washington, DC 20207, or delivered

to the Office of the Secretary, Consumer Product Safety Commission,

Room 502,

[[Page 59044]]

4330 East-West Highway, Bethesda, Maryland 20814-4408, telephone (301)

504-0800.

FOR FURTHER INFORMATION CONTACT: Jacqueline Ferrante, Ph.D., Division

of Poison Control and Scientific Coordination, Directorate for Health

Sciences, Consumer Product Safety Commission, Washington, DC 20207;

telephone (301) 504-0477 ext. 1199.

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), 16 CFR 1700.5.

2. Ketoprofen

Ketoprofen is a nonsteroidal anti-inflammatory drug (``NSAID'').

This class of compounds also includes ibuprofen and naproxen.

Ketoprofen is used to relieve minor aches and pains such as those

associated with colds, toothaches, menstrual cramps, and muscular

aches. It is also used to reduce fever.[2] 1

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\1\ Numbers in brackets refer to documents listed at the end of

this notice.

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For the past ten years, ketoprofen has been a prescription drug.

Like all prescription drugs, it was required to be in child-resistant

packaging by the Commission's regulation of human oral prescription

drugs, 16 CFR 1700.14(a)(10). The U.S. patent on ketoprofen expired in

1993. On October 6, 1995, the Food and Drug Administration (``FDA'')

granted nonprescription (``over-the-counter,'' or ``OTC'') status to

ketoprofen. [2]

The OTC formulations, ketoprofen and ketoprofen tartrazine, contain

12.5 milligrams (mg) of ketoprofen per dose. The recommended dose is 1

tablet every 4 to 6 hours. The maximum daily dose is 6 tablets. The

drug is not recommended for children under 16 years old except under

the supervision of a doctor. OTC ketoprofen should not be used (1) with

any other analgesic or anti-pyretic, (2) for more than 3 days for

fever, (3) for more than 10 days for pain, or (4) during the last

trimester of pregnancy unless directed by a physician. [2]

3. Special Packaging

The current marketers are voluntarily placing ketoprofen in child-

resistant packaging. However, a mandatory special packaging standard

for ketoprofen products would ensure that other companies that may

market such products in the future would use CR packaging.

Two other NSAIDs that previously became available OTC are ibuprofen

and naproxen. After ibuprofen was introduced OTC, there was an

increased incidence of accidental ingestions of the drug by children

under 5. [2]

In part to avoid a similar experience with naproxen, in 1995, the

Commission then issued a rule requiring CR packaging for naproxen

preparations containing 250 mg or more per retail package. 60 FR 38671.

The rule became effective February 6, 1996. Similar reasoning applies

to ketoprofen.

A mandatory standard for ketoprofen 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 Ketoprofen

The Commission's Directorate for Epidemiology and Health Sciences

reviewed the toxicity of ketoprofen. Side effects commonly associated

with ketoprofen, as with other NSAID's, are gastrointestinal (GI)

complications. These include nausea, vomiting, diarrhea, constipation,

heartburn, and abdominal pain. Other common adverse effects include

headache, dizziness, visual disturbances, rash, and hypersensitivity

reactions.[2]

Ketoprofen may also cause more severe adverse GI effects, such as

gastric or duodenal ulcer with bleeding or perforation; intestinal

ulcers; ulcerative stomatitis or colitis; gingival ulcer; perforation

and hemorrhage of the esophagus, stomach, small or large intestine;

hematemesis; and rectal bleeding. Renal injuries also may result from

chronic use of ketoprofen.[2]

The staff reviewed the relevant medical literature which cites

several cases of severe adverse reactions to ketoprofen administration.

In one case, a 61 year old woman suffered acute renal failure after

taking 400 mg of ketoprofen daily for 10 days. She recovered after

peritoneal dialysis. In addition, the literature reports one case of

pancreatitis after 12 days of ketoprofen therapy and two cases of

ketoprofen induced hepatitis. Other cases reported in the literature

involved co-ingestion of other substances.[2]

The FDA maintains a data base known as the Adverse Events Reporting

System (``AERS'') for reports of adverse reactions detected after

marketing a drug or biological product. Drug manufacturers are required

to report to the FDA any known adverse effects associated with their

products, but only an estimated 1% of all adverse reactions are

actually reported. Also, reports may reflect effects from an underlying

disease process or a reaction to multiple drugs. Of the 903 ketoprofen-

associated cases reported to the FDA between 1986 and October 1995, the

most common adverse reactions were abdominal pain (122), diarrhea (87),

nausea (82), GI hemorrhage (70), rash (55), indigestion (39), labored

breathing (34), allergic reaction (30), dizziness (30), and hives

(30).[2]

Among the ketoprofen cases in the AERS database are 51 more serious

reactions, i.e., hospitalizations, reactions resulting in permanent

disability, or deaths. Five of these involved children under 16 years

of age. Three 15 year old children required hospitalization for severe

renal injury, and one 15 year old suffered a life-threatening GI

hemorrhage and perforation. These events followed 10-18 days of therapy

with daily doses of 200-225 mg ketoprofen. A 10 year old also required

hospitalization for severe

[[Page 59045]]

vision abnormalities after 15 days of treatment with 150 mg

ketoprofen.[2]

The medical literature reports 2 overdoses, both involving other

substances as well. In one case, a 12 year old girl ingested an unknown

amount of ketoprofen plus 12 hydrocodone/acetaminophen tablets. She

developed tonic-clonic seizures with loss of consciousness and

metabolic acidosis. The symptoms resolved within 2 hours and she

recovered fully. In the other incident, an adult ingested 12 capsules

of sustained release ketoprofen 200 mg (total=2.4 grams) with 375

milliliters (12.5 ounces) of vodka. Only mild effects resulted since

the victim vomited within 1 hour of the ingestion.[2]

The AERS database reports no pediatric ketoprofen overdoses, but

there were some incidents involving adults. One intentional overdose of

1,000 mg ketoprofen resulted in moderate to severe kidney injury

(kidney pain, bloody urine, increase creatinine levels). Ingestion of

500 mg of ketoprofen plus an unknown amount of ciprofloxacin produced

death in a 50 year old woman. The symptoms which included GI

hemorrhage, thrombocytopenia, coagulation disorders, and decreased

prothrombin, were most likely related to ketoprofen.[2]

The AERS system also reports two neonatal poisoning cases in which

the mothers took ketoprofen at some point in their pregnancy. One

infant died shortly after birth from acute renal failure. In the second

case (which involved multiple medications) twins developed acute renal

failure shortly after birth. One twin died and the other recovered but

was neurologically impaired.[2]

The staff reviewed accidental ingestion data for children under age

5. The American Association of Poison Control Center (``AAPCC'')

collects incident data through its Toxic Exposure Surveillance System

(``TESS'') which covers incidents from 1985 to 1994. Poisoning

incidents involving ketoprofen are not recorded separately from other

NSAIDs unless they were fatal. No deaths involving ketoprofen were

reported during this period.[2]

CPSC's data base, the National Electronic Injury Surveillance

System (``NEISS'') monitors emergency room visits to selected hospitals

throughout the United States. Review of NEISS data from 1988 to June

1996 shows three cases involving ketoprofen and children under 5 years

old. All three incidents occurred in 1996. None were fatal or required

hospitalization.[2]

C. Level for Regulation

The Commission is proposing a rule that requires special packaging

for OTC ketoprofen products containing more than 50 mg ketoprofen per

retail package. This level is based on established guidelines for

medical treatment following pediatric ingestion of NSAID's.[5] These

guidelines suggest medical treatment for young children who ingest five

times the maximum single therapeutic dose. For ketoprofen, the maximum

single therapeutic dose is 75 mg or 1.08 mg/kg assuming an average

adult weight of 70 kg. The dose of ketoprofen requiring medical

intervention would be five times 1.08 mg/kg, which in a 10-kg child

would be more than 50 mg of ketoprofen, or four OTC tablets.[2]

D. Statutory Considerations

1. Hazard to Children

As noted above, the toxicity data concerning children's ingestion

of ketoprofen demonstrate that this compound can cause serious illness

and injury to children. Moreover, the preparations are readily

available to children. The Commission preliminarily 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 preliminarily finds that the degree and nature of the hazard

to children from ingesting ketoprofen 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.[4]

The current marketers of OTC ketoprofen voluntarily use packaging

that is child resistant. Similar designs have been shown to meet the

revised testing protocol for senior adult use effectiveness. Therefore,

the Commission concludes that CR packaging for ketoprofen is

technically feasible, practicable, and appropriate.[3]

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;

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 factors with respect to the

various determinations made in this notice, and preliminarily finds no

reason to conclude that the rule is unreasonable or otherwise

inappropriate.

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 final 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. The companies that are

currently marketing ketoprofen are voluntarily using CR packaging. The

Commission does not have any indication that significant quantities of

ketoprofen will be marketed in non-CR packaging before a 180 day

effective date, except for 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 and proposes that a final

rule would take effect 180 days after publication of the final rule. A

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.,

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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.

The Commission's Directorate for Economic Analysis prepared a

preliminary assessment of the impact of a rule to require special

packaging for ketoprofen preparations with more than 50 mg ketoprofen

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 ketoprofen are using CR packaging.

Furthermore, the relatively low costs of CR packages should not be an

entry burden for future marketers.

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 PPPA

requirements for ketoprofen 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). Therefore,

because the 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)(25),

reading as follows (although unchanged, the introductory text of

paragraph (a) is republished 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:

* * * * *

(25) Ketoprofen. Ketoprofen preparations for human use and

containing more than 50 mg of ketoprofen in a single retail package

shall be packaged in accordance with the provisions of Sec. 1700.15

(a), (b), and (c).

* * * * *

Dated: November 15, 1996.

Sadye E. Dunn,

Secretary, Consumer Product Safety Commission.

List of Relevant Documents

1. Briefing memorandum from Jacqueline Ferrante, Ph.D., HSPS, to

the Commission, ``Proposed Rule to Require Child-Resistant Packaging

for Ketoprofen,'' October 15, 1996.

2. Memorandum from Susan C. Aitken, Ph.D., HSHE, to Jacqueline

Ferrante, Ph.D., HSPS, ``Toxicity of Ketoprofen,'' August 19, 1996.

3. 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 for OTC Pharmaceuticals Containing Ketoprofen,'' August

19, 1996.

4. Memorandum from Charles Wilbur, HSPS, to Jacqueline Ferrante,

Ph.D., HSPS, ``Technical Feasibility, Practicability, and

Appropriateness Determination for the Proposed Rule to Require

Child-Resistant Packaging for OTC Products Containing Ketoprofen,''

August 20, 1996.

5. Vale, J.S. and Meredith, T.J. Acute Poisoning Due to Non-

steroidal Anti-inflammatory Drugs: Clinical Features and Management.

Med. Toxicol. 1:12-31, 1986.

[FR Doc. 96-29691 Filed 11-19-96; 8:45 am]

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