[Federal Register Volume 66, Number 169 (Thursday, August 30, 2001)]
[Notices]
[Pages 45841-45843]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-21880]



[[Page 45841]]

=======================================================================
-----------------------------------------------------------------------

CONSUMER PRODUCT SAFETY COMMISSION


Poison Prevention Packaging; Notice of Stay of Enforcement for 
Lidoderm Patch

AGENCY: Consumer Product Safety Commission.

ACTION: Stay of enforcement.

-----------------------------------------------------------------------

SUMMARY: This notice announces the Commission's decision to stay 
enforcement of special packaging requirements for the orphan drug, 
Lidoderm. The Commission will stay enforcement under the 
conditions stated at the end of this notice.

DATES: The stay will be effective on August 30, 2001.

FOR FURTHER INFORMATION CONTACT: Geri Smith, Office of Compliance, 
Consumer Product Safety Commission, Washington, DC 20207; telephone 
(301) 504-0608, extension 1160.

SUPPLEMENTARY INFORMATION:

A. Background

    Under the Poison Prevention Packaging Act (``PPPA''), the 
Commission has the authority to require special packaging for drugs (as 
well as certain other household products) if it finds that child 
resistant (``CR'') packaging is necessary to protect children from 
serious personal injury or illness from handling using or ingesting the 
drug and that CR packaging is technically feasible, practicable and 
appropriate. 15 U.S.C. 1472(a). In 1995, the Commission issued a rule 
requiring CR packaging for lidocaine products with more than 5 
milligrams (mg) of lidocaine in a single package. 16 CFR 1700.14 
(a)(23).
    Lidoderm is a dermal patch that contains lidocaine. Each 
Lidoderm patch contains 700 mg lidocaine. Lidoderm 
is marketed in the form of five patches inside a non-CR resealable foil 
envelope to maintain the integrity of the product. One non-CR carton of 
Lidoderm contains six envelopes (each envelope contains five 
patches) for a total of 30 patches per carton.
    In May 1999, Commission staff discovered that Lidoderm 
was being packaged in non-CR packaging and notified the distributor, 
Endo Pharmaceuticals Inc. (``Endo'') of the special packaging 
requirement for lidocaine products. To comply with the PPPA, the 
immediate container for a product that requires special packaging must 
be CR. Thus, for Lidoderm patches, each patch must be 
packaged in an individual CR pouch or a single resealable CR pouch must 
contain all of the patches (i.e., no carton and no foil envelope, only 
a resealable CR pouch). At Endo's request, the Commission granted Endo 
a temporary stay of enforcement on May 15, 2000, on the condition that 
Endo provide pharmacists with an outer CR package to dispense the 
product while it was developing a plan and timeline to package each 
patch in a CR pouch.
    On August 14, 2000, Endo petitioned the Commission for a partial 
exemption for Lidoderm from special packaging requirements 
stating that ``it is not practicable to market each Lidoderm 
patch in a child-resistant envelope.'' The petitioner argues that to do 
so is cost prohibitive and would force it to discontinue production of 
Lidoderm. Endo asks for an exemption so that it may replace 
the non-CR carton with the CR pouch so that the six envelopes (5 
patches per envelope) are marketed in the CR pouch, not in the non-CR 
carton.

B. The Product

    Lidoderm is a lidocaine-containing dermal patch available 
only by prescription. It is manufactured by Teikoku Seiyaku, Co., Ltd., 
a Japanese company, and the only manufacturer the Food and Drug 
Administration (``FDA'') has approved to manufacture 
Lidoderm. Endo is the only distributor the FDA has approved 
for Lidoderm. The FDA designated Lidoderm as an 
orphan drug on October 24, 1995 and approved it for marketing on March 
19, 1999. Endo started marketing Lidoderm on September 15, 
1999. Orphan drugs are intended for rare diseases affecting less than 
200,000 people or affecting more than 200,000, but for which there is 
no expectation that the costs of drug development will be recovered 
from sales. The Orphan Drug Act encourages the development of orphan 
drugs, through economic incentives such as tax credits for clinical 
research and seven years of marketing exclusivity.
    Lidoderm is prescribed to treat post-herpetic neuralgia 
(``PHN''), a rare, chronic condition that results from nerve injury 
caused by shingles. Shingles occurs following reactivation of the 
herpes zoster virus (the same virus responsible for chickenpox) and is 
characterized by painful fluid-filled skin blisters. PHN is more common 
in the elderly. Approximately 10% of all patients with shingles develop 
PHN. Endo estimates that about 200,000 Americans have PHN. There is no 
cure for PHN, and treatment is aimed at controlling the pain by various 
methods including drug therapy (e.g., analgesics, antidepressants, 
topical anesthetics, and anticonvulsants), acupuncture, and nerve 
block.
    Each carton of Lidoderm contains 30 patches packaged in 
six resealable foil envelopes with five patches per envelope. Neither 
the carton nor the individual envelopes are CR. Currently, Endo is 
including a CR reclosable pouch large enough for the six envelopes in 
each carton. Each Lidoderm patch is 22 square inches (10 cm x 
14 cm) and contains 700 mg of lidocaine. The amount of lidocaine 
systemically absorbed from Lidoderm depends on both the 
duration of exposure and the surface area of skin covered. The 
recommended dose is up to three patches at one time only once for up to 
12 hours in a 24-hour period. Patches may be cut into smaller sizes 
prior to removal of the release liner. The petitioner did not provide 
data related to the stability of the lidocaine in a cut or used patch, 
but instructions on the product envelope advise that the patch adhesive 
contains water and will dry out if the package is left open.
    According to the petition, Lidoderm is unlike other patch 
systems in that the lidocaine in Lidoderm is not contained in 
a reservoir, but is embedded in the patch adhesive. Therefore, the 
patch releases a low level of lidocaine into the skin over a long time 
period ensuring that it produces analgesia (pain reduction) rather than 
anesthesia (numbness). Since only a small percentage (3%  
2%) of lidocaine is absorbed dermally from the Lidoderm patch 
when used therapeutically, about 95% of the lidocaine will remain in a 
used patch. Endo states that the lidocaine is less accessible from this 
patch system than from other formulations (such as, creams and liquids) 
and that a child would need to chew or suck on the patch for some time 
before any lidocaine would be absorbed through the mouth or swallowed. 
However, there are no oral absorption data indicating the extent of 
oral exposure necessary for a child to absorb a toxic dose. Endo 
provides a warning with the product to store and dispose of 
Lidoderm out of the reach of children and pets.

C. Endo's Request

    In its petition, Endo asks essentially that the temporary stay of 
enforcement granted by the Commission on May 15, 2000, be made a 
permanent exemption from special packaging requirements. Endo argues 
that full compliance with the PPPA, which requires that the immediate 
container of a lidocaine-containing drug be CR, would be cost-
prohibitive. Endo maintains that the costs of new equipment, plant re-
engineering, and testing for FDA approval are prohibitive and would

[[Page 45842]]

force them to discontinue marketing Lidoderm. Teikoku 
estimates a large total cost for the changes required to place each 
patch in a CR pouch. This includes the cost of: (1) New envelope 
processing machines; (2) producing three FDA submission batches; (3) 
extended specification compliance testing on all three batches; (4) 
accelerated stability testing; and (5) real-time stability testing. The 
petitioner maintains that ``manufacturing and packaging one patch per 
envelope would result in a significant increase in the cost of 
manufacturing Lidoderm because there would be significant 
increases in the amount of labor and materials.''
    Endo also argues that it would take much longer than the current 
packaging method to produce an equivalent amount of Lidoderm 
in individual CR pouches. Endo states that this change in the 
production schedule for Lidoderm is an ``undue burden'' for 
Teikoku because it would affect Teikoku's production of other products. 
Teikoku is unwilling to allow another manufacturer to take over 
production because the manufacturing process for Lidoderm is 
proprietary. CPSC has not been able to verify the accuracy of Endo's 
cost estimates. However, Endo maintains that it will discontinue 
production of Lidoderm if forced to place each patch in CR 
packaging. If that were to happen, Lidoderm would no longer 
be a therapeutic option for PHN patients.

D. PPPA Requirements for an Exemption

    The Commission's regulations provide for a company or other 
interested persons to submit a petition requesting an exemption from 
PPPA requirements. 16 CFR part 1702. Those rules require a petitioner 
to provide a justification for the exemption based on one or more of 
the following grounds: (1) Special packaging is not necessary to 
protect children from serious injury or illness from the substance; (2) 
special packaging is not technologically feasible, practicable, or 
appropriate for the substance; and/or (3) special packaging is 
incompatible with the substance. 16 CFR 1702.7. Similarly, the 
Commission's rules provide that if the Commission finds that a 
petitioner has presented ``reasonable grounds'' for an exemption, it 
shall publish a proposed amendment exempting that substance from 
special packaging requirements.
    ``Reasonable grounds'' are:

    Information and data sufficient to support the conclusion that:
    (a) The degree or nature of the hazard to children in the 
availability of the substance, by reason of its packaging, is such 
that special packaging is not required to protect children from 
serious personal injury or serious illness resulting from handling, 
using, or ingesting the substance, or
    (b) Special packaging is not technically feasible, practicable, 
or appropriate for the substance, or
    (c) Special packaging is incompatible with the particular 
substance.

16 CFR 1702.17.
    In its petition, Endo states as its justification that ``it is not 
practicable to market each Lidoderm patch in a child-
resistant envelope.'' Endo argues that the high cost and practicable 
difficulties, discussed above, of packaging each individual 
Lidoderm patch in a CR container justify an exemption.
    Endo states that there have been no reports of adverse events or 
accidental exposures of Lidoderm to children. Although Endo 
states that Lidoderm does not present the same degree of 
poisoning risk to children as other lidocaine products, Endo does not 
argue and does not provide any data indicating that the lidocaine in 
Lidoderm patches is not toxic to children. Thus, Endo does 
not seem to be relying on lack of toxicity to children as a 
justification for an exemption.
    Legislative history of the PPPA indicates that the term 
``practicability'' means that ``special packaging meeting the standard 
would be susceptible to modern mass-production and assembly-line 
techniques.'' S. Rep. 845 91st Cong., 2d Sess 10 (1970). Endo does not 
argue that Lidoderm cannot be produced with CR packaging that 
complies with the PPPA. Rather, Endo asserts that such packaging would 
be so costly that it could not continue to market Lidoderm. 
Thus, the Commission cannot make the requisite finding that CR 
packaging would not be practicable for Lidoderm that would 
justify an exemption under the Commission's regulations.

E. Stay of Enforcement

    Endo has, however, presented information indicating the need for 
the orphan drug Lidoderm, the prohibitive cost involved in CR 
packaging for each Lidoderm patch, the limited market for the 
product, and the protection for children that would be provided by 
packaging Lidoderm patches in an outer CR package. The 
Commission finds that these circumstances justify the stay of 
enforcement. The stay will be issued with the following conditions:
    1. Endo Pharmaceuticals must, as stated in section IV of the 
petition, ``replace the outer carton for Lidoderm with a CR 
reclosable pouch containing six resealable foil envelopes (5 patches 
per envelope)'' with instructions to pharmacists that they must 
dispense Lidoderm envelopes in the outer pouch. Moreover, 
additional outer CR pouches must be provided to pharmacists upon 
request in order to accommodate prescriptions of less than a full 
package of 30 patches.
    2. The outer CR package must bear a prominent and conspicuous label 
stating the following:

``WARNING:
    New and used patches could harm small children if chewed or 
swallowed. Envelopes in this package are NOT child resistant. You 
MUST keep envelopes inside this child-resistant package with the 
zipper closed.

Keep new and used patches out of the reach of children.''

    3. The envelopes containing the five Lidoderm patches 
(the immediate packaging) must continue to bear the warning label 
``Package not child resistant. Keep used and unused patches out of the 
reach of children.''
    4. Lidoderm must remain designated by the FDA as an 
orphan drug indicated solely for the treatment of PHN. If Endo obtains 
orphan drug status for Lidoderm for the treatment of any 
other condition, Endo shall direct to the Commission's Office of 
Compliance, a request for a determination of whether the terms of this 
stay shall apply to the product.
    5. Lidoderm must be manufactured only by Teikoku Seiyaku 
Co., Ltd, at its present location in Japan under the current material 
operating conditions and procedures described in Section V of the 
petition. Any questions related to changes in such operating conditions 
or procedures can be directed to the Commission's Office of Compliance.
    6. Endo Pharmaceuticals must (1) notify the Commission's 
Directorate for Health Sciences within five business days of becoming 
aware of any poisonings or other exposures (i.e., physical contact) to 
the patches by children under 5 years old; and (2) purchase American 
Association of Poison Control Center data for Lidoderm once a 
year and submit it to the Commission's Directorate for Health Sciences.
    7. Endo must report annually to the Office of Compliance confirming 
that the conditions upon which the stay has been granted remain in 
effect. Additionally, Endo must notify the Office of Compliance 30 days 
in advance of any change that materially affects its compliance with 
any provision of the stay.


[[Page 45843]]


    Dated: August 24, 2001.
Todd Stevenson,
Acting Secretary, Consumer Product Safety Commission.
[FR Doc. 01-21880 Filed 8-29-01; 8:45 am]
BILLING CODE 6355-01-P