> October 14, 2003

Division of Dockets Management (HF-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

*Re*: [Reopening of Docket No. 78N-0301, Regarding the Monograph Status
of Patch, Plaster, and Poultice Products]{.underline}

The undersigned, Chattem, Inc. (Chattem), submits the following comments
and data in response to the Food and Drug Administration's (FDA)
reopening of the administrative record for the rulemaking for
over-the-counter (OTC) external analgesic drug products.[^1] These
comments and data concern FDA's proposed amendment of the Tentative
Final Monograph (TFM) to exclude patch, plaster, and poultice dosage
forms from classification as Category I, or monograph conditions
(generally recognized as safe and effective). We respectfully disagree
with this proposed amendment and with FDA's opinion that insufficient
data exists to classify these products as Category I.

Section I of this submission presents specific comments related to FDA's
proposed amendment reclassifying patch, plaster, and poultice products
as Category III. Section II comments on specific documents in the
administrative record relating to the data required to reclassify these
products in Category I. Section III presents additional data for
inclusion in the administrative record in answer to the seven specific
questions posed by FDA in the notice of the reopening of the record.

Chattem is an active participant in the Consumer Healthcare Products
Association (CHPA) Task Force on Alternative Dosage Forms (Task Force).
In addition to the comments presented here, Chattem endorses and
subscribes fully to the proposal submitted by the Task Force regarding
the inclusion of and testing requirements for patch, plaster, and
poultice products. Chattem supports fully the continued communication
between the Task Force and FDA in developing a standard to allow these
products to be proven safe and effective to FDA's satisfaction, so that
these beneficial and convenient products may continue to be marketed.

# **FDA's proposed amendment reclassifying patch, plaster, and poultice products as Category III**

FDA has proposed to amend the TFM to exclude patch, plaster, and
poultice dosage forms from Category I. This amendment is inappropriate
because it fails to take into account the additional safety and efficacy
benefits provided by these dosage forms, and because it will
disadvantage consumers.

## **Patch products have advantages over recognized dose forms**

The TFM includes in Category I counterirritant products in cream,
lotion, and ointment dosage form. The active ingredient in patch
products and in lotions, creams, and ointments work locally in a similar
manner. However, patches deliver the active ingredient in a uniformly
distributed, measured dose. Patch products offer incremental advantages
over other safe and effective dosage forms. Accordingly, patch products
employing Category I active ingredients should be included as Category I
in the TFM.

Patches differ from creams, lotions, and ointments, in that the consumer
has the ability to control the delivery of active ingredient by removing
a patch product from the skin to effectively stop further absorption of
the active ingredient. Moreover, a patch releases its active ingredient
slowly over time.

Furthermore, the patch dosage form is incrementally superior to the
other types of dosage forms because it necessarily delivers an active
ingredient over a fixed surface area to which the product is applied.
Moreover, the patch delivery mechanism allows the consumer the option to
apply the active ingredient to a limited area of skin and releases the
active ingredient in a controlled manner. Therefore, the concentration
of active ingredient in the patch and the size of the patch effectively
determine the dose received by the consumer. While a consumer could in
theory apply several patches either adjacent to one another or across
various body parts, the coverage area is limited by the very size and
cost of the patch. Furthermore, because the patch remains a visible
symbol of the medication's presence and because the patch must be
physically removed from the skin in order to apply another dose of
medication, consumers are less likely to reapply patches than they are
alternative dosage forms. The additional patch-specific labeling
proposed by the Task Force, for example limiting the number of patches
that may be applied, will strengthen this safety aspect, as well.

The patch dosage form also presents a low risk for contact with
sensitive body parts such as eyes and mucous membranes, and a low risk
of accidental ingestion. When applying the external analgesic patch to
the skin, little or no residue attaches to the hands, and the site of
application does not become oily or greasy. Because no residue is
present, the chance of getting the active ingredient(s) into unwanted
areas such as the eye is substantially reduced. Furthermore, the solid
patch form of the active ingredient is unlikely to be ingested by
children or adults, thus alleviating toxicity concerns.[^2]

A patch provides the consumer with additional advantages, for example,
predictable, sustained delivery of active over time that can not be
rubbed off. The result is to assure the user of effective symptomatic
relief without messiness or staining. In addition, patches are at least
as efficacious as creams, lotions, and ointments because of their
delivery properties. As recognized by FDA, patches prevent moisture
evaporation from the skin and thus "facilitate penetration of the active
ingredient into the affected area, resulting in sustained local action
of the drug."[^3] Chattem's market research provides additional evidence
of this improved efficacy, as users experienced greater pain relief with
the patch than with their current pain rub. A significant proportion (as
high as 86% and 96% in two of the studies) indicated that they would use
the patch as a replacement for, or in addition to, their current
product.[^4] In two other studies, 62% of users indicated that they
preferred the patch to other products they had used.[^5]

## **Exclusion of patch products from Category I would disadvantage consumers**

FDA's proposal to exclude patch products will disadvantage consumers. If
the Final Monograph does not recognize patch products as Category I,
manufacturers of these products will have to expend substantial sums of
money conducting the tests required to support a New Drug Application
(NDA), and will have to raise the price of the products in order to
recoup these expenses. Yet a significant proportion of consumers prefer
patch products to creams, lotions, and ointments for the same use.[^6]
Consumers will then have to choose between paying this increased price
for the product that they prefer, or purchasing a less desirable but
less expensive product recognized as Category I in the Final Monograph.

# **Comments on testing requirements established in the administrative record**

In documents in the administrative record, FDA has expressed concern
about the safety and efficacy of patch products. In particular, FDA has
expressed concern about the products' cutaneous safety, systemic safety,
efficacy, and dose delivery of active ingredient from the article to the
skin. In the documents recently admitted to the administrative record,
FDA has established its requirements for showing that patch products are
safe and effective for use as counterirritants. These documents outline
in great detail FDA's standards for this research and data.[^7]

## **Efficacy of Category I active ingredients has already been established**

FDA has stated that manufacturers of patch products must conduct
efficacy testing in order to justify a product's inclusion in Category
I, despite the fact that the product uses a Category I ingredient at a
Category I dosage.[^8] This requirement is inappropriate for products
that merely deliver a Category I active ingredient in a new dosage form.

In recommending study protocols to support the inclusion of Category III
external analgesic products in Category I, the Advisory Review Panel on
OTC Topical Analgesic, Antirheumatic, Otic, Burn, and Sunburn Prevention
and Treatment Drug Products (Panel) specified that "\[m\]anufacturers
are expected to furnish only data relevant to *unanswered questions*
regarding the safety and efficacy of the ingredients in their product.
They are not expected to furnish all the data. . . ."[^9] The Panel
noted that "\[s\]afety studies are required if the data submitted to
data (sic) have not substantiated claims that an ingredient is safe when
applied externally on the intact or damaged skin. Efficacy studies are
required if the data submitted to date have not substantiated the claim
that an ingredient is effective."[^10] The reverse must be true, as
well. If the data have established that an ingredient is effective FDA
does not require additional testing. While a manufacturer might
undertake such testing for its own purposes, a regulatory requirement of
such testing would be wasteful and duplicative.

The language used by the Panel in recommending particular types of
efficacy testing for external analgesic products also supports the
conclusion that additional efficacy testing is not required. The Panel
stated, "The following clinical studies are required to reclassify all
topical counterirritant *active ingredients* classified as Category III
for effectiveness. . . ."[^11] Furthermore, when initially establishing
the OTC drug review process, FDA acknowledged that "\[m\]any thousands
of \[OTC\] drugs are readily comparable in that the labeling is similar
and the active ingredients are the same, but are present in slightly
different dosages. Although each is a separate product, the same
scientific and medical evidence is relevant in reviewing all OTC drugs
within a given therapeutic class."[^12]

The experience and data that the Panel deemed sufficient to support the
ingredients' inclusion in Category I in cream, lotion, and ointment form
must also be sufficient to support their inclusion in other dosage
forms. As long as patch products are using monograph ingredients with
monograph labeling at monograph concentrations, and are otherwise proven
to be safe and effective, additional efficacy data on the ingredient
itself are not required.

Only issues that are specific to patch products must be addressed
through additional testing. Chattem agrees with FDA that additional data
is necessary relating to the delivery of active ingredient from the
patch to the skin and to dermal safety issues arising because of the
patch's potential occlusive properties.[^13] The Task Force is proposing
additional testing that will provide this additional data.

## **Percutaneous absorption testing is not necessary**

In numerous documents in the administrative record, FDA has expressed
concern that because of the potential occlusive properties of the patch
products, these products pose a heightened risk of toxicity resulting
from increased percutaneous absorption. FDA has stated that
manufacturers of patch products therefore must conduct percutaneous
absorption testing to prove that their products are safe.[^14] However,
FDA has not addressed this issue with other menthol products or with
patches delivering other active ingredients that raise toxicity
concerns. As with those patches, percutaneous absorption testing should
not be required for patches indicated for use as counterirritants.

FDA's concern regarding external analgesic patch products is
inconsistent with FDA's treatment of similar products. FDA currently
allows ointments containing a concentration of 2.6 to 2.8 percent
menthol to be marketed as antitussive products with the specific
direction that the consumer "cover \[the area\] with a warm, dry cloth
if desired."[^15] Covering the area with a cloth has a similar effect to
covering the area with a bandage or a patch. Furthermore, allowing an
ointment to be used in this manner poses greater risks than the patch
products because of the potentially unlimited skin area to which the
product may be applied, as discussed above in section I(A). Yet in
allowing menthol products to be marketed in this manner for the
antitussive indication, FDA neither received nor required any data
regarding the rate of percutaneous absorption of the menthol, indicating
that FDA does not consider this to be a significant concern.[^16]

Additionally, in the administrative record, FDA has expressed particular
concern about percutaneous absorption of methyl salicylate as an active
ingredient.[^17] One metabolite of methyl salicylate that is relevant in
addressing the possibility of toxicity is salicylic acid.[^18] Yet in
proposing the Corn and Callus Remover Monograph, the Advisory Review
Panel on OTC Miscellaneous External Drug Products specifically included
salicylic acid in plaster and pad dosage forms on the simple basis that
it was "unaware of any report of salicylism resulting from the topical
use of salicylic acid as a corn and callus remover."[^19] It required no
studies on percutaneous absorption or salicylism.[^20] When FDA later
included salicylic acid as a Category I ingredient for treatment of soft
corns in a plaster vehicle, FDA again did not require data regarding
salicylism or percutaneous absorption.[^21] The studies supporting this
use addressed only the dermal safety, and not the systemic safety, of
the products, even though the studies involved use of the product over a
period of up to 10 days, the period for which FDA has asserted that
systemic toxicity must be studied for external analgesic products
containing methyl salicylate.[^22]

FDA then also included salicylic acid as a Category I active ingredient
in plaster form in the Wart Remover Final Monograph on the basis of the
data supporting its inclusion in the Corn and Callus Remover
Monograph.[^23] Even when amending the relevant language, FDA relied on
two efficacy studies alone, and did not require any additional studies
related to systemic safety.[^24] Despite a treatment period of 12 weeks
in the studies, and the possible cumulative absorption issues that such
use might have raised, FDA clearly did not consider salicylism to be a
relevant concern for those products. Because FDA did not determine that
salicylism presented a sufficient risk to require percutaneous testing
research in those products, it should not require this additional
testing for external analgesic products with occlusive properties,
either.

# **Data regarding 5% menthol patch**

FDA has stated that it "is not aware of sufficient data to classify any
OTC external analgesic active ingredient in a patch, plaster, or
poultice dosage form as Category I."[^25] It further states that in
order for poultice and plaster dosage forms to be generally recognized
as safe and effective, FDA specifically needs more information in seven
areas.[^26]

Sufficient data and information presently exists to justify
classification of 5% menthol in a patch dosage form as Category I. We
provide the requested information below. Should FDA deem this
information insufficient in itself to support the inclusion of 5%
menthol in patch form as Category I, Chattem will commit to undertake
all testing reasonably necessary to produce the data required for FDA to
reach this conclusion, and will continue to cooperate with FDA through
the Task Force to determine the extent of testing required.

The data presented here is the result of research on the Icy Hot® Patch.
The Icy Hot Patch contains 5% menthol as its active ingredient. It is
comprised of a nonwoven polyester patch that is soft and dry on the
outside with an inert "adhesive-like" formula on the inside that adheres
the patch to the skin without the need of bioadhesives. This breathable,
gas permeable system is therefore not occlusive. Thus, the active
ingredient, menthol, is protected from loss prior to use by a thin,
perforated occlusive polypropylene lining that is easily removed when
opposing force is applied to the opposite ends of the patch. The primary
packaging is a heat sealed aluminum foil pouch. The pouch is resealable
using zip-top technology to further maintain product stability after
opening.

The Icy Hot Patch is marketed in two sizes. The original Icy Hot Patch
measures 3-1/8 by 4-5/8 inches (8 by 12 cm) and was launched in April
2001. Since its launch, more than 6.5 million cartons of the Icy Hot
Patch have been sold in the U.S. The larger patch measures 3-15/16 by
7-13/16 inches (10 cm by 20 cm) and was launched in May 2003.

## **Safe and effective concentration of the drug ingredients, especially under occlusion of a plaster**

Menthol at a concentration of 5% is safe and effective under occlusive
conditions, as shown by research on the Icy Hot Patch and in other
literature.

### **Safety**

#### **Chattem RIPT Study**

Chattem sponsored a Repeated Insult Patch Test (RIPT) study with two
developmental patch products, one utilizing a hydrogel vehicle and the
other non-hydrogel,[^27] which establishes that the patches do not pose
dermal safety concerns. Both products contained 5% menthol as the active
ingredient, and the studied non-hydrogel product was identical to the
currently marketed Icy Hot Patch and Icy Hot Back Patch in all ways
except size. A synopsis of the RIPT results from the hydrogel and
non-hydrogel sensitization test, combining the findings from Consumer
Product Testing Company final reports identified as C00-0602.01
(Non-hydrogel Study CSE-391) and C00-0602.02 (Hydrogel Study CSE-392) is
attached as Appendix 1, and the complete final reports are attached as
Appendices 2 and 3.

The protocol utilized was modeled in part after the Modified Draize test
recommended by FDA's Center for Drug Evaluation and Research (CDER) for
skin sensitization studies.[^28] In general, the Chattem study utilized
procedures and evaluations similar to those recommended by FDA such that
non-immunologic irritant skin responses and/or the induction of allergic
contact sensitization would have been detected, if present.

The study enrolled 113 subjects, of which 102 subjects completed the
study. The patch was applied to the upper back for 24-hour periods three
times weekly for three weeks. Scoring of skin reactions was performed
after a 24 or 48 hour rest period, on a 6-point scale: No visible skin
reaction (0); Barely perceptible or spotty erythema (+); Mild erythema
covering most of the test site (1); Moderate erythema, possible presence
of mild edema (2); Marked erythema, possible edema (3); Severe erythema,
possible edema, vesiculation, bullae and/or ulceration (4).

The majority of test subjects (approximately 90%) completed the repeat
exposure and challenge without demonstrable skin reaction. The remainder
had barely perceptible to moderate, transient erythematous reactions
consistent with irritation, scored as a level-2 or lower. Ten subjects
had reactions to both the hydrogel and the non-hydrogel patches, while
three other subjects reacted slightly to one patch and not the other.
Among the subjects who did react, 83% had irritation only at a single
observation point. These data clearly establish that the rate of
reaction to the 5% menthol patch is well within the expected range for
any counterirritant product, and that this product does not pose greater
safety risks than the currently marketed creams, lotions, and ointments.

#### **Health-Related Complaint Data**

Chattem has collected data from health-related experience reports, made
spontaneously by consumers, throughout the marketing of both Icy Hot
Patch products.[^29] While these reports may not provide either the
quantitative precision or certainty of cause and effect relationships
that may be obtained through controlled clinical trials, the collection
of complaint data provides useful information regarding safety. FDA
recognized as much in requiring that in the OTC drug review, "proof \[of
safety\] shall include results of significant human experience during
marketing."[^30] Such data are recognized to be useful in identifying
both circumstances associated with adverse events that may not have been
directly tested in clinical trials, and rare or low-incidence adverse
events not captured in clinical trials of limited size.[^31]

Between April 1, 2001 and August 5, 2003, more than 20 million Icy Hot
patches were sold,[^32] yet Chattem received a total of only 35
health-related complaints, comprising a total of 41 events. This yields
an extremely low ratio of health-related reports per units sold of less
than 1 complaint for each 500,000 patches sold. The rates of particular
health-related events are included as Appendix 4. These rates are
consistent with those reported in the Proposed Rule wherein one
manufacturer reported one complaint per 310,000 dosage units sold, while
a second reported a rate of one per 950,000.[^33]

A search of reports made under the MedWatch program showed that no
serious events have been reported for the patch. Likewise, none of the
experiences reported to Chattem were serious, as defined under the
MedWatch classification.[^34] The types of adverse experiences reported
to Chattem were generally consistent with menthol's reported ability to
cause contact dermatitis in rare instances.[^35] Some of the adverse
experiences (*e.g.*, cases of racing heart/palpitations) occurred in
individuals using multiple concomitant medications and with preexisting
risk factors for disease. Thus, experiences were not clearly
attributable to the application of the Icy Hot patches.

#### **Market Research**

Chattem marketing research also supports the conclusion that 5% menthol
in patch form is safe. Chattem has conducted six studies that support
the safety and efficacy of the Chattem products. A synopsis of these
studies is attached as Appendix 5. Although none of the studies was
conducted with the sole intent of assessing safety, they offered an
opportunity for the participants to comment on their likes and dislikes
about the product.

In the Concept and Use Test of the Icy Hot Back Patch conducted in
December 2002 (Study MR-5), 67 of the 100 respondents noted that they
liked that the patch was not irritating to skin.[^36] In the Home Use
Test of the Back Patch, conducted in 83 subjects in December 2002 (Study
MR-6), 92.8% of respondents noted that the patch did not irritate skin.
In the Home Use Test (Study MR-1) only 4% of the 600 subjects noted that
the patch caused skin to break out or rash.

In these three studies and three additional studies (Studies MR-2, MR-3,
and MR-4), respondents did not mention skin irritation or any other
safety issues in response to open-ended questions.[^37] Furthermore,
study MR-3 involved an analysis of the responses to business reply cards
inserted in 15,000 Icy Hot Patch packages. The low overall response rate
(2.6%) and the failure to see any spontaneous comments regarding skin
irritation or any other safety issues provide additional assurance that
such occurrences are rarely of concern to consumers. Surely, had
consumers experienced skin irritation, they would have offered comment,
given this opportunity to do so. The lack of response about skin
irritation is all the more persuasive because the mechanism of action of
counterirritants is based on topical stimulation of pain receptors in
the skin. Thus, mild erythema and pain are to be expected and are
signals of effectiveness.

#### **Other studies**

The RIPT and cumulative irritation tests conducted by Sato
Pharmaceuticals and included in the administrative record, also provide
support for this conclusion.[^38] These studies tested a product that
included menthol at a concentration of 0.4%, in combination with methyl
salicylate and dl-camphor. In addition, a study accepted by FDA in the
establishment of the Monograph for OTC Cough, Cold, Allergy,
Bronchodilator and Antiasthmatic Products, applying 2.8% menthol under a
patch for 48 hours, resulted in "no instances of inflammation, wheal,
hives, or primary irritation."[^39]

### **Effectiveness**

As discussed above in section II(A), substantial literature exists to
establish the efficacy of menthol at the concentrations accepted as
Category I in the TFM. Furthermore, FDA has accepted that menthol is
efficacious at these levels, as discussed above.

#### **Literature**

In addition to the literature in the administrative record addressing
the efficacy of menthol as a counterirritant, three recent articles that
are attached as Appendices 6 through 8 are typical of the plethora of
existing information. The first, a review by Eccles, notes, "menthol has
both irritant and local anesthetic actions when used in higher
concentrations. Menthol in 5-10% concentration in mineral oil causes a
burning sensation when applied to the skin and this sensation has been
attributed to stimulation of nociceptors in the skin."[^40] This review
further discusses the physiologic changes that result in the
counterirritant effects.[^41] A study by Yosipovitch *et al.* of thermal
and pain thresholds, skin microcirculation, and transepidural water loss
concluded that menthol "fulfills the definition of a
counterirritant."[^42] Furthermore, this study found no visible erythema
after the application of menthol.[^43] The final study tested the
changes in blood flow by laser Doppler velocimetry after application of
a product containing 15% menthol in combination with eucalyptus oil and
anhydrous lanolin, against placebo. The changes in blood flow resulting
from application of the test product were statistically significant,
indicating that the product is effective as a counterirritant.[^44]

#### **Market Research**

Chattem market research also supports the efficacy of 5% menthol in
patch form. In an in-home usage test of the Icy Hot Patch (MR-1), 89% of
persons suffering from muscle, joint, and related pain classified their
pain relief from the product as either "very adequate" or
"adequate."[^45] In study MR-3, 61% of respondents found the product to
be effective.[^46] In response to open-ended questions in the same
study, 31% mentioned effectiveness as a "like". Furthermore, in study
MR-4, 80.3% of users reported that they experienced "adequate" or "very
adequate" pain relief.[^47]

## **Data on percutaneous absorption under occlusion**

While menthol toxicity is possible, it is extremely rare and is unlikely
to result from the percutaneous absorption of menthol, even when the
menthol is applied under occlusion. This is true in part because
percutaneous absorption of a drug can be difficult to achieve even where
it is intended. As noted by Zhai and Maibach, "skin is not readily
breached at a therapeutic level because of barrier resistance."[^48] The
authors note that several studies have "confirmed the view that
occlusion does not necessarily increase the percutaneous absorption of
all chemicals."[^49]

Furthermore, toxicity from menthol is highly unlikely, whatever the
delivery method. Menthol has very low toxicity.[^50] The Eccles review
noted that "\[f\]or such a commonly ingested substance it is surprising
that there are relatively few studies on the toxicology of menthol and
this supports the generally held opinion that menthol is a relatively
nontoxic and safe substance."[^51] In those studies in which menthol
toxicity was produced in laboratory animals, death was attributable to
the menthol's anesthetic properties.[^52] It is highly unlikely that
enough menthol could be absorbed through the skin to depress the central
nervous system. Furthermore, "in metabolic studies on rats a daily dose
of 800 mg kg^-1^ was given for 20 days without any report of serious
adverse effects, apart from induction of liver enzymes."[^53] The dose
at which 50 percent of the tested animals survive (LD50) in rats has
been determined to be 3,180 mg kg^-1^ equivalent to a 222g oral exposure
in an average 70 kg person assuming similar metabolism.[^54] A person
over the age of twelve is highly unlikely to systemically absorb menthol
at a rate equivalent to or higher than this rate as a result of applying
of a patch---or even several patches---containing menthol at a
concentration of 5%.

## **The length of contact time that it is safe to leave the patch \[poultice or plaster\] on the skin; how often the patch \[plaster or poultice\] needs to be changed for effective use**

### **Safe length of exposure** 

The results of the Chattem RIPT study, discussed above in section
III(A)(1)(a) and included as Appendices 1 through 3, demonstrate that
this patch product can safely be applied for a period of 24 hours. This
result is consistent with other tests of patch products that employ
menthol as an active ingredient. For instance, the cumulative irritancy
test and the test termed "Usage Test II" conducted by Sato
Pharmaceutical and included in the administrative record applied the
patch for 24 hours with satisfactory safety results.[^55] The RIPT study
conducted by Sato demonstrated that it is safe to leave the patch in
place for the longer period of 48 hours.[^56]

In the regulations governing corn and callus removers and wart removers,
FDA has recognized that products containing salicylic acid may safely be
applied to the skin for 48 hours.[^57] Percutaneous absorption of
salicylic acid potentially raises more significant toxicity issues than
does percutaneous absorption of menthol, as discussed above.
Accordingly, the safe length of exposure to the 5% menthol patch is at
least 24 hours.

### **Frequency of change**

Chattem marketing data supports the effectiveness of the product for
eight-hour use, as recommended in the existing labeling of both sizes of
Icy Hot Patch.[^58] In each of the marketing studies, users were given
instructions consistent with this labeling. As discussed above in
section III(A)(2)(b), the users consistently found the product to be
effective when used according to this labeling.

## **Frequency of application that is considered to be safe and effective**

The frequency of application that is presently indicated in the product
labeling, which provides for the use of no more than 4 patches every 24
hours, is safe and effective. This frequency of use also is consistent
with the restrictions on menthol as a counterirritant presently included
in the TFM, which provide for use "not more than 3 to 4 times
daily."[^59]

As discussed above in section III(A)(1)(b), few adverse events have been
reported under the existing labeling. In addition, this use is
consistent with the results of Usage Tests I and II conducted by Sato
Pharmaceuticals, which tested a menthol-containing patch. In Usage Test
I, safety was demonstrated when subjects applied the patch once every
eight hours for five days.[^60] In Usage Test II, a pilot study for
efficacy, the subjects applied the product three times daily.[^61]

Chattem consumer research also supports the conclusion that the product
is safe and effective for use in this time period. In one study (MR-5),
the average amount of time that users reported wearing the back patch
was 4.09 hours.[^62] Of these users, 67% noted that they liked that the
patch was not irritating to skin. In study MR-6, also, 92.8% were in the
Top 2 Box percent with respect to the statement "does not irritate
skin."[^63] Study MR-4 resulted in 80.3% of users of the product under
its current labeling reporting that they experienced "adequate" or "very
adequate" pain relief.[^64]

Although use at this frequency is safe and effective, actual use of the
product by consumers is much less frequent. In one study of the small
patch (MR-1), subjects used an average of about 4.5 patches in a
two-week period.[^65] In a second study (MR-5), subjects used the back
patch an average of 2.6 times in the one-week usage period.[^66]
Approximately half used the back patch one or two times per week, and
only 12% used it four or more times per week.[^67]

## **Whether or not directions and a warning are necessary regarding checking the area at specified intervals for erythema to prevent blistering, and what time intervals are recommended**

Directions and a warning are not necessary regarding checking the area
at specified intervals for erythema to prevent blistering. Studies on
the 5% menthol patch have shown that erythema is extremely rare, and
blistering is almost nonexistent. In the Chattem RIPT study, the
subjects were not instructed to check the patch, yet no subject
experienced blistering.[^68] The most severe reaction experienced by
subjects was moderate erythema, and this occurred in only two subjects
out of the 102 who completed the study.

The health related experience report data and the market research data
presented above in section III(A) also helps to establish that the
product as presently marketed does not give rise to significant safety
and efficacy concerns. Data already entered into the record regarding
other external analgesic patch products, including the results of
testing of the Sato products, also supports generally the conclusion
that such labeling is not necessary. In all of these situations, no
warning has been given to consumers, yet the rate of adverse events, and
particularly the rate of severe adverse event such as blistering,
remains exceptionally low.

The absence of such labeling is also consistent with FDA's recognition
that such labeling is not necessary in similar patch products, such as
those for removal of corns and calluses, and of warts.[^69]

## **The age groups for whom patches \[poultices and plasters\] are recommended for safe use**

The product has been shown to be safe for use in consumers above age 12.
Because skin of the very young has different absorptive characteristics
than typical adult skin, and the studies conducted on patch products to
this point have not included significant numbers of children, existing
data are not sufficient to prove the product's safety in this age group.
Accordingly, the labeling for the product should be limited to use in
those over age 12. This is consistent with the existing labeling of the
Icy Hot Patch products.

The products are safe for use in all other age groups, including the
elderly. Although FDA has expressed concern about the absorptive
characteristics of elderly skin,[^70] the absorptive characteristics are
not sufficiently different in this age group to significantly affect the
products' safety and efficacy. This conclusion is supported by the
Panel's determination not to include age restrictions on the labeling
for cream, lotion, and ointment products. The Panel stated, "Although it
is possible that penetration of drugs through geriatric skin differs
from drug penetration through skin of younger adults and may warrant
special consideration, the Panel obtained no information which allowed
it to come to a conclusion on this issue."[^71] Furthermore, while the
Panel discussed in detail its concerns related to absorption under
occlusion in relation to the skin differences in infants, it did not
consider this additional concern in regard to elderly skin.[^72] Because
FDA accepted the Panel's determination that no labeling restriction was
necessary, based on a lack of evidence, FDA should also accept that no
labeling restrictions are necessary for the patch products, on the same
basis. Additional testing on the percutaneous absorption of the active
ingredient, if required by FDA, will also show the rate of absorption to
be very low. Even if there is some increase where elderly skin is used,
the absorption will be demonstrated to be minimal and will not raise
concerns.

Furthermore, FDA did not limit the age groups to whom corn & callus
remover products and wart remover products may be marketed, in the
relevant monographs. These products raise the same percutaneous
absorption and skin sensitization issues as the external analgesic patch
products, and therefore FDA's requirements should be the same for the
two types of products.

## **Labeling of currently marketed products**

The current labeling of the Icy Hot Patch products is attached as
Appendices 11 and 12.

# **Conclusion**

The proposed amendment to the Tentative Final Monograph to exclude
patch, plaster, and poultice dosage forms from classification as
Category I is inappropriate because sufficient data exists to support
their inclusion as generally recognized as safe and effective. These
products present to consumers unique advantages over the existing dosage
forms of creams, lotions, and ointments, and their exclusion from the
monograph would significantly disadvantage them. The data presented in
this submission, in conjunction with the additional data already present
within the administrative record, is sufficient to establish the safety
and efficacy of patches containing menthol at a concentration of 5%,
such as the Chattem patch products. Furthermore, the testing
requirements for patches that FDA outlined in the administrative record
are excessive and duplicative. Efficacy testing is not necessary if the
active ingredient use is within Category I. In other areas, FDA has
noted that percutaneous absorption, even of potentially toxic
ingredients, is not necessary. It should not be a substantial concern
with regard to these products, either. Accordingly, the amendment should
be removed, and patch, plaster, and poultice products specifically
included within Category I.

In order to expedite the resolution of this process, we request FDA's
continued openness and cooperation with the efforts of the Task Force.
Should additional testing of these products be necessary, we look
forward to continued communication with FDA throughout the product
testing process to ensure that all results fully conform to FDA's
requirements.

Respectfully Submitted,

Donald Kay Riker, Ph.D.

Vice President of Research & Development and Chief Scientific Officer

Chattem, Inc.

Appendices

  ----------------------------------------------------------------- -----
  Synopsis of Chattem RIPT Test                                     1

  Complete RIPT Study Report, Non-Hydrogel Study CSE-391            2

  Complete RIPT Study Report, Hydrogel Study CSE-392                3

  Health Related Experience Reports                                 4

  Analysis of Market Research Data on the Icy Hot Patch             5

  R. Eccles, Menthol and Related Cooling Compounds, 46 J. Pharmacy  6
  & Pharmacology 618 (1994)                                         

  Gil Yosopovitch *et al.*, Effect of topically applied menthol on  7
  thermal, pain and itch sensations and biophysical properties of   
  the skin, 288 Archives Dermatologic Res. 245 (1996)               

  Chang-Zeng Hong, MD & Frank G. Shellock, PhD, Effects of a        8
  Topically Applied Counterirritant (Eucalyptamint) on Cutaneous    
  Blood Flow and on Skin and Muscle Temperatures: A                 
  Placebo-Controlled Study, 70 Am. J. Physical Med. &               
  Rehabilitation 29 (1991)                                          

  Hongbo Zhai & Howard I. Maibach, Effects of Skin Occlusion on     9
  Percutaneous Absorption: An Overview, 14 Skin Pharmacology &      
  Applied Skin Physiology 1 (2001)                                  

  P.M. Jenner *et al*., Food Flavourings and Compounds of Related   10
  Structure. I. Acute Oral Toxicity, 2 Food & Cosmetics Toxicology  
  327 (1964)                                                        

  Labeling of Icy Hot Patch                                         11

  Labeling of Icy Hot Back Patch                                    12
  ----------------------------------------------------------------- -----

[^1]: 68 Fed. Reg. 42324 (July 17, 2003).

[^2]: For example, the patch does not present the potential for being
    mistaken for a tube of toothpaste, as does a tube of cream, lotion,
    or ointment.

[^3]: 47 Fed. Reg. 522, 526 (Jan. 5, 1982).

[^4]: Analysis of Market Research Data on the Icy Hot Patch 2 (attached
    as Appendix 5).

[^5]: *Id.* at table, pages 3-4 (studies MR-3 and MR-4).

[^6]: As noted in section I(A), Chattem marketing research establishes
    that consumers find the patch to be preferable to other products.
    Three studies also assessed the respondents' intent to purchase the
    patch in the future. The majority of respondents (from 60% in MR-1
    to 84.4% in MR-6) reported that they would probably, or definitely,
    buy the patch. *See id.* at 3. In addition, in two other studies,
    80% and 71.5% of the respective respondents said that they would
    repurchase the patch. *Id.*, table at 3-4. Users in all market
    research studies sponsored by Chattem were positive about the
    product form and application. When asked about product attributes,
    two particular "likes" related to convenience were cited in each of
    the six market research studies. First, 25.9-79.5% of patch users in
    each of the six studies cited "easy to use" as a "like," a "true"
    attribute, or a "performance characteristic" of the product. *Id.*
    at 2. Second, patch products are seen as a way to avoid the "greasy
    mess" that is often associated with creams, lotions, and ointments,
    as demonstrated by the fact that 13.6-95.2% of patch users in each
    of the six studies cited "not messy" as a "like," a "true"
    attribute, or a "performance characteristic" related the patch.
    *Id.*

[^7]: *See, e.g.,* Letter from Debra L. Bowen, M.D., CDER, to Daniel J.
    Manelli, Farkos and Manelli, P.L.L.C. 9, Oct. 1, 1996 (LET69).

[^8]: "FDA requires data to show effectiveness for the label indication
    for relief of pain in joints and muscles." Memorandum of Meeting,
    October 4, 1994, between Hisamitsu Pharmaceutical Co., Inc.,
    Representatives and Food and Drug Administration Representatives 3
    (MM9). "\[T\]he agency requires specific clinical trials to
    demonstrate the effectiveness of counterirritants." 37 Fed. Reg. 85,
    86 (Jan. 5, 1972).

[^9]: 44 Fed. Reg. 69768, 69857 (Dec. 4, 1979) (emphasis added).

[^10]: *Id.*

[^11]: *Id.* at 69863-69864 (emphasis added).

[^12]: 37 Fed. Reg. at 86.

[^13]: *See* Letter from Debra L. Bowen, M.D., CDER, to Donald E. Segal,
    Esq., Akin, Gump, Strauss, Hauer & Feld 2, March 12, 1996 (LET68).

[^14]: *E.g.*, Letter from William E. Gilbertson, Pharm.D., CDER, to
    John S. Herr, Food and Drug Service, Inc. 4, Sept. 11, 1990 (LET50);
    Letter from William E. Gilbertson, Pharm.D., CDER, to John S. Herr,
    Food and Drug Service, Inc., Aug. 2, 1995 (LET67).

[^15]: 21 C.F.R. § 341.74(d)(2)(ii).

[^16]: 48 Fed. Reg. 48576, 48585-48586 (Oct. 19, 1983).

[^17]: "Although the levels of menthol could be determined from a
    biological fluid, salicylic acid poses a greater risk than menthol."
    Letter from Debra L. Bowen, M.D., CDER, to Daniel J. Manelli, Farkos
    and Manelli, P.L.L.C. 9, Oct. 1, 1996 (LET69).

[^18]: *See id.* at 7.

[^19]: 47 Fed. Reg. at 526.

[^20]: *See id.* at 527.

[^21]: 52 Fed. Reg. 5412, 5413 (Feb. 20, 1987). *See* Letter from Bowen
    to Manelli, Oct. 1, 1996, at 6 (informing manufacturer that a study
    over one to two weeks is necessary).

[^22]: 52 Fed. Reg. at 5413.

[^23]: 52 Fed. Reg. 9992, 9992 (March 27, 1987).

[^24]: 55 Fed. Reg. 33246, 33253 (Aug. 14, 1990).

[^25]: 68 Fed. Reg. at 42325.

[^26]: *Id.*

[^27]: The non-hydrogel test article is sold commercially as the Icy Hot
    Patch; the hydrogel test article is not in commerce.

[^28]: CDER, Guidance for Industry: Skin Irritation and Sensitization
    Testing of Generic Transdermal Drug Products, at B. Recommendations
    for a Skin Sensitization Study (Modified Draize Test) (December
    1999).

[^29]: Chattem ensures that it receives information about health-related
    experiences that consumers suspect are related to Chattem products
    by including in the product labeling the company mailing address and
    World Wide Web address. In total for all of its products, Chattem
    receives 600-800 contacts monthly, with about 50% of these by mail,
    30% by telephone, and 20% by email. The Consumer Affairs Department,
    in conjunction with Product Safety or Quality Assurance, responds to
    consumer contacts and follows up or investigates issues as outlined
    in the relevant Chattem standard operating procedures (SOP). To
    facilitate this process, all consumer contacts and follow up
    information regarding contacts are maintained in a database.
    Furthermore, Chattem has established a relationship with the
    Cincinnati Drug and Poison Information Center (DPIC). Under this
    agreement, telephone calls made to Chattem after normal business
    hours and on weekends regarding health related experiences to
    Chattem's toll free number for DPIC. DPIC handles these calls, and
    then provides the information to Chattem the next business morning.
    This information is entered into the Chattem database, and Chattem
    further investigates this information also according to the SOP.

[^30]: 21 C.F.R. § 330.10(a)(4)(1).

[^31]: This rationale is the basis for Food and Drug Administration
    adverse event reporting programs such as MedWatch.

[^32]: Sales figures for the period of May 5, 2001 to August 23, 2003,
    indicate that 4,274,048 boxes of Icy Hot were sold to outlets
    excluding Wal-Mart. At 5 patches per box, this amounts to 21,370,240
    patches sold.

[^33]: 44 Fed. Reg. at 69828.

[^34]: Serious is defined as unexpected or producing death,
    life-threatening event, in-patient hospitalization, persistent or
    significant disability/incapacity, or a congenital anomaly/birth
    defect.

[^35]: *See, e.g.*, 44 Fed. Reg. at 69827.

[^36]: Appendix 5 at 1.

[^37]: *Id.*

[^38]: Letter from John S. Herr, Food and Drug Service, to Dockets
    Management Branch, FDA, Aug. 22, 1990 (RPT4).

[^39]: 41 Fed. Reg. 38312, 38349 (Sept. 9, 1976).

[^40]: R. Eccles, Menthol and Related Cooling Compounds, 46 J. Pharmacy
    & Pharmacology 618, 621 (1994) (attached as Appendix 6).

[^41]: *See id*. at 624.

[^42]: Gil Yosopovitch *et al*., Effect of topically applied menthol on
    thermal, pain and itch sensations and biophysical properties of the
    skin, 288 Archives Dermatologic Res. 245 (1996) (attached as
    Appendix 7).

[^43]: *Id.* at 248.

[^44]: Chang-Zeng Hong, MD & Frank G. Shellock, PhD, Effects of a
    Topically Applied Counterirritant (Eucalyptamint) on Cutaneous Blood
    Flow and on Skin and Muscle Temperatures: A Placebo-Controlled
    Study, 70 Am. J. Physical Med. & Rehabilitation 29 (1991) (attached
    as Appendix 8).

[^45]: Appendix 5, table at 1.

[^46]: *Id.*, table at 3.

[^47]: *Id.*, table at 4.

[^48]: Hongbo Zhai & Howard I. Maibach, Effects of Skin Occlusion on
    Percutaneous Absorption: An Overview, 14 Skin Pharmacology & Applied
    Skin Physiology 1, 2 (2001) (attached as Appendix 9).

[^49]: *Id*. at 3.

[^50]: Eccles at 628.

[^51]: *Id*. at 627.

[^52]: *Id*.

[^53]: *Id*.

[^54]: P.M. Jenner *et al*., Food Flavourings and Compounds of Related
    Structure. I. Acute Oral Toxicity, 2 Food & Cosmetics Toxicology
    327, 339 (1964) (attached as Appendix 10).

[^55]: *See* Letter from John S. Herr, Food and Drug Service, to Dockets
    Management Branch, FDA, Aug. 22, 1990 (RPT4); Letter from William
    Gilbertson, Pharm.D., FDA, to John S. Herr, Food and Drug Service,
    May 3, 1994 (LET61).

[^56]: *See* Letter from John S. Herr, Food and Drug Service, to Dockets
    Management Branch, FDA, Att. at 4, Aug. 22, 1990 (RPT4).

[^57]: 21 C.F.R. §§ 358.150, -.550.

[^58]: The present labeling provides for the use of no more than 4
    patches every 24 hours. *See* Appendices 11 and 12.

[^59]: 48 Fed. Reg. at 5869

[^60]: *See* Letter from John S. Herr, Food and Drug Service, to William
    Gilbertson, Pharm.D., FDA, App. B, Oct. 15, 1994 (LET66).

[^61]: *See* Letter from William Gilbertson, Pharm.D., FDA, to John S.
    Herr, Food and Drug Service 3, May 3, 1994 (LET61).

[^62]: *See* Appendix 5, table at 5.

[^63]: *See* *id.*, table at 6.

[^64]: *See* *id.*, table at 4.

[^65]: *See* *id.*, table at 1. Note that the users received a box
    containing five patches.

[^66]: *See* *id.*, table at 5.

[^67]: *See* *id.*

[^68]: *See* Appendices 1-3.

[^69]: *See* 21 C.F.R. §§ 358.150, -.550.

[^70]: *See, e.g*., Memorandum of Meeting, October 4, 1994, between
    Hisamitsu Pharmaceutical Co., Inc., Representatives and Food and
    Drug Administration Representatives 3 (MM9).

[^71]: 44 Fed. Reg. at 69773.

[^72]: *Id*. at 69773-69774.