Supplement to the March 2010 issue of
Diclofenac Sodium 3% Gel
for the Treatment of Actinic Keratosis
Case-based Experience
Proceedings from a Clinical Dermatology Roundtable
Support provided by PharmaDerm, a division of Nycomed US Inc. www.jcadonline.com
Participants
Introduction
The diagnosis and management of actinic keratosis (AK) is esti-
mated to account for more than 10 percent of all patient visits to
Mark G. Lebwohl, MD dermatologists.1 Despite recognition that ultraviolet (UV) radiation
Professor and Chairman
resulting from sun exposure is a principal cause of AK, the inci-
Department of Dermatology
Mount Sinai School of Medicine dence of the disorder continues to rise.2,3 In the Northern hemi-
New York, New York
sphere, the reported prevalence of AK has ranged from 11 to 25 per-
cent.4,5 Known risk factors for AK are summarized in Table 1.
As a result of field cancerization, patients often have multiple
AKs on sun-exposed areas.2,8 Not surprisingly, AKs often coexist
with other signs of photodamage/photoaging. While patients may
Neal Bhatia, MD present with symptoms of pruritus or irritation, AKs are usually
Associate Clinical Professor
University of Wisconsin asymptomatic.6,9 Although some patients may want AKs treated for
Medical School aesthetic or symptomatic reasons, the most compelling motivation
Madison, Wisconsin
for treating AKs is their potential to progress to squamous cell carci-
noma (SCC). The cellular abnormalities associated with AK lie on
one end of a continuum that terminates with invasive carcinoma,
leading some to consider AKs in-situ intraepidermal neo-
plasms.8,10,11 Fortunately, most AKs do not progress to SCC, with sev-
Roger I. Ceilley, MD
eral sources suggesting progression occurs in approximately 10
Clinical Professor of Dermatology percent of patients.8,13 A recent longitudinal study demonstrated
University of Iowa
Iowa City, Iowa
that the risk of progression of AK to invasive SCC was 0.39 percent
at one year and 1.97 percent at four years.14 While the risk of pro-
gression from AK to SCC has been long recognized, data suggests
AKs may also be capable of progressing into basal cell carcinoma
(BCC). Most sources agree that AKs should be treated.2,3,8,9,11,15
Patients and clinicians have a wide spectrum of treatment
Dr. James Del Rosso, DO, FAOCD options available for the management of AK. Therapeutic options
Dermatology Residency Director
Valley Hospital Medical Center
can be classified as either field-based or lesion-directed therapies
Las Vegas, Nevada (Table 2). The topical field-based therapies offer the potential ben-
efit of treating subclinical lesions by interfering with the pathogen-
esis of AK.3,11 Topical therapies approved by the United States Food
and Drug Administration (FDA) possess distinct dosing regimens
and vary in their ability to be used on anatomic locations other than
Abel Torres, MD, JD the face and scalp (Table 3). The three active ingredients approved
Professor and Chairman for topical treatment of AK also vary drastically in their mechanisms
Department of Dermatology
Loma Linda University of action. Whereas imiquimod and 5-fluorouracil (5-FU) induce an
Loma Linda, California inflammatory reaction, diclofenac sodium 3% gel is anti-inflamma-
tory in nature.16 Data regarding the proposed mechanism(s) of
This supplement is based on a roundtable discussion that took place on
October 15, 2009, during the 2009 Fall Clinical Dermatology Conference in Las
James M. Spencer, MD, MS Vegas, Nevada. Mark G. Lebwohl, MD, moderated the roundtable discussion,
Associate Clinical Professor
Department of Dermatology which included Neal Bhatia, MD; Roger I. Ceilley, MD; James Q. Del Rosso, DO;
Mt. Sinai School of Medicine and Abel Torres, MD. James Spencer, MD, also contributed to the development
New York, New York
of the framework for the roundtable discussion. The supplement and roundtable
The authors would like to recognize the contributions of Jamison
Strahan, MD, Mohs Surgery Fellow in the Department of Dermatology discussion were supported by PharmaDerm, a division of Nycomed US Inc.
at Loma Linda University, in the development of several of the case
presentations. Editorial and medical writing assistance provided by
DAW Communications, South Norwalk, Connecticut.
TABLE 1. Risk factors for actinic keratosis2,3,5,6,7 TABLE 2. Treatment modalities for actinic keratosis11
• Increasing age
LESION-DIRECTED TREATMENTS FIELD-DIRECTED TREATMENTS
• Male gender
• Occupational/recreational exposure to sunlight
• Cryotherapy • Diclofenac sodium 3% gel
• Living near the equator
• Fair skin and a tendency to sunburn (as assessed by Fitzpatrick
classification) • Laser therapy • 5-fluorouracil 0.5%, 5%
• Genetic disorders affecting the repair abilities of the skin (e.g.,
xeroderma pigmentosum)
• Curettage • Imiquimod 5% cream
• Immune system impairments secondary to disease (e.g., AIDS)
• Excision • Photodynamic therapy
• Iatrogenic immunosuppression (e.g., post-organ transplantation)
TABLE 3. FDA-approved topical therapies for actinic keratosis
MUCOUS MEMBRANES
PREGNANCY
DRUG NAME DOSING AND ADMINISTRATION TREATMENT AREA (EXCLUDING OPHTHALMIC OR
CATEGORY
INTRAVAGINAL)
Diclofenac sodium
Twice daily for 60–90 days Not limited Not limited B
3% gel19
48 years of age (mean age of 68.2 years) target lesions. A Phase 4, multicenter, single-arm, open-label
with five or more AK lesions in 1 to 3 blocks (5cm2) on the study (N=76) in patients >48 years of age (mean age of 68.2
forehead, central face, or scalp. Efficacy and tolerability were years) with five or more AK lesions in 1 to 3 blocks (5cm2) on the
evaluated for a treatment period of 90 days with monthly visits forehead, central face, or scalp. Efficacy and tolerability were
(Days 30, 60, and 90) and a follow-up visit at Day 120. A 1-year evaluated for a treatment period of 90 days with monthly visits
post-treatment evaluation was conducted (N=47). (Days 30, 60, and 90) and a follow-up visit at Day 120. A 1-year
post-treatment evaluation was conducted (N=47).
TABLE 5. Goals of field-directed therapies
after the last application of diclofenac sodium 3% gel.
• Clear clinically evident and sub-clinical AKs Eligible patients had not received any treatment for AKs (to
the designated areas of the face) during the preceding year.
• Inhibit progression to invasive carcinoma Efficacy measures included the target lesion number score
(TLNS) defined as the total number of lesions in the desig-
• Induce longer lesion-free periods nated treatment area at baseline and subsequent visits and
the cumulative lesion number score (CLNS) defined as the
• Reduce the need for frequent treatments number of original and new AK lesions in the same areas at
all visits after the baseline visit. Of the 47 patients who
Adapted from Stockfleth E, Ferrandiz C, Grob JJ, et al. completed the one-year assessment, at least 75-percent
Development of a treatment algorithm for actinic keratoses: a
European Consensus. Eur J Dermatol. 2008;18(6):651–659.11 clearance of target lesions was achieved by 91 percent of
patients (95% CI, 83–99%). Among subjects in the original
Phase IV multicenter trial, 75-percent clearance as
above treatment regimens, Dr. Ceilley reviewed results from assessed by TLNS was achieved by 85 percent of the cohort
an extension study designed to evaluate the long-term 30 days post-treatment.26 Complete clearance of target
effects of treatment with diclofenac sodium 3% gel on clin- lesions, a considerably stricter efficacy measure, was
ically diagnosed AK lesions recently published by Nelson achieved by more than three-quarters of patients at one
29
and Rigel. The original study was a single-arm, multicen- year post-therapy (Figure 1). One year post-treatment,
ter, open-label trial that enrolled 76 subjects (67 com- patients exhibited a 95-percent mean reduction from base-
pleted) each with a minimum of five AK lesions in 1 to 3 line in target lesions. This can be compared to the 90-per-
26
areas on the face, forehead, or scalp. Subjects received cent mean reduction in TLNS observed 30-days post-treat-
treatment with diclofenac sodium 3% gel twice daily for 90 ment in the original trial (Figure 2).
days with a follow up at 120 days (i.e., 30 days post-treat- Differences in study designs and patient populations do
ment). In the extension study, patients returned for a single not allow for direct comparison. The long-term efficacy of
observation and evaluation visit approximately one year other topical therapies have also been studied. In a study by
12 S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY [ M A R C H 2 0 1 0 • VO LU M E 3 • N U M B E R 3 ]
Diclofenac Sodium 3% Gel for the Treatment of Actinic Keratosis—Case-based Experience: Proceedings from a Clinical Dermatology Roundtable
Lee et al,35 42.6 percent of patients exhibiting complete matitis, rash, dry skin, and exfoliation occurred more fre-
clearance of AKs eight weeks after completion of a twice- quently in diclofenac-treated subjects compared to those
weekly, 16-week regimen of imiquimod 5% cream had recur- receiving vehicle. Nonetheless, the roundtable members
35
rence of AKs in the treated area 12 to 18 months later. Most agreed that patients need to be told of the possible
of those individuals with recurrence developed one new AK adverse reactions. If they occur, patients should follow up
36
during the follow-up period. A study by Krawtchenko et al with their physician.
evaluated the long-term outcomes following treatment with Some patients have very specific concerns regarding
several AK therapies including an FDA-approved regimen of the available treatment modalities for AK. For instance, Dr.
36
5-FU 5% cream (i.e., twice daily for four weeks). Four weeks Del Rosso’s patient described in Case 11 was very explicit
post-therapy, 96 percent (23/24) of patients treated with 5- regarding his reservations about cryotherapy (i.e., wanting
FU exhibited complete clearance of lesions in the treated to prevent “white spots”). Hypopigmentation following
area. One year after completion of therapy, however, 43 per- cryotherapy is a realistic concern as almost 30 percent of
cent (10/23) of those patients experienced recurrence of ini- lesions demonstrating a complete response after cryother-
tially cleared lesions. Moreover, at one-year post-treatment, apy exhibit hypopigmentation.37 While the patient’s desire
only 33 percent (8/24) of patients demonstrated clearance to avoid therapy with imiquimod was largely based on the
of the treatment field. This suggests that in the remaining 67 irritation and inflammation he experienced previously, Dr.
percent of patients, there was an initial incomplete clear- Del Rosso was also cognizant of the patient’s coexisting,
ance, development of new lesions, and/or recurrence of pre- albeit relatively minor, atopic dermatitis. Imiquimod
viously cleared lesions. appears capable of exacerbating eczema. The prescribing
Rationale for treatment with diclofenac sodium 3% gel. information for imiquimod cream warns that the agent can
In addition to the demonstrated long-term efficacy of potentially exacerbate any inflammatory condition of the
diclofenac sodium 3% gel, the panel of dermatologists dis- skin.12 Eczematous reactions have been documented at sites
cussed several other characteristics that make it an appro- distant from the application site, suggesting a systemic
priate treatment in the above four cases. Patient satisfaction response to imiquimod.38 In addition, another potential
with a given treatment may influence willingness to repeat advantage of treatment with diclofenac sodium 3% gel in
that therapy in the future. When patients were treated with the experience of the panelists, is that many patients find
diclofenac sodium 3% gel and 5-FU 5% cream in a split-face gels easier to apply to the scalp than creams.
study, patients reported considerably higher levels of satis- Frequency and need for follow-up visits. Although no
27
faction with diclofenac sodium 3% gel. Satisfaction with a guidelines exist regarding the precise frequency of follow up
given treatment may influence not only a patient’s compli- for patients with chronic AK, the panel members were in
ance with a given regimen but also his/her willingness to agreement that most patients should be examined every 6
22
return for follow-up visits and re-evaluation. to 12 months. Patients with SCC or BCC should be seen more
In Cases 8, 9, 10, and 11, Dr. Ceilley highlighted that regularly and patients should be encouraged to conduct reg-
in these patients, a field-directed therapy was preferable, ular self-examinations for lesions. The participants also sug-
given frequent appearance of new AKs in these patients. gest that even patients whose AKs completely clear follow-
With all of the patients described, there was a desire by ing treatment should be seen regularly such that new, dis-
physicians and patients to utilize a therapy with a low crete lesions can be treated rather than “waiting for more to
potential for a visible reaction. Although the risk of severe develop.” With education, patient expectations regarding
visible reaction with diclofenac sodium 3% gel has been the treatment and natural course of AK can be managed.
demonstrated to be low, Dr. Del Rosso stressed that Patients should understand that new lesions presenting at
patient expectations should be realistic. For instance, in follow up are not necessarily indicative of treatment failure
pivotal trials, 84 percent of patients receiving 90 days of but instead, highlight the chronicity of the disorder. The
therapy with diclofenac sodium 3% gel reported some above case reports demonstrate the benefits and effective-
19
form of application-site reaction. These events were gen- ness of diclofenac sodium 3% gel for the long-term manage-
erally mild or moderate in severity and only contact der- ment of patients with AK.
[ M A R C H 2 0 1 0 • VO LU M E 3 • N U M B E R 3 ] S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY 13
When deciding upon a topical therapy for this patient, the
Patient Presentation—Case 12
physician considered the mechanism of action of potential
• Patient: 69-year-old man
therapies. Imiquimod, an immune-response modifier, is
• History
History of psoriasis for many years, treated with thought to function by activating antigen-presenting cells
artificial ultraviolet exposure and sunlight and causing the release of numerous cytokines.12,20 Topical
Treated for squamous cell carcinoma on the right
tip of the nose four years prior by curettage and imiquimod treatment has been associated with psoriasis
electrodessication exacerbations in susceptible patients.39,40 It has been
Fitzpatrick skin type II hypothesized that increased levels of interferon-α, a recog-
No occupational sun exposure, but lived much of
his life in a subtropical climate (i.e., Israel) nized contributor to psoriasis pathogenesis, secondary to
• Physical exam treatment with imiquimod, play a role in this phenomenon.
Sharply demarcated erythematous scaling As such, Dr. Lebwohl felt that imiquimod was an inappropri-
plaques, particularly on the buttocks
Numerous erythematous scaling macules, some ate option for this patient.
with hyperkeratotic crusts on the entire forehead As mentioned previously, whereas imiquimod and 5-FU
Additional actinic keratoses on exposed surfaces are pro-inflammatory, diclofenac sodium 3% gel is believed
of his body
to treat AK via anti-inflammatory mechanisms.16 Although
not fully elucidated, the antidysplastic effects of diclofenac
have been hypothesized to be related to its action as a non-
steroidal anti-inflammatory drug in inhibiting the cyclooxy-
genase-2 pathway.16,26,28,41 Diclofenac may also have effects
on apoptosis, cell proliferation, and angiogenesis.28,41 A
recently published study by Dirschka et al42 reported that
histological examination of AKs pre- and post-treatment
with diclofenac sodium 3% gel demonstrated significantly
Forehead at presentation
fewer mitoses and decreased inflammatory infiltrate after
treatment.42 Treatment also resulted in significant reduction
in mutational inactivation of the p53 tumor suppressor
gene and proliferation marker Ki-67 as assessed by anti-
p53 and anti-MiB-1antibodies, respectively. The hyaluronic
acid base of diclofenac sodium 3% gel may also actively
AK and Coexisting Psoriasis assist in the drug’s efficacy by enhancing delivery and
retention of active drug to the superficial layers of skin.28,41,43
AK can coexist with virtually any dermatological or As discussed in Cases 1 through 5, diclofenac sodium 3%
general medical condition. In Case 12, Dr. Lebwohl gel may offer the advantage over other therapies of being
described an elderly male patient who presented, not for better tolerated by the patient. This may be particularly
treatment of AK, but for evaluation and management of important for patients with pre-existing conditions in which
the inflammatory skin disease psoriasis (see Patient the integrity of the skin is already compromised.
Presentation—Case 12). UV and solar therapy, while effec- Case outcome. Given the above considerations, Dr.
tive for the treatment of psoriasis, had potentially Lebwohl prescribed the patient in Case 12 diclofenac
increased the patient’s risk for AK. sodium 3% gel twice daily for 90 days. Over the next three
Treatment rationale. The patient’s psoriasis had gener- months, the patient experienced minor irritation that was
ally responded to narrowband UVB phototherapy in the well tolerated. At follow up, more than 90 percent of the
past. In this case, his refractory plaques on the buttocks AKs cleared and the patient was very satisfied with the
were treated with intralesional triamcinolone acetonide at outcome. This case highlights the need to consider coex-
10 sites. Dr. Lebwohl believes that the numerous AK lesions isting dermatological conditions when managing AK
on the patient’s forehead supported the use of field therapy. patients.
14 S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY [ M A R C H 2 0 1 0 • VO LU M E 3 • N U M B E R 3 ]
Diclofenac Sodium 3% Gel for the Treatment of Actinic Keratosis—Case-based Experience: Proceedings from a Clinical Dermatology Roundtable
AK of the Lip Patient Presentation—Case 13
• Patient: 37-year-old Caucasian man
AK typically occurs in areas likely to experience exces-
• History
sive sun exposure. As we have discussed, commonly States “lower lip is scaly and rough for months”
affected locations include the scalp, face, neck, forearms, Has resided in predominantly sunny locations
(e.g., Las Vegas and Southern California)
dorsum of the hands, and the chest. As described in Case
Extensive recreational sun exposure
13, the lower lip is another common location for AK to (e.g., baseball)
appear (see Patient Presentation—Case 13).2 This case No previously treated dermatological conditions
focused on a 37-year-old man who presented to Dr. Del • Clinical assessment
Diffuse actinic keratosis of the lower mucosal lip
Rosso with diffuse AK of the lower lip. AK of the lip presents
Thin, no nodularity, no focal lesions
several unique therapeutic challenges. The high visibility of
No hyperkeratotic foci
the lip raises concerns regarding the risk of inflammation Photodamage on face, scalp, neck , upper chest,
with treatment and the potential for scarring. The increased and upper extremities
No lesions suspicious for skin malignancy
likelihood of irritation can also complicate management of
these lesions.44
Efficacy and tolerability of diclofenac sodium 3% gel
on lip AKs. While describing his rationale for selecting a
treatment regimen for the present patient, Dr. Del Rosso
described an open-label, single-arm trial in which the effi-
cacy and tolerability of topical diclofenac sodium 3% for
the treatment of AKs on the lip was demonstrated.44 The trial
enrolled 22 subjects, each with a diagnosis of AK of the
upper and lower lip with at least one visible lesion on the
Exam at presentation Following two months of
vermilion. At baseline, the patients had a mean of 4.5 treatment with diclofenac
lesions within the treatment field. One month post-treat- sodium 3% gel
ment (i.e., Day 120), patients demonstrated a mean 85-per-
cent reduction in target lesions. Approximately 90 percent
of subjects demonstrated at least 75-percent clearance of
their target lesions at Day 120. Overall, 68 percent of very pleased with the results. Given the potential for recur-
patients “strongly agreed” that they experienced no skin rence, Dr. Del Rosso opted to recommend the continuation
irritation next to the lesions. Furthermore, 79 percent of of therapy for another month, resulting in a total of three
patients treated with topical diclofenac sodium 3% for AK months of therapy.
lesions on their lips “strongly agreed” that they were satis- As discussed in earlier cases, AK is best thought of as a
fied with the treatment. Additionally, more than 80 percent chronic condition. With this young patient, although he had no
of subjects “strongly agreed” that they would recommend prior history of AK, he is at risk for developing additional AKs in
the product to others with the same type of lesions. Overall, the future and therefore patient education and the use of pho-
in this study it was demonstrated that topical diclofenac toprotection on both the skin and lips are vital components of
sodium 3% can be an effective, safe, and well-tolerated management. The judicious use of wide-brimmed hats and
treatment of lip AKs. sunscreen are effective means of preventing AK and should be
Management and patient education. After consultation stressed to all patients.2,3,45,46 Sun avoidance is indicated during
with the patient, therapy with twice-daily diclofenac sodium sodium diclofenac 3% gel treatment. Sun avoidance also is
3% gel was prescribed. After two months of treatment, the important while receiving 5-FU or imiquimod therapy, as expo-
lip lesion demonstrated complete clearance (see Patient sure to UV rays may result in an increased inflammatory reac-
Presentation—Case 13). The patient reported no irritation, tion and/or increased sensitivity to sunburn.12,23,47 Data from
inflammation, or adverse events. Overall, the patient was recent Phase IV studies suggest that phototoxicity and photo-
[ M A R C H 2 0 1 0 • VO LU M E 3 • N U M B E R 3 ] S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY 15
sensitization reactions are rare during treatment with References
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(Solaraze). J Drugs Dermatol. 2004;3(4):401–407. imiquimod. Australas J Dermatol. 2004;45(1):47–50.
27. Smith SR, Morhenn VB, Piacquadio DJ. Bilateral compar- 40. Rajan N, Langtry JA. Generalized exacerbation of psoria-
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28. Jarvis B, Figgitt DP. Topical 3% diclofenac in 2.5% keratoses. Int J Dermatol. 2007;46(1):12–18.
hyaluronic acid gel: a review of its use in patients with 42. Dirschka T, Bierhoff E, Pflugfelder A, Garbe C. Topical
actinic keratoses. Am J Clin Dermatol. 2003;4(3):203–213. 3.0% diclofenac in 2.5% hyaluronic acid gel induces
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regression of cancerous transformation in actinic ker- ment options. Am J Clin Dermatol. 2000;1(3):167–179.
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Dermatol Venereol. 2009. factor sunscreens in the suppression of actinic neopla-
43. Cox NH. Diclofenac for actinic keratoses: a formulation sia. Arch Dermatol. 1995;131(2):170–175.
issue. Clin Exp Dermatol. 2006;31(6):819–820. 47. Efudex [package insert]. Costa Mesa, CA: Valeant
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18 S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY [ M A R C H 2 0 1 0 • VO LU M E 3 • N U M B E R 3 ]
PROFESSIONAL BRIEF SUMMARY - See package insert for full prescribing information
Rx Only
SOLARAZE® GEL
Diclofenac Sodium-3%
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:
FOR DERMATOLOGIC USE ONLY. NOT FOR OPHTHALMIC USE.
Teratogenic Effects: Pregnancy Category B
INDICATIONS AND USAGE The safety of Solaraze® (diclofenac sodium) Gel has not been established during pregnancy.
Solaraze® (diclofenac sodium) Gel is indicated for the topical treatment of actinic keratoses However, reproductive studies performed with diclofenac sodium alone at oral doses up to
(AK). Sun avoidance is indicated during therapy. 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
CLINICAL STUDIES
estimated systemic human exposure) in rabbits have revealed no evidence of teratogenicity
Clinical trials were conducted involving a total of 427 patients (213 treated with Solaraze® and
despite the induction of maternal toxicity. In rats, maternally toxic doses were associated with
214 with a gel vehicle). Each patient had no fewer than five AK lesions in a major body area,
dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival.
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 * Based on body surface area and assuming 10% bioavailability following topical application
of age or older (male and female) with no clinically significant medical problems outside of of 2 g Solaraze® Gel per day (1 mg/kg diclofenac sodium).
the AK lesions and had undergone a 60-day washout period from disallowed medications
Diclofenac has been shown to cross the placental barrier in mice and rats. There are, however,
(masoprocol, 5-fluorouracil, cyclosporine, retinoids, trichloroacetic acid/lactic acid/peel,
no adequate and well controlled studies in pregnant women. Because animal reproduction
50% glycolic acid peel) and hyaluronan-containing cosmetics. Patients were excluded from
studies are not always predictive of human response, this drug should not be used during
participation for reasons of known or suspected hypersensitivity to any Solaraze® ingredi-
pregnancy unless the benefits to the mother justify the potential risk to the fetus. Because of
ent, pregnancy, allergies to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs),
the risk to the fetus resulting in premature closure of the ductus arteriosus, diclofenac should
or other dermatological conditions which might affect the absorption of the study medica-
be avoided in late pregnancy.
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® Labor and Delivery
Gel (approximately 0.5 g) onto the affected skin, using their fingers, and gently smoothing the The effects of diclofenac on labor and delivery in pregnant women are unknown. Because of
gel over the lesion. In addition, all patients were instructed to avoid sun exposure. Complete the known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system (closure
clearing of the AK lesions 30 days after completion of treatment was the primary efficacy of the ductus arteriosus), use of diclofenac during late pregnancy should be avoided and, as
variable. No long-term patient follow-ups, after the 30-day assessments, were performed for with other nonsteroidal anti-inflammatory drugs, it is possible that diclofenac may inhibit uter-
the detection of recurrence. ine contractions and delay parturition.
Nursing Mothers
Complete Clearance of Actinic Keratosis Lesions 30 Days
Post-Treatment (all locations) 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,
Solaraze® Gel Vehicle p-value taking into account the importance of the drug to the mother.
Study 1 90 days treatment 27/58 (47%) 11/59 (19%) <0.001 Pediatric Use
Actinic keratosis is not a condition seen within the pediatric population. Solaraze® should not
Study 2 90 days treatment 18/53 (34%) 10/55 (18%) 0.061 be used by children.
Geriatric Use
Study 3 60 days treatment 15/48 (31%) 5/49 (10%) 0.021 No overall differences in safety or effectiveness were observed between geriatric subjects
and younger subjects, and other reported clinical experience has not identified differences
Study 3 30 days treatment 7/49 (14%) 2/49 (4%) 0.221 in responses between the elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
CONTRAINDICATIONS
ADVERSE REACTIONS
Solaraze® (diclofenac sodium) Gel is contraindicated in patients with a known hypersensitivity
Of the 423 patients evaluable for safety in adequate and well-controlled trials, 211 were
to diclofenac, benzyl alcohol, polyethylene glycol monomethyl ether 350 and/or hyaluronate
treated with Solaraze® drug product and 212 were treated with a vehicle gel. Eighty-seven
sodium.
percent (87%) of the Solaraze®-treated patients (183 patients) and 84% of the vehicle-treated
WARNINGS patients (178 patients) experienced one or more adverse events (AEs) during the studies. The
As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure majority of these reactions were mild to moderate in severity and resolved upon discontinu-
to diclofenac. Diclofenac sodium should be given with caution to patients with the aspirin ation of therapy.
triad. The triad typically occurs in asthmatic patients who experience rhinitis with or without
Of the 211 patients treated with Solaraze®, 172 (82%) experienced AEs involving skin and the
nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or
application site compared to 160 (75%) vehicle-treated patients. Application site reactions
other NSAIDs.
(ASRs) were the most frequent AEs in both Solaraze® and vehicle-treated groups. Of note, four
PRECAUTIONS reactions, contact dermatitis, rash, dry skin and exfoliation (scaling) were significantly more
General prevalent in the Solaraze® group than in the vehicle-treated patients.
Solaraze® (diclofenac sodium) Gel should be used with caution in patients with active gastro-
Eighteen percent of Solaraze®-treated patients and 4% of vehicle-treated patients discontinued
intestinal ulceration or bleeding and severe renal or hepatic impairments. Solaraze® should not
from the clinical trials due to adverse events (whether considered related to treatment or
be applied to open skin wounds, infections, or exfoliative dermatitis. It should not be allowed
not). These discontinuations were mainly due to skin irritation or related cutaneous adverse
to come in contact with the eyes.
reactions.
The safety of the concomitant use of sunscreens, cosmetics or other topical medications and
OVERDOSAGE
Solaraze® is unknown.
Due to the low systemic absorption of topically-applied Solaraze® Gel, overdosage is unlikely.
Information for Patients There have been no reports of ingestion of Solaraze®. In the event of oral ingestion, result-
In clinical studies, localized dermal side effects such as contact dermatitis, exfoliation, dry ing in significant systemic side effects, it is recommended that the stomach be emptied by
skin and rash were found in patients treated with Solaraze® at a higher incidence than in those vomiting or lavage. Forced diuresis may theoretically be beneficial because the drug is
with placebo. excreted in the urine.
If severe dermal reactions occur, treatment with Solaraze® may be interrupted until the DOSAGE AND ADMINISTRATION
condition subsides. Exposure to sunlight and the use of sunlamps should be avoided. 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
Safety and efficacy of the use of Solaraze® together with other dermal products, including
Solaraze® Gel is applied to adequately cover each lesion. Normally 0.5 g of gel is used on each
cosmetics, sunscreens, and other topical medications on the area being treated, have not
5 cm x 5 cm lesion site. The recommended duration of therapy is from 60 days to 90 days.
been studied.
Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30
Drug Interactions days following cessation of therapy. Lesions that do not respond to therapy should be carefully
Although the systemic absorption of Solaraze® is low, concomitant oral administration of other re-evaluated and management reconsidered.
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 98NSGD050308
negative in the transformation assay utilizing BALB/3T3 mouse embryo cells.