the long-term management of actinic keratosis: treatment ......actinic keratosis (ak) is one of the...

Supplement to the February 2009 issue of

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The Long-term Management of Actinic Keratosis:Treatment Options and Their Implications

Proceedings from a Clinical Dermatology Roundtable

Support provided by PharmaDerm, a division of Nycomed US Inc.

PharmaDerm_AK_Roundtable_Supplement.qxd 2/4/09 12:11 PM Page C1

Actinic keratosis (AK) is one of the most common skin condi-

tions seen by dermatologists in clinical practice. AK most often

results from chronic ultraviolet (UV) light exposure, usually from the

sun. However, sunlamps and tanning lamps may also contribute to

the development of AKs. AKs develop after the affected skin region

becomes genetically altered and the natural immune surveillance of

the skin is unable to contain all of the potential altered epidermal

foci, which can progress to visible AK and possibly to squamous cell

carcinoma (SCC). The process of genetically altering the epidermis

occurs over several years and affects the skin diffusely in chronically

exposed regions. Therefore, once the process begins, AK develop-

ment is a progressive and chronic process, and visible AK lesions

represent only the tip of the iceberg. Due to the chronic nature of AK,

patients will often require multiple courses of therapy and long-term

management. While individual, well-defined AK lesions may be

treated in the office with an ablative modality, such as cryotherapy,

it is often necessary to address a treatment field that is affected dif-

fusely by both visible and subclinical AK lesions with a topical ther-

apy. Available topical agents vary in terms of their mechanisms of

action, extent of visible inflammation in the treatment field, and

application schedules. Efficacy, tolerability, extent and duration of

visible inflammation, and compliance are important factors when

selecting a topical therapeutic option for patients.

Irritation and inflammation were once considered prerequisites

for an effective topical treatment of AK. Clinical data from trials of

diclofenac sodium 3% gel (Solaraze®, PharmaDerm, a division of

Nycomed US Inc., Florham Park, New Jersey), however, suggest that

AK can be effectively treated with a topical agent without much of the

erythema and irritation associated with some other topical options.

For some patients, such tolerability may outweigh the convenience

of more rapid treatment, especially when AKs are located in more

visible areas, which is very common.

In October 2008, a panel of leading dermatologists participated in

a roundtable to discuss the best practices for long-term management of

AK. The discussion included a brief review of AK epidemiology and

pathogenesis and then concentrated on treatment issues. After a review

of commonly used treatment modalities and a discussion of current

treatment algorithms, the participants focused on the available clinical

data for diclofenac sodium 3% gel. Finally, the clinicians discussed the

implications of long-term management, especially regarding the impor-

tance of efficacy, tolerability, compliance, and patient satisfaction.

Introduction by James Q. Del Rosso, DO, FAOCD—Moderator

Participants

Dr. James Del Rosso, DO, FAOCD

Dermatology Residency Director

Valley Hospital Medical Center

Clinical Associate Professor

(Dermatology)

University of Nevada School of

Medicine, Las Vegas, Nevada

Associate Professor (Dermatology)

Touro University College of

Osteopathic Medicine

Henderson, Nevada

Roger I. Ceilley, MD

Assistant Clinical Professor of

Dermatology

University of Iowa Department of

Dermatology

Iowa City, Iowa

Mark D. Kaufmann, MD

Assistant Clinical Professor

Dermatology

Mount Sinai School of Medicine

New York, New York

Mark G. Lebwohl, MD

Professor and Chairman,

Department of Dermatology

Mount Sinai School of Medicine

New York, New York

David M. Pariser, MD

Professor


Eastern Virginia Medical School

Norfolk, Virginia

Abel Torres, MD, JD

Professor and Chairman


Loma Linda University

Loma Linda, California

This supplement is based on a roundtable discussion that took place on

October 16, 2008 during the 2008 Fall Clinical Dermatology Conference in Las

Vegas, Nevada. Dr. Del Rosso moderated the discussion. Roundtable partici-

pants included Drs. Ceilley, Kaufmann, Lebwohl, and Torres, with additional

commentary by Dr. Pariser. This supplement was supported by PharmaDerm, a

division of Nycomed US Inc.


The Long-term Management of Actinic Keratosis:Treatment Options and Their ImplicationsProceedings from a Clinical Dermatology Roundtable

[FEBRUARY 2009 • VOLUME 2 • NUMBER 2] SUPPLEMENT TO THE JOURNAL OF CL INIC AL AND AESTHETIC DERMATOLOGY 3

Actinic Keratosis Prevalence is on the Rise

AK represents the second most common skin diagno-

sis seen by dermatologists,1 accounting for more than

five million office visits annually and more than $900 mil-

lion in healthcare costs each year in the United States.2

Lesions can often be diagnosed by their gritty, rough, or

sandpaper-like texture. Visibly, they appear as skin-col-

ored, pink, or red macules, often with superficial scaling

or as thin or thick keratotic papules.3–5 Given their associ-

ation with UV light exposure, AKs are most commonly

noted on sun-exposed areas of the body, including the

scalp, face, neck, dorsum of the hands, upper chest,

shoulders, and forearms. AK lesions can also occur on

both the cutaneous and mucosal surfaces of the lip.

It is recommended that AKs be treated because they

exhibit the potential to progress to SCC. Histologically, AK

lies on one end of a spectrum of epidermal cellular abnor-

malities whose range extends to SCC in situ and invasive

SCC.3 Microscopically, AK is characterized by atypical ker-

atinocytic proliferation in the epidermis,6 and while some

lesions may regress without treatment, the risk of an indi-

vidual lesion progressing to SCC is believed to be as high

as 10 percent.4,7 Conversely, approximately 82 percent of

SCC lesions were found to arise from, or be in close prox-

imity to, an AK lesion.8 Equally concerning is the fact that

the incidence of AK appears to be on the rise.9 It is impor-

tant to recognize that in a given patient, an AK lesion

serves as both a marker for the propensity of the individ-

ual to develop SCC in photodamaged skin and as a pre-

cursor lesion that may itself progress to SCC.

Medical and Ablative Therapeutic Options forActinic Keratosis

A number of treatment options are available for the

management of AK, and they can be classified as ablative

or medical. Each treatment option has distinct advan-

tages and disadvantages. Therefore, the option best

suited for a patient is dependent on individual patient

preferences, the lesion characteristics, and the clinical

expertise of the treating physician. As will be discussed,

in some cases treatment regimens can be used in tandem

to increase efficacy while improving safety and tolerabil-

ity profiles.

Ablative therapeutic options. Curettage (which may

be followed by electrodesiccation) is sometimes used to

treat isolated lesions, especially hyperkeratotic or refrac-

tory AKs. Additionally, a tissue sample of the removed

lesion allows for histologic confirmation, especially in

cases where the clinical diagnosis is unclear. In practice,

however, liquid nitrogen cryotherapy (LN2) is the main-

stay of ablative treatment options for AK. The efficacy and

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4 SUPPLEMENT TO THE JOURNAL OF CL INIC AL AND AESTHETIC DERMATOLOGY [ FEBRUARY 2009 • VOLUME 2 • NUMBER 2]

safety of LN2 is generally regarded as being dependent

on the amount of time the cryogen is applied to the skin.

As there is no standardized approach to how LN2 is used

to treat AK other than common utilization of the spray

technique, application time varies among practitioners

and is generally dependent on the size and thickness of

the lesion.10

LN2 is a well-established treatment modality for

AK, yet there is a relative dearth of prospective studies

designed to evaluate both the efficacy and safety of the

procedure. In a study by Thai et al,11 67.2 percent of

lesions treated with LN2 demonstrated a complete

response three months after treatment.11 The rates of

response were dependent on the duration of freeze

times with shorter freeze times associated with lower

response rates. Of the lesions that demonstrated a

complete response at three months, 29 percent were

associated with hypopigmentation. Hyperpigmentation

was documented in six percent of lesions and scar for-

mation occurred in two percent of lesions. A majority

(52%) of the cryosurgery procedures were associated

with pain, stinging, or a burning sensation. Less com-

mon adverse events included erythema, edema, blis-

tering, and infection.

LN2 is considered a lesion-directed therapy as

opposed to a field-directed therapy. It is well suited for

patients with a relatively few number of AK lesions (Table

1). Because treatment with cryotherapy targets individ-

ual lesions, use of LN2 does not address subclinical AK

lesions in the treatment field and has no apparent

impact on the development of new AKs over time. A

study by Jorizzo et al12 demonstrated that more than 92

percent of patients treated with LN2 alone developed AK

lesions within six months, suggesting a need for consis-

tent follow up.12

Photodynamic therapy (PDT) is another nonsurgical,

ablative therapy for treatment of AKs. PDT is applicable to

treatment of individual lesions and, like other medical

options, can also be used as a field-directed treatment

covering a large number of lesions over a wide area of

skin. PDT combines the use of a topical drug that induces

the formation of photoactive porphyrins (PAPs) in the tar-

get cells. After time for the PAPs to partition into the

desired subcellular structures, the treatment area is illu-

minated with light in a wavelength that reacts with the

PAPs to cause tissue destruction. Two PDT systems are

approved by the Food and Drug Administration (FDA) for

treatment of AKs in the United States, one using 5-

aminolevulinic acid (ALA) and blue light and one using

methylaminolevulinate and red light. The efficacy of

these two systems for treating AKs is similar and com-

pares well to other medical options.13–15

Medical options. For the treatment of multiple AKs, a

few topical therapies are available in the therapeutic

armamentarium of clinicians. These field-directed treat-

ments target a large number of lesions over a wide area

of skin. Currently, three distinct topical therapies are

approved for the treatment of AK-imiquimod, 5-fluo-

rouracil (5-FU), and diclofenac sodium (Table 2). Their

mechanisms of action suggest that at least two of these

agents, diclofenac and imiquimod, rather than being

purely destructive, actually address components of the

underlying pathogenesis of AK.2 While each modality dif-

fers in its mechanism of action, safety profile, and tolera-

bility, they share several common traits. Each drug regi-

men requires patient compliance entailing a regular

application schedule. All of the topical therapies, as they

are applied to an entire field of involvement (e.g., scalp,

cheek, forehead, hand, dorsum), treat both currently vis-

ible lesions and also subclinical lesions, referred to as

field-directed therapy. Although, each topical treatment

has been associated with some degree of inflammation

and may cause erythema, burning, and irritation in some

patients, the predictability of visible inflammation and

the degree of tolerability varies among the available top-

ical agents.

The antineoplastic agent 5-FU has been used as a

topical treatment for AK for decades and treats AK lesions

by interfering with DNA and RNA synthesis.16,17,20 Topical 5-

FU is available in a 5% cream and a 0.5% cream. Whereas

Strengths

Well suited for isolated lesions

Applied by clinician; patient compli-

ance does not impact efficacy

Performed in one office visit

Can be combined with topical

therapies

Weaknesses

Less appropriate for multiple/

confluent lesions

Clinician technique impacts efficacy

Frequent pigmentation changes

Visible lesion-directed only. Does

not treat subclinical lesions

within the treatment field

Table 1. Properties of Cryotherapy


The Long-term Management of Actinic Keratosis: Treatment Options and Their Implications: Proceedings from a Clinical Dermatology Roundtable


it is recommended that 5-FU 5% be

applied twice a day based on FDA-

approved labeling, 5-FU 0.5%

cream was studied as a once-daily

therapy for up to four-weeks dura-

tion in clinical studies and is FDA

approved using this application fre-

quency.16,17 Additionally, the 5-FU

0.5% is formulated using the micros-

phere (Microsponge®, AMCOL Health

& Beauty Solutions, Inc., Hoffman

Estates, Illinois) cream vehicle.16 The

5-FU 0.5% is currently approved for

the treatment of AK lesions on the

face and anterior scalp.20 As its

mechanism as a chemotherapeutic

agent is via cytodestruction, topical

5-FU is associated with an antici-

pated, highly predictable, markedly

visible, inflammatory reaction

within the region of application. Associated signs and

symptoms include frequent pain, erythema, erosions,

and crusting. Changes in pigmentation and scarring have

also been reported in some cases.17,20 Topical 5-FU is not

indicated for use on mucosal areas.16,17 Patients should

be advised that treatment with 5-FU results in an

unsightly reaction both during treatment and for at least

a few weeks following treatment.16,17

Imiquimod 5% cream is approved for the treatment

of AKs on the face and scalp.18 Imiquimod is an immune

response modulator and functions by activating antigen-

presenting cells, leading to stimulation of both the innate

and acquired immune response of the host against the

disease.18,21 Currently, the drug is indicated for applica-

tion to the affected area twice a week for 16 weeks. A pair

of Phase 3 clinical trials demonstrated that a 16-week

course of imiquimod resulted in complete clearance of

lesions in 45.1 percent of subjects.18 Treatment with

imiquimod resulted in partial clearance (i.e., more than

75% of baseline lesions cleared) in approximately 59

percent of patients.18 The use of imiquimod on the lips

and nostrils is not recommended in the FDA-approved

product labeling.18 Local skin reactions during treatment

with imiquimod are common and may include erythema,

flaking, scaling, dryness, and scabbing/crusting.18,21 As

with 5-FU, patients should be educated that they will

likely experience some amount of visible inflammation at

the application site, although the intensity of the inflam-

matory response is more variable and typically less

uncomfortable as compared to what occurs with use of 5-

FU.18 While the efficacy of imiquimod has been demon-

strated, it can take up to 16 weeks for maximum efficacy

to be seen with use of the FDA-approved application reg-

imen. Topical imiquimod has also been studied for treat-

ment of AK using a variety of regimens, which vary in

application frequency and duration.

The third topical agent approved for the treatment of

AK is diclofenac sodium 3% gel. While the mechanism of

action of diclofenac sodium has not been fully eluci-

dated, its efficacy for AKs is believed to relate to its abil-

ity to inhibit the cyclooxygenase-2 (COX-2) pathway, a

cascade that appears to correlate with the presence of AK

and SCC.22–24 Phase 3 clinical trials have demonstrated

that diclofenac sodium is associated with a complete

clearance rate of target lesions in 50 percent of patients

and a complete clearance rate of cumulative lesions in 47

percent of patients.25 Diclofenac sodium is typically

applied twice daily for 60 to 90 days.19 A Phase 4 trial

demonstrated a 90-percent mean decrease in the num-

ber of AKs 30 days after completion of a 90-day course of

Table 2. Summary of Approved Topical Treatments for Actinic Keratosis16–19

Treatment indication

Application schedule

Duration of therapy

Indicated formucosal use

Most commonadverse eventsreported in pivotaltrials (%)

Imiquimod 5% cream

Clinically typical, non-hyperkeratotic, non-hypertrophic actinickeratoses on the faceor scalp in immuno-competent adults

Twice a week

16 weeks

Should not beapplied near the nos-trils or mouth

Erythema (93%)Dryness (83%)Burning (75%)Erosion (44%)Pain (43%)Edema (35%)

Diclofenac sodium3% gel

Multiple actinic ker-atoses

Twice daily

60 to 90 days

Proven safety and effi-cacy for use on the lip

Rash (35%)*

Pruritus (31%)Dry Skin (27%)Contact Dermatitis(19%)Pain (15%)

5-Flourouracil5% cream

Multiple actinic orsolar keratoses

Twice daily

2 to 4 weeks

Application tomucous membranesshould be avoided

NA†

5-Flourouracil0.5% cream

Multiple actinic orsolar keratosesof the face and anterior scalp

Once daily

Up to 4 weeks

Should not be applied near thenostrils or mouth

Erythema (97%)Flaking/Scaling/

Dryness (93%)Scabbing/Crusting (79%)Edema (49%)Erosion/Ulceration (48%)Weeping Exudate (22%)

* = Adverse-event data for 60-day use.† = Approved for use in 1970. Detailed safety data from pivotal trials unavailable.



treatment.22 Diclofenac sodium has no limitations on

body area treated and appears well suited for treatment

of mucosal and cutaneous lip lesions.19,23 In a recent

study, 95 percent of patients treated with diclofenac

sodium for AKs on their lips reported they would recom-

mend the treatment to others with similar lesions.23

While the recommended duration of treatment with

diclofenac sodium can be up to 90 days, improvement in

the number of lesions is seen throughout treatment, and

in fact, has been shown to continue to improve through

30-days post-treatment.22 In clinical trials, diclofenac

sodium gel has been well tolerated by patients.22,23,26 After

60 days of treatment, pain and pruritus at the application

site were more frequent in vehicle-treated subjects than

in those using diclofenac sodium. Interestingly, derma-

tologists report that some patients, and even some clini-

cians, misconstrue a lack of visible inflammation and/or

absence of local side effects as an indication of

decreased efficacy. Both clinicians and patients have

come to adopt the “no pain, no gain” mentality based on

experience over the years primarily with LN2 and/or 5-FU.

Importantly, due to different mechanisms of action, it is

possible to achieve efficacy for AKs without the presence

of visible inflammation or side effects, as evidenced by

outcomes with diclofenac sodium in clinical studies.19,22–26

Differences in Mechanism of Action Among TopicalTherapies for AK

The available FDA-approved topical agents for AK—

5-FU, imiquimod, diclofenac—differ in the purported

mechanisms of action that are believed to be operative

for treatment of AK. With all three agents, available data

demonstrate that the mechanisms of action allow for

treatment of currently visible and subclinical

lesions.10,12,16–21 These differences in mechanism of action

appear to correlate with the anticipated type and inten-

sity of visible inflammation and symptomatology and

potential to induce high long-term clearance rates of

AK.10,12,16–21 Topical 5-FU reduces AKs through a chemother-

apeutic mechanism that is cytodestructive, accounting

for its rapid onset of effect, relatively short duration of

therapy (up to 4 weeks), predictable visible inflammatory

reaction, and high rate of associated symptomatic dis-

comfort.10,12,16,17,20 Topical imiquimod amplifies both innate

and acquired immune response, explaining the variable

intensity of visible inflammation among patients, which

reflects therapeutic activity.18,21 The mechanism of action

of imiquimod explains the variations in treatment regi-

mens that have been suggested and the presence of a

visible inflammatory response, which is typically associ-

ated with symptomatology that is not as severe as topical

5-FU.9,18,21 Topical diclofenac appears to reduce the pres-

ence and development of AKs by inhibiting the COX-2

pathway.19 This pathway has been shown to be up-regu-

lated in AK and SCC lesions and is believed to correlate

with the development and progression of these

lesions.27,28 By inhibiting the COX-2 pathway, topical

diclofenac blunts a signal that is believed to be a compo-

nent of the drive to form AKs and potentially progress to

SCC. The mechanism of action of topical diclofenac

appears to explain its association with a longer duration

of therapy and a significantly lower tendency to produce

visible cutaneous inflammation and associated symp-

toms, especially as compared to other topical therapies

for AK such as 5-FU.19,22–28

Topical Diclofenac Sodium for the Treatment ofActinic Keratosis

Diclofenac sodium 3% gel (Solaraze®) has been

approved for the treatment of AK since 2000. Diclofenac

is believed to preferentially inhibit the COX-2 pathway,

and appears to play a role in promoting apoptosis, mod-

ifying cell proliferation, and inhibiting angiogenesis.24

Previous studies have demonstrated that diclofenac

sodium 3% gel is effective and well tolerated in the treat-

ment of AK. Since other treatment options are more con-

sistently associated with visible inflammation and local

side effects, the initial studies with topical diclofenac

sodium were encouraging and led to its evaluation for the

treatment of AK.27

Phase 3 trials of diclofenac sodium gel. Randomized,

double-blind, pivotal trials were conducted to evaluate

the efficacy and safety of diclofenac sodium 3% gel for

treating AK with a total of 427 patients participating—213

receiving diclofenac sodium and 214 receiving a gel vehi-

cle. In two studies, patients were treated with study med-





ication for 90 days and followed for 30 days post-treat-

ment. In Study 1, Wolf et al27 demonstrated that 50 per-

cent of patients achieved 100-percent clearance of target

lesions.27 More than three-quarters (77%) of patients

demonstrated complete or significant lesion improve-

ment. In the second Phase 3 trial, 80 percent of patients

achieved cumulative clearance of AK lesions on their face

and 63 percent of patients achieved cumulative clear-

ance of AK lesions on their arms/forearms.19 A third piv-

otal trial differed in that subjects were randomized to 1 of

4 treatment groups (i.e., either vehicle or diclofenac

sodium for either 30 or 60 days).19,28 After 60 days of

treatment with topical diclofenac therapy, 53 percent of

patients experienced complete clearance of lesions on

their faces. In the same study, while patients receiving

diclofenac sodium 3% gel demonstrated higher rates of

clearance (versus vehicle) in most anatomic areas evalu-

ated, the results did not reach statistical significance.

When all three trials were pooled, treatment with

diclofenac sodium 3% gel was associated with higher

rates of complete clearance than treatment with vehicle

in all anatomic areas tested (Figure 1).19

Phase 4 trial with diclofenac sodium gel. A Phase 4,

multicenter, single-arm, open-label trial of diclofenac

sodium 3% gel was conducted to further quantify effi-

cacy. Subjects received a 90-day treatment with

diclofenac sodium 3% gel and were evaluated at 30, 60,

and 90 days as well as at a post-treatment follow-up visit

at Day 120 (30 days post-treatment). Efficacy assess-

ments included the Target Lesion Number Score (TLNS),

the Cumulative Lesion Number Score (CLNS), and a qual-

itative efficacy measure, the Investigator’s Global

Improvement Index (IGII).22

Of the 76 patients entering the study, 67 completed

the trial. Subjects demonstrated a steady decrease in

mean TLNS and CLNS (a measure of target and new

lesions in an area) starting at Day 30 and continuing

through end of treatment (Day 90) and through 30 days

post-treatment (Day 120). A 90-percent mean decrease in

target lesions (i.e., TLNS) was recorded at Day 120 (Figure

2). As early as Day 30, a marked decrease in TLNS was

observed. At Day 120, 85 percent of patients demon-

strated a >75-percent clearance of target lesions while 58

percent demonstrated complete clearance of target

lesions. The most common adverse events were dry skin,

rash, and exfoliation, reported by 30 percent, 14 percent,

and nine percent of subjects, respectively.22

When following patients with AK, dermatologists are

often faced with the challenge of trying to determine if a

lesion that is evident several months/years after prior

treatment is a new lesion or a previously “treated” lesion

that has re-emerged. Given the postulated mechanism of

action of topical diclofenac, clinicians have hypothesized

that it may be effective at preventing new/recurring AK

lesions long after a course of treatment has ended. As

such, a Phase 4 extension study was conducted to evalu-

ate the long-term therapeutic effects of diclofenac sodium

gel 3% for AK at approximately one year after completion of

Figure 1. Percent of patients with complete clearance of cumula-tive actinic keratosis lesions 30 days post-treatment withdiclofenac sodium 3% gel by anatomic location (pooled datafrom pivotal trials).19

Reprinted with permission from PharmaDerm, a division of Nycomed US Inc., Florham Park, NJ.

Figure 2. Mean number of target AK lesions during and aftertreatment with diclofenac sodium 3% gel.22

Reprinted with permission from Nelson C, Rigel D, Smith S, et al. Phase IV, open-label assess-

ment of the treatment of actinic keratosis with 3.0% diclofenac sodium topical gel (Solaraze). J

Drugs Dermatol. 2004;3(4):401–407.



treatment. The results were presented at the 2009 Winter

Clinical Dermatology Conference (January 16–21, 2009,

Kohala Coast, Hawaii), and preparation of a manuscript for

publication is forthcoming.

Treating AK lesions on the lip. The treatment of AK

lesions on the lip can present a challenge to dermatologists.

The lip is generally regarded as susceptible to inflammation

and edema, and given its high visibility, scarring is consid-

ered a highly unacceptable outcome. As such, surgical treat-

ments of AK on the lip are approached with marked caution

and are often avoided. Topical treatment with imiquimod or

5-FU, while less invasive than cryosurgery, curettage, or laser

ablation, are not FDA approved for mucosal surfaces, though

they have been used anecdotally in selected cases. When

applied to the vermilion area of the lip (visible mucosal

area), the degree of inflammation may be very marked with

topical imiquimod or 5-FU. This poses a potentially greater

risk of scarring that is dependent on the intensity of the

response, which is unfortunately unpredictable in each

patient. Diclofenac sodium 3% gel has shown proven safety

and efficacy for use on the lip and vermilion. A recent study

by Nelson et al23 evaluated the efficacy of diclofenac sodium

3% gel on AK lesions of the upper and lower cutaneous and

mucosal lip.23 In this open-label trial, subjects were treated

with diclofenac sodium 3% gel twice daily for 90 days and

followed up at Day 120 (30 days post-treatment). As with the

Phase 4 study discussed above, efficacy was evaluated by

TLNS, CLNS, and IGII scores. A total of 22 patients entered

the study and 19 completed the study. Statistically signifi-

cant mean percent decreases of target lesions were seen at

Day 90 (67%) and Day 120 (85%). The percentage of sub-

jects experiencing at least a 75-percent reduction in the

number of target lesions increased from Day 30 through Day

120. Similarly, the percentage of patients experiencing com-

plete clearance as assessed by both CLNS and TLNS

increased at each post-baseline visit. By Day 120, all

patients (20/20) were assessed as significantly improved or

completely cleared by clinicians as measured by the IGII

(Figure 3). Tolerability was highly favorable with only a mild-

to-moderate inflammatory reaction observed in some

patients during treatment, which tended to dissipate over

time. There were no episodes of scarring or disfigurement

observed as treatment sequelae. Patient acceptability of the

use of topical diclofenac for AK of the lip was very high.23

Split-face AK trial. The efficacy of the currently avail-

able topical treatments for AK has been demonstrated in

multiple vehicle-controlled studies, but there is a conspic-

uous scarcity of head-to-head trials in which two active

treatments are compared. A trial by Smith et al26 aimed to

compare the efficacy and tolerability of 5-FU 5% cream and

diclofenac sodium 3% gel utilizing a single-center, bilat-

eral, open-label, evaluator-blinded methodology. The

study enrolled 30 subjects, each with at least three AK

lesions on each side of his or her face/scalp. Subjects were

instructed to apply diclofenac sodium 3% gel to one side

of their faces twice daily for 90 days. At Day 63, they were

instructed to begin a twice-daily, 28-day regimen of 5-FU

on the contralateral side of their faces such that at the end

of the trial each patient received four weeks of therapy with

5-FU and 90 days of therapy with topical diclofenac

sodium. At Day 120, 93 percent of patients receiving

diclofenac and 100 percent of patients receiving 5% 5-FU

were found to have at least a 66-percent clearance. Both

treatments demonstrated similar lesion clearance rates 30

days post-treatment (5-FU: 98%; diclofenac: 89%). The

two treatments, however, demonstrated marked differ-

ences in terms of tolerability (see figures on page 11). As

will be discussed in more detail, topical diclofenac was

associated with much lower rates of erythema, scaling,

oozing/crusting, and edema and markedly higher rates of

patient satisfaction when compared to 5-FU.26

The safety and efficacy of diclofenac sodium 3% gel

for the treatment of AK has been demonstrated in multiple

Figure 3. Percentage of subjects demonstrating complete or significantimprovement as assessed by IGII during and after treatment of liplesions with diclofenac sodium 3% gel.23 Reprinted with permission from Nelson

CG, Spencer J, Nelson CG, Jr. A single-arm, open-label, efficacy and tolerability study of diclofenac

sodium 3% gel for the treatment of actinic keratosis of the upper and lower lip. J Drugs Dermatol.

2007;6(7):712–717.




trials. Clearance rates appear to increase over time with

available data supporting a 90-day course in many

patients. As previously stated, further data regarding the

long-term efficacy of topical diclofenac for AK were pre-

sented at the 2009 Winter Clinical Dermatology Conference

(January 16–21, 2009, Kohala Coast, Hawaii) and prepara-

tion of a manuscript for publication is forthcoming.

Current Guidelines/Algorithms for Long-TermManagement of Actinic Keratosis

It is only over the last decade that AK treatment options

available to clinicians and patients have extended beyond

topical 5-FU and surgical procedures. These treatment options

come at a time when the prevalence of AK is on the rise.

However, with the advent of new treatment options also

comes the potential for confusion among clinicians regarding

selection of therapy. With an increasing availability of data

from prospective, randomized, clinical trials, several treat-

ment guidelines and algorithms have emerged to assist physi-

cians in choosing an appropriate treatment regimen for their

patients. At this time it is impossible to develop one set of

guidelines or recommendations for all patients with AK,

although treatment guidelines attempt to assist clinicians in

making rational therapeutic decisions. The roundtable discus-

sion of these guidelines as well as the presentation of new

clinical data resulted in a number of excellent treatment sug-

gestions by the leading dermatologists attending the meeting.

British Association of Dermatologist Guidelines. In

2007, the British Association of Dermatologists published

guidelines for the management of patients with AK. The

authors evaluated available data on all of the available

therapies for AK. They concluded that 5-FU is an effective

treatment although they noted that the consistency of antic-

ipated application site side effects often require that less

aggressive application schedules be used. The authors

observed that topical imiquimod, while having demon-

strated efficacy, also commonly induces a marked inflam-

matory response with side effects similar to that reported

with 5-FU, although the severity of associated symptoms is

less. Diclofenac sodium 3% gel was found to offer efficacy

combined with a higher degree of tolerability than other

topical therapy options. LN2 was judged to be superior to

PDT for the treatment of thick AK lesions, although it carries

risks of hypopigmentation and scarring. The cost implica-

tions of PDT treatment, inclusive of physician, staff, drug,

equipment, and time-related expenses, may prove prohibi-

tive. Finally, while controlled studies of curettage or exci-

sional surgery are lacking, these approaches were found to

be of value when histological evaluation is warranted (e.g.,

refractory lesions, hypertrophic AK).29

Current treatment practices. When analyzing the cur-

rent state of AK treatment, Warino et al observed that

despite the proven efficacy and safety of newer topical

therapies, LN2 remains the standard of care for the man-

agement of AK.2 However, the British Association of

Dermatologists supports the use of topical medications

Table 3. Summary of results from a prospective study comparing the

efficacy of cryosurgery alone to sequential therapy of cryosurgery

followed by diclofenac sodium 3% gel32

Day 135

100% target lesionclearance

100% cumulativelesion clearance

Average reduction(target)

Average reduction(cumulative)

Mean number oftarget lesions

Cryosurgery plus

diclofenac sodium

3% gel arm (n=244)

64%

46%

89%

80%

8.9 to 1.1 (88%decrease)

Cryosurgery alone arm

(n=277)

32%

21%

68%

43%

8.2 to 2.7 (67%decrease)

Figure 4. Clearance of AK lesions after treatment with cryosurgerymonotherapy versus cryosurgery plus diclofenac sodium 3% gel(Day 135).32

Reprinted with permission from Berlin JM, Rigel DS. Diclofenac sodium 3% gel in the treatment of

actinic keratoses postcryosurgery. J Drugs Dermatol. 2008;7(7):669–673.



in cases where multiple superficial AK lesions are present

and medical providers support that these cases repre-

sent the most common use of topical medications.2,30

Medical providers advise that in some cases therapy with

5-FU can be “temporarily disfiguring” and are associated

with application site reactions that can persist for

weeks.30

During the roundtable discussion at the 2008 27th

Anniversary Fall Clinical Dermatology Conference™, der-

matologists related that their experiences mirrored much

of the available data and treatment recommendations.

They reported that PDT, while effective, is often reserved

for use in immunosupressed patients or those patients

with multiple hyperkeratotic lesions on the extremities,

although efficacy for hypertrophic AK has not been

proven to be greater with PDT. In addition to an elevated

cost, clinicians expressed concern that the treatment pro-

tocol for AK with PDT has not been standardized.

Similarly, concern about the standardization of LN2 tech-

nique exists. The panelists agreed that there has been no

reliable formal study regarding the length of time the

cryogen should be applied to the skin, and that there is

wide variability among clinicians in techniques used to

apply LN2 for AK. In fact, each clinician may randomly

vary their own technique from lesion to lesion or patient

to patient.

Of the topical therapies available for AK, the round-

table panel expressed that diclofenac sodium 3% gel is

the least irritating, the best tolerated, and associated

with the fewest number of patient concerns during treat-

ment. The panel also stressed the importance of setting

appropriate patient expectations before beginning any

topical therapy treatment. These expectations should

include efficacy, the magnitude of possible side effects,

and the timing of both inflammation and resolution of the

lesions. Attendees suggested that even after seemingly

comprehensive patient education, some patients are

invariably surprised by the extent of inflammation experi-

enced with topical 5-FU and imiquimod.

In cases where the side effects of treatment become

visibly and/or symptomatically intolerable, clinicians

reported that they sometimes lessen the frequency of

application of topical therapies, but that such modifica-

tions may prolong the necessary duration of therapy and

may potentially reduce efficacy. The roundtable panel

also stressed that due to the long history of experience

with 5-FU and its associated side effects, many clini-

cians and patients inherently believe that visible inflam-

mation is a necessary component of effective treatment

of AK. However, the predictability and intensity of visible

inflammation that develops is largely related to the

mechanism of action of the individual drug. Importantly,

the body of evidence that demonstrates topical

diclofenac is able to effectively treat AK without associ-

ated intense visible inflammation dispels this con-

tention and offers, in certain situations, a more “user

friendly” option for the treatment of patients with AK.

There is relatively little data available regarding the

Figure 6. Moderate-to-severe edema observed during a bilateral com-parison of 3% diclofenac sodium 3% gel (DFS) and 5-flourouracil 5%cream (5-FU).26 Reprinted with permission from Smith SR, Morhenn VB, Piacquadio DJ. Bilateral

comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream

in the treatment of actinic keratoses of the face and scalp. J Drugs Dermatol. 2006;5(2):156–159.

Figure 5. Moderate-to-severe erythema observed during a bilateralcomparison of diclofenac sodium 3% gel (DFS) and 5-flourouracil 5%cream (5-FU).26 Reprinted with permission from Smith SR, Morhenn VB, Piacquadio DJ. Bilateral

comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream

in the treatment of actinic keratoses of the face and scalp. J Drugs Dermatol. 2006;5(2):156–159.




long-term efficacy of treatments for AK. Data from

short-term trials indicate that all approved treatments

for AK will result in significant reduction in lesions a

month or so after treatment, leaving tolerability as the

differentiating factor. It is interesting to note that in a

recent trial by Krawtchenko et al,31 subjects were

screened one year after treatment with 5% 5-FU cream,

cryosurgery, or imiquimod 5% cream. Of patients

demonstrating clinical clearance shortly after therapy

ended, only six percent of patients treated with LN2

and 35 percent of the patients treated with 5-FU sus-

tained clearance one year after therapy ended. Long-

term results with topical imiquimod were superior to 5-

FU.31 The results of the study clearly indicate that

patients with AK, even those that respond well to ther-

apy initially, will often need additional treatment in the

future. This is especially true when patients are initially

treated with options that are more ablative in nature. It

is therefore important that clinicians consider the toler-

ability of the therapies they prescribe for the treatment

of AK. Another very important consideration is that top-

ical therapies allow for “field treatment” and therefore

address therapy for both currently visible and subclini-

cal AKs. Ablative therapies, such as LN2 and curettage,

only address the individual lesions and do not sup-

press the emergence of AK from subclinical lesions

present in the surrounding area.

Sequential therapy. Treatment of AKs need not rely

only on monotherapy. Patients with multiple lesions are

candidates for sequential therapy in which both LN2 and

topical therapies are used consecutively on the same

patient. Sequential therapy allows clinicians to treat well-

demarcated lesions with LN2 and subsequently treat a

field of diffuse lesions using topical therapy. The consen-

sus of the panel was that sequential therapy is a useful

option when a patient presents with multiple lesions and

some of those lesions are particularly amenable to LN2

(e.g., thick lesions).

In a trial conducted by Berlin and Rigel,32 subjects

had all AK lesions contained within a given target area

treated with LN2. Half of the study population had no

further treatment while half received diclofenac sodium

3% gel for 90 days (beginning 15 days after LN2; when

patients had healed). A considerably greater percentage

of subjects receiving sequential therapy achieved 100-

percent cumulative clearance at the end of the study

(Day 135) compared to patients receiving LN2 alone

(46% versus 21%) (Figure 4). Additionally, the rate of

complete target clearance was twice as high (64%) in

the sequential treatment group when compared to the

group receiving LN2 alone (32%) (Figure 4).32 These

data, in addition to other measures, suggest that

sequential therapy with LN2 and topical diclofenac is

more efficacious than LN2 alone (Table 3). Sequential

therapy of LN2 followed by diclofenac sodium 3% gel

appears to lead to an additive effect that results in more

effective treatment of clinical and subclinical lesions

than LN2 alone.

Figures 7a and 7b. This patient was treated with diclofenac sodium gel 3% on the right side of his face (a) and 5-FU on the left side ofhis face (b). This is an unretouched photo on the last day of treatment (Day 90). There were a total of 90 days of diclofenac sodium 3%gel and 28 days of 5-flourouracil 5% cream.Reprinted with permission from Stacy Smith, MD.



Considerations in Long-Term Management ofActinic Keratosis

The management of AK is rarely limited to a single

office visit. Long-term treatment and management of the

condition is usually necessary. In practice, patient satisfac-

tion with a given treatment may be based on a number of

factors including efficacy and tolerability of the treatment as

well as how closely the drug meets patient expectations.

Patient expectations and education can help

increase compliance. Patient adherence to a treatment

regimen can be influenced by their understanding of the

disorder being treated as well as their expectations

regarding the treatment. It is important that patients

understand that the presence of AK is a marker of diffuse

photodamage, which contributes to future development

of skin cancers as well as photoaging.

Patients should be advised that the emergence of

new lesions does not indicate a failure of previous treat-

ment. Rather, emergence of new AKs over time represents

progression of the underlying disease process occurring

within their skin. The genetics of their skin have been fun-

damentally altered over time due to years of cumulative

UV light exposure. Furthermore, patients should be coun-

seled that subclinical lesions may become visible when

treatment with topical therapies is initiated.16–19

Tolerability and compliance. The consensus of the

roundtable panel was that, of the three topical therapies

approved for use in treating AK, topical diclofenac exhibits

a more favorable tolerability profile compared with other

topical pharmacological agents for AK. High compliance

rates have been demonstrated in clinical trials with topi-

cal diclofenac for AK. After 90 days of twice-daily treat-

ment in a Phase 4 study, 75 percent of subjects reported

missing six or less applications of the drug.22 In a recent

clinical trial, 100 percent of the 244 patients randomized

to receive treatment with topical diclofenac for 90 days

that completed the 135-day trial had compliance rates of

at least 85 percent as assessed by patient diaries.32

In addition to demonstrated efficacy and safety,

diclofenac sodium 3% gel is also associated with high

rates of patient satisfaction. In one clinical trial, 84 per-

cent of patients were satisfied with topical diclofenac use

overall after 90 days of twice-daily application for lip

lesions. Similarly, 95 percent of patients reported they

Summary Points from Advisory Panelon Actinic Keratosis Management

• Actinic keratosis (AK) is a chronic disorder. It isimportant that patients are educated that optimaltreatment requires periodic, long-term followupand that intermittent courses of treatment may beneeded as new AK lesions emerge over time. Thegoal is prevention of invasive SCC, and early detec-tion should progression to SCC occur.

• As AKs are present predominantly in visible areas,the extent and intensity of visible treatment reac-tions, such as edema and blistering with cryother-apy (LN2) or erythema and crusting with topical 5-fluorouracil (5-FU) or imiquimod, are very impor-tant considerations with regard to ultimate treat-ment selection for each patient. Patients need tobe aware up front of the likely visible reactions totreatment and associated symptomatology beforeconsenting to whatever therapies are chosen.

• Sequential treatment of AKs is commonly used inclinical practice. This approach, which typicallycombines use of LN2 with a topical agent, pro-vides the advantages of additive therapeutic ben-efit, more immediate treatment of currently visibleAKs with ablative therapy, and “field treatment” ofboth visible and subclinical AKs.

• Patients with AK usually present with multiplelesions and frequently return with additional AKsmonths to years later. Patients are more likely torepeat a treatment if they find it to be both effec-tive and well tolerated.

Summary Points from Advisory Panel on TopicalTherapies Used to Treat Actinic Keratosis

• Clinical trials have demonstrated that the short-term efficacy of many of the available topicaltreatments for AK is comparable. Data regardingthe long-term efficacy of treatment is scarce.Therefore, issues of tolerability and patient com-pliance may become the deciding factors whenchoosing AK therapy.

• In the past, 5-FU was the only available topicaltherapy for AK, but newer topical agents that causeless visible inflammation are available to cliniciansand patients. In general, 5-FU is most consistentlyassociated with visible inflammation. Therapiesassociated with visible inflammation may lead toadditional office visits, telephone care, and insome cases, dissatisfaction with the treatment.

• Patient expectations and satisfaction with a pre-scribed treatment can greatly influence compli-ance with current and future treatment regimens,and as such, the associated risk of visible inflam-mation should be addressed with patients prior toselecting a topical therapy.

• Diclofenac sodium 3% gel has demonstrated effi-cacy in the treatment of AKs, including lesionslocated on the lip. The inhibition of the COX-2pathway by topical diclofenac likely accounts forthe drug’s lower tendency to produce visible cuta-neous inflammation than other topical therapiesfor AK. The extended duration of topicaldiclofenac treatment does not appear to adverselyimpact compliance or patient satisfaction.




would recommend topical diclofenac to others with the

same type of lip lesions.23 When patients were treated

with diclofenac sodium 3% gel and 5-FU 5% cream in a

split-face study, both demonstrated substantial efficacy,

but patients reported higher levels of satisfaction with

topical diclofenac. In the same study, there was a marked

difference in tolerability between the two treatments. On

the side of the face treated with diclofenac sodium 3%

gel, only 27 percent of patients were observed to have

moderate or severe erythema compared to more than 80

percent of patients found to have moderate or severe ery-

thema on the facial side treated with 5-FU (Figure 5).

Similarly, treatment with diclofenac sodium 3% gel was

associated with lower rates of moderate or severe edema

than 5-FU (Figure 6). Diclofenac sodium 3% gel caused

far less visible inflammation and associated symptoma-

tology than 5-FU 5% cream despite a longer duration of

therapy (Figures 7a and 7b).26

Conclusion and Consensus of the Roundtable Panel

AK is a chronic condition that requires long-term

management. Compliance is a very compelling issue

when treating AK. Efficacy and tolerability must be taken

into consideration when recommending treatment.

Patients should not only be educated about the nature of

the disease and the need for treatment, but should also

be made aware of the visible reaction and associated

symptoms that they are likely to encounter during treat-

ment, especially those which are more predictable, as

with topical 5-FU.

Several topical treatments have demonstrated effi-

cacy at reducing AK lesions, but they differ markedly in

their side effect and tolerability profiles and application

schedules. Diclofenac sodium 3% gel has far greater tol-

erability than other topical agents and provides compa-

rable efficacy rates based on available studies. The dif-

ferences in tolerability among topical therapies for AK

can impact patient satisfaction and long-term patient

compliance with current and future treatment regimens.

Additionally, topical therapies, such as diclofenac, 5-FU,

and imiquimod, may be combined with ablative treat-

ment, such as LN2, to achieve additive benefit. This com-

bination approach allows for more immediate treatment

of currently visible lesions and addresses management

of subclinical AK lesions in the surrounding field of

involvement.

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2. Warino L, Tusa M, Camacho F, et al. Frequency and

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3. Schwartz RA, Bridges TM, Butani AK, et al. Actinic ker-

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13. Piacquadio DJ, Chen DM, Farber HF, et al.


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15. Pariser DM, Lowe NJ, Stewart DM, et al. Photodynamic

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scalp. J Drugs Dermatol. 2006;5(2):156–159.

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Support provided by PharmaDerm, a division of Nycomed US Inc.

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Copyright © 2009 Matrix Medical Communications. All rights reserved.


SOLARAZE® GELDiclofenac Sodium-3%FOR DERMATOLOGIC USE ONLY. NOT FOR OPHTHALMIC USE.

INDICATIONS AND USAGE

Solaraze® (diclofenac sodium) Gel is indicated for the topical treatment of actinic keratoses

(AK). Sun avoidance is indicated during therapy.

CLINICAL STUDIES

Clinical trials were conducted involving a total of 427 patients (213 treated with Solaraze® and

214 with a gel vehicle). Each patient had no fewer than five AK lesions in a major body area,

which was defined as one of five 5 cm x 5 cm regions: scalp, forehead, face, forearm and

hand. Up to three major body areas were studied in any patient. All patients were 18 years

of age or older (male and female) with no clinically significant medical problems outside of

the AK lesions and had undergone a 60-day washout period from disallowed medications

(masoprocol, 5-fluorouracil, cyclosporine, retinoids, trichloroacetic acid/lactic acid/peel,

50% glycolic acid peel) and hyaluronan-containing cosmetics. Patients were excluded from

participation for reasons of known or suspected hypersensitivity to any Solaraze® ingredi-

ent, pregnancy, allergies to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs),

or other dermatological conditions which might affect the absorption of the study medica-

tion. Application of dermatologic products such as sunscreens, cosmetics, and other drug

products was not permitted. Patients were instructed to apply a small amount of Solaraze®

Gel (approximately 0.5 g) onto the affected skin, using their fingers, and gently smoothing the

gel over the lesion. In addition, all patients were instructed to avoid sun exposure. Complete

clearing of the AK lesions 30 days after completion of treatment was the primary efficacy

variable. No long-term patient follow-ups, after the 30-day assessments, were performed for

the detection of recurrence.

CONTRAINDICATIONS

Solaraze® (diclofenac sodium) Gel is contraindicated in patients with a known hypersensitivity

to diclofenac, benzyl alcohol, polyethylene glycol monomethyl ether 350 and/or hyaluronate

sodium.

WARNINGS

As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure

to diclofenac. Diclofenac sodium should be given with caution to patients with the aspirin

triad. The triad typically occurs in asthmatic patients who experience rhinitis with or without

nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or

other NSAIDs.

PRECAUTIONS

General

Solaraze® (diclofenac sodium) Gel should be used with caution in patients with active gastro-

intestinal ulceration or bleeding and severe renal or hepatic impairments. Solaraze® should not

be applied to open skin wounds, infections, or exfoliative dermatitis. It should not be allowed

to come in contact with the eyes.

The safety of the concomitant use of sunscreens, cosmetics or other topical medications and

Solaraze® is unknown.

Information for Patients

In clinical studies, localized dermal side effects such as contact dermatitis, exfoliation, dry

skin and rash were found in patients treated with Solaraze® at a higher incidence than in those

with placebo.

If severe dermal reactions occur, treatment with Solaraze® may be interrupted until the

condition subsides. Exposure to sunlight and the use of sunlamps should be avoided.

Safety and efficacy of the use of Solaraze® together with other dermal products, including

cosmetics, sunscreens, and other topical medications on the area being treated, have not

been studied.

Drug Interactions

Although the systemic absorption of Solaraze® is low, concomitant oral administration of other

NSAIDs such as aspirin at anti-inflammatory/analgesic doses should be minimized.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There did not appear to be any increase in drug-related neoplasms following daily topical

applications of diclofenac sodium gel for 2 years at concentrations up to 0.035% diclofenac

sodium and 2.5% hyaluronate sodium in albino mice.

A photococarcinogenicity study with up to 0.035% diclofenac in the Solaraze® vehicle gel was

conducted in hairless mice at topical doses up to 2.8 mg/kg/day. Median tumor onset was

earlier in the 0.035% group (Solaraze® contains 3% diclofenac sodium).

Diclofenac was not genotoxic in in vitro point mutation assays in mammalian mouse lym-

phoma cells and Ames microbial test systems, or when tested in mammalian in vivo assays

including dominant lethal and male germinal epithelial chromosomal studies in mice, and

nucleus anomaly and chromosomal aberration studies in Chinese hamsters. It was also

negative in the transformation assay utilizing BALB/3T3 mouse embryo cells.

Fertility studies have not been conducted with Solaraze® Gel. Diclofenac sodium showed no

evidence of impairment of fertility after oral treatment with 4 mg/kg/day (7 times the estimated

systemic human exposure) in male or female rats.

Pregnancy:

Teratogenic Effects: Pregnancy Category B

The safety of Solaraze® (diclofenac sodium) Gel has not been established during pregnancy.

However, reproductive studies performed with diclofenac sodium alone at oral doses up to

20 mg/kg/day (15 times the estimated systemic human exposure*) in mice, 10 mg/kg/day

(15 times the estimated systemic human exposure) in rats, and 10 mg/kg/day (30 times the

estimated systemic human exposure) in rabbits have revealed no evidence of teratogenicity

despite the induction of maternal toxicity. In rats, maternally toxic doses were associated with

dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival.

* Based on body surface area and assuming 10% bioavailability following topical application

of 2 g Solaraze® Gel per day (1 mg/kg diclofenac sodium).

Diclofenac has been shown to cross the placental barrier in mice and rats. There are, however,

no adequate and well controlled studies in pregnant women. Because animal reproduction

studies are not always predictive of human response, this drug should not be used during

pregnancy unless the benefits to the mother justify the potential risk to the fetus. Because of

the risk to the fetus resulting in premature closure of the ductus arteriosus, diclofenac should

be avoided in late pregnancy.

Labor and Delivery

The effects of diclofenac on labor and delivery in pregnant women are unknown. Because of

the known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system (closure

of the ductus arteriosus), use of diclofenac during late pregnancy should be avoided and, as

with other nonsteroidal anti-inflammatory drugs, it is possible that diclofenac may inhibit uter-

ine contractions and delay parturition.

Nursing Mothers

Because of the potential for serious adverse reactions in nursing infants from diclofenac

sodium, a decision should be made whether to discontinue nursing or to discontinue the drug,

taking into account the importance of the drug to the mother.

Pediatric Use

Actinic keratosis is not a condition seen within the pediatric population. Solaraze® should not

be used by children.

Geriatric Use

No overall differences in safety or effectiveness were observed between geriatric subjects

and younger subjects, and other reported clinical experience has not identified differences

in responses between the elderly and younger patients, but greater sensitivity of some older

individuals cannot be ruled out.

ADVERSE REACTIONS

Of the 423 patients evaluable for safety in adequate and well-controlled trials, 211 were

treated with Solaraze® drug product and 212 were treated with a vehicle gel. Eighty-seven

percent (87%) of the Solaraze®-treated patients (183 patients) and 84% of the vehicle-treated

patients (178 patients) experienced one or more adverse events (AEs) during the studies. The

majority of these reactions were mild to moderate in severity and resolved upon discontinu-

ation of therapy.

Of the 211 patients treated with Solaraze®, 172 (82%) experienced AEs involving skin and the

application site compared to 160 (75%) vehicle-treated patients. Application site reactions

(ASRs) were the most frequent AEs in both Solaraze® and vehicle-treated groups. Of note, four

reactions, contact dermatitis, rash, dry skin and exfoliation (scaling) were significantly more

prevalent in the Solaraze® group than in the vehicle-treated patients.

Eighteen percent of Solaraze®-treated patients and 4% of vehicle-treated patients discontinued

from the clinical trials due to adverse events (whether considered related to treatment or

not). These discontinuations were mainly due to skin irritation or related cutaneous adverse

reactions.

OVERDOSAGE

Due to the low systemic absorption of topically-applied Solaraze® Gel, overdosage is unlikely.

There have been no reports of ingestion of Solaraze®. In the event of oral ingestion, result-

ing in significant systemic side effects, it is recommended that the stomach be emptied by

vomiting or lavage. Forced diuresis may theoretically be beneficial because the drug is

excreted in the urine.

DOSAGE AND ADMINISTRATION

Solaraze® Gel is applied to lesion areas twice daily. It is to be smoothed onto the affected

skin gently. The amount needed depends upon the size of the lesion site. Assure that enough

Solaraze® Gel is applied to adequately cover each lesion. Normally 0.5 g of gel is used on each

5 cm x 5 cm lesion site. The recommended duration of therapy is from 60 days to 90 days.

Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30

days following cessation of therapy. Lesions that do not respond to therapy should be carefully

re-evaluated and management reconsidered.

Rx Only

Complete Clearance of Actinic Keratosis Lesions 30 Days

Post-Treatment (all locations)

Solaraze® Gel Vehicle p-value

Study 1 90 days treatment 27/58 (47%) 11/59 (19%) <0.001

Study 2 90 days treatment 18/53 (34%) 10/55 (18%) 0.061



98NSGD050308

PROFESSIONAL BRIEF SUMMARY - See package insert for full prescribing information


the long-term management of actinic keratosis: treatment ......actinic keratosis (ak) is one of the...

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