|
Diclofenac Sodium
SolarazeÔ
(diclofenac sodium) Gel, 3% w/w
DESCRIPTION
SolarazeÔ(diclofenac
sodium) Gel, 3%, contains the active ingredient, diclofenac sodium, in a clear,
transparent, colorless to slightly yellow gel base. Diclofenac sodium is a white
to slightly yellow crystalline powder. It is freely soluble in methanol, soluble
in ethanol, sparingly soluble in water, slightly soluble in acetone, and partially
insoluble in ether. The chemical name for diclofenac sodium is:
Sodium [o-(2,6-dichloranilino) phenyl] acetate
Diclofenac sodium has a molecular weight of 318.13
The CAS number is CAS-15307-79-6.
SolarazeÔ
also contains benzyl alcohol, hyaluronate sodium, polyethylene glycol monomethyl
ether, and purified water.
1 g of SolarazeÔ
(diclofenac sodium) Gel contains 30 mg of the active substance, diclofenac sodium.
CLINICAL PHARMACOLOGY
The mechanism of action of diclofenac sodium in the treatment
of actinic keratosis (AK) is unknown. The contribution to efficacy of individual
components of the vehicle has not been established.
Pharmacokinetics
Absorption
When SolarazeÔ
is applied topically, diclofenac is absorbed into the epidermis. In a study
in patients with compromised skin (mainly atopic dermatitis and other dermatitic
conditions) of the hands, arms or face, approximately 10% of the applied dose
(2 grams of 3% gel over 100 cm 2) of diclofenac was absorbed systemically
in both normal and compromised epidermis after seven days, with four times daily
applications.
After topical application of 2 g SolarazeÔ
three times daily for six days to the calf of the leg in healthy subjects, diclofenac
could be detected in plasma. Mean bioavailability parameters were AUC0-t
9±19 ng.hr/mL(mean±SD)
with a Cmax of 4±5 ng/mL and a Tmax
of 4.5±8 hours. In comparison, a single oral
75 mg dose of diclofenac (Voltarenä)
produced an AUC of 1600 ng.hr/mL. Therefore, the systemic bioavailability after
topical application of SolarazeÔ is
lower than after oral dosing.
Blood drawn at the end of treatment from 60 patients with AK
lesions treated with SolarazeÔ in three
adequate and well-controlled clinical trials were assayed for diclofenac levels.
Each patient was administered 0.5g of SolarazeÔ
Gel twice a day for up to 105 days. There were up to three 5 cm X
5 cm treatment sites per patient on the face, forehead, hands, forearm, and
scalp. Serum concentrations of diclofenac were on average at, or below 20 ng/mL.
These data indicate that systemic absorption of diclofenac in patients treated
topically with SolarazeÔ is much lower
than that occurring after oral daily dosing of diclofenac sodium.
No information is available on the absorption of diclofenac
when SolarazeÔ is used under occlusion.
Distribution
Diclofenac binds tightly to serum albumin. The volume of distribution
of diclofenac following oral administration is approximately 550 mL/kg.
Metabolism
Biotransformation of diclofenac following oral administration
involves conjugation at the carboxyl group of the side chain or single or multiple
hydroxylations resulting in several phenolic metabolites, most of which are
converted to glucuronide conjugates. Two of these phenolic metabolites are biologically
active, however to a much smaller extent than diclofenac. Metabolism of diclofenac
following topical administration is thought to be similar to that after oral
administration. The small amounts of diclofenac and its metabolites appearing
in the plasma following topical administration makes the quantification of specific
metabolites imprecise.
Elimination
Diclofenac and its metabolites are excreted mainly in the urine
after oral dosing. Systemic clearance of diclofenac from plasma is 263±56
mL/min (meanSD). The terminal plasma half-life is 1-2 hours.
Four of the metabolites also have short terminal half-lives of 1-3 hours.
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 SolarazeÔ
and 214 with 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
SolarazeÔ ingredient, pregnancy,
allergies to aspirin or other nonsteriodal antiinflammatory drugs (NSAIDs),
or other dermatological conditions which might affect the absorption of the
study medication. Application of dermatologic products such as sunscreens, cosmetics,
and other drug products were 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.
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Complete Clearance of Actinic Keratosis Lesions 30 days
Post-Treatment (all locations)
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Solarazeä Gel
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Vehicle
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p-value
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Study 1 90 days treatment
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27/58 (47%)
|
11/59 (19%)
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<0.001
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Study 2 90 days treatment
|
18/53 (34%)
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10/55 (18%)
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0.061
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Study 3 60 days treatment
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15/48 (31%)
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5/49 (10%)
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0.021
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30 days treatment
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7/49 (14%)
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2/49 (4%)
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0.221
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Complete Clearance of Actinic Keratosis Lesions 30 days
Post-Treatment (by location)
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Scalp
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Forehead
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Face
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Arm/Forearm
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Back of Hand
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Study 1 90 days treatment
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|
|
|
|
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Solarazeä
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1/4 (25%)
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17/30 (57%)
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9/17 (53%)
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4/12 (33%)
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6/16 (38%)
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Vehicle
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3/9 (33%)
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8/24 (33%)
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5/17 (29%)
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4/12 (33%)
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0/14 (0)
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p-value
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0.7646
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0.0908
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0.1682
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1.000
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0.0650
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Study 2 90 days treatment
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|
|
|
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Solarazeä
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2/6 (33%)
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9/19 (47%)
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4/5 (80%)
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5/8 (63%)
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1/17 (6%)
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Vehicle
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0/4 (0)
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6/22 (27%)
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2/8 (25%)
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0/5 (0)
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3/16 (19%)
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p-value
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0.4235
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0.1870
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0.0727
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0.0888
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0.2818
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Study 3 60 days treatment
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|
|
|
|
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Solarazeä
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3/7 (43%)
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13/31 (42%)
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10/19 (53%)
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0/1 (0)
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2/8 (25%)
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Vehicle
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0/6 (0)
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5/36 (14%)
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2/13 (15%)
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0/2 (0)
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1/9 (11%)
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p-value
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0.2271
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0.0153
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0.0433
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-
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0.4637
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30 days treatment
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|
|
|
|
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Solarazeä
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2/5 (40%)
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4/29 (14%)
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3/14 (21%)
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0/0 (0)
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0/19 (0)
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Vehicle
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0/5 (0)
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2/29 (7%)
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2/18 (11%)
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0/1 (0)
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1/9 (11%)
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p-value
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0.2299
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0.3748
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0.4322
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-
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0.6521
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All data combined
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|
|
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Solarazeä
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8/22 (36%)
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43/109 (39%)
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26/55 (47%)
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9/21 (43%)
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9/50 (18%)
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Vehicle
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3/24 (13%)
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21/111 (19%)
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11/56 (20%)
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4/20 (20%)
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5/48 (10%)
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p-value
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0.0903
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0.0013
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0.0016
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0.2043
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0.3662
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DOSAGE AND ADMINISTRATION
SolarazeÔ
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 SolarazeÔ 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.
HOW SUPPLIED
Available in tubes of 25 g and 50 g. Each gram of gel contains
30 mg of diclofenac sodium.
Storage: Store at controlled room temperatures: 15°-
30°C (59°- 86°F) Protect from heat. Avoid freezing.
SIDE EFFECTS
Of the 423 patients evaluable for safety in adequate and well-controlled
trials, 211 were treated with SolarazeÔ
drug product and 212 were treated with vehicle gel. Eighty-seven percent (87%)
of the SolarazeÔ 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 discontinuation
of therapy.
Of the 211 patients treated with SolarazeÔ,
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 SolarazeÔ
and vehicle treated groups. Of note, four reactions, contact dermatitis, rash,
dry skin, and exfoliation (scaling) were significantly more prevalent in the
SolarazeÔ 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.
Table 1 below presents the AEs reported at an incidence of
>1% for patients treated with either SolarazeÔ
Gel or Vehicle (60-and 90-day treatment groups) during the phase 3 studies.
Table 1. Adverse events reported (>1% in any treatment group)
during Solaraze phase 3 clinical trials Incidences for 60-day and 90-day treatments
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60-day Treatment
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90-day Treatment
|
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Solaraze (%)
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Gel Vehicle(%)
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Solaraze (%)
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Gel Vehicle (%)
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N=48
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N=49
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N=114
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N=114
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BODY AS A WHOLE
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21
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20
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20
|
18
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Abdominal Pain
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2
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0
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1
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0
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Accidental Injury
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0
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0
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4
|
2
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Allergic Reaction
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0
|
0
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1
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3
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Asthenia
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0
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0
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2
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0
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Back Pain
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4
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0
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2
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2
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Chest Pain
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2
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0
|
1
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0
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Chills
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0
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2
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0
|
0
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Flu Syndrome
|
10
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6
|
1
|
4
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Headache
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0
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6
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7
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6
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Infection
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4
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6
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4
|
5
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Neck Pain
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0
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0
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2
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0
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Pain
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2
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0
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2
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2
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CARDIOVASCULAR SYSTEM
|
2
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4
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3
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1
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Hypertension
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2
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0
|
1
|
0
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Migraine
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0
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2
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1
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0
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Phlebitis
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0
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2
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0
|
0
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DIGESTIVE SYSTEM
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4
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0
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6
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8
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Constipation
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0
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0
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0
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2
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Diarrhea
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2
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0
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2
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3
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Dyspepsia
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2
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0
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3
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4
|
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METABOLIC AND NUTRITIONAL DISORDERS
|
2
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8
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7
|
2
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Creatine Phosphokinase Increased
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0
|
0
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4
|
1
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Creatinine Increased
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2
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2
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0
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1
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Edema
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0
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2
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0
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0
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Hypercholesteremia
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0
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2
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1
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0
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Hyperglycemia
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0
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2
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1
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0
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SGOT Increased
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0
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0
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3
|
0
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SGPT Increased
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0
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0
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2
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0
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MUSCULOSKELETAL SYSTEM
|
4
|
0
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3
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4
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Arthralgia
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2
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0
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0
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2
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Arthrosis
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2
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0
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0
|
0
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Myalgia
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2
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0
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3
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1
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NERVOUS SYSTEM
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2
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2
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2
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5
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Anxiety
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0
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2
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0
|
1
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Dizziness
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0
|
0
|
0
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4
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Hypokinesia
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2
|
0
|
0
|
0
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RESPIRATORY SYSTEM
|
8
|
8
|
7
|
6
|
Asthma
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2
|
0
|
0
|
0
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Dyspnea
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2
|
0
|
2
|
0
|
Pharyngitis
|
2
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8
|
2
|
4
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Pneumonia
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2
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0
|
0
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1
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Rhinitis
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2
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2
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2
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2
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Sinusitis
|
0
|
0
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2
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0
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SKIN AND APPENDAGES
|
75
|
86
|
86
|
71
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Acne
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0
|
2
|
0
|
1
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Application Site Reaction
|
75
|
71
|
84
|
70
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Acne
|
0
|
4
|
1
|
0
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Alopecia
|
2
|
0
|
1
|
1
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Contact Dermatitis
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19
|
4
|
33
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4
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Dry Skin
|
27
|
12
|
25
|
17
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Edema
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4
|
0
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3
|
0
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Exfoliation
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6
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4
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24
|
13
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Hyperesthesia
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0
|
0
|
3
|
1
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Pain
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15
|
22
|
26
|
30
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Paresthesia
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8
|
4
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20
|
20
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Photosensitivity Reaction
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0
|
2
|
3
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0
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Pruritus
|
31
|
59
|
52
|
45
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Rash
|
35
|
20
|
46
|
17
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Vesiculobullous Rash
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0
|
0
|
4
|
1
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Contact Dermatitis
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2
|
0
|
0
|
0
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Dry Skin
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0
|
4
|
3
|
0
|
Herpes Simplex
|
0
|
2
|
0
|
0
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Maculopapular Rash
|
0
|
2
|
0
|
0
|
Pain
|
2
|
2
|
1
|
0
|
Pruritus
|
4
|
6
|
4
|
1
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Rash
|
2
|
10
|
4
|
0
|
|
Skin Carcinoma
|
0
|
6
|
2
|
2
|
|
Skin Nodule
|
0
|
2
|
0
|
0
|
|
Skin Ulcer
|
2
|
0
|
1
|
0
|
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SPECIAL SENSES
|
2
|
0
|
4
|
2
|
|
Conjunctivitis
|
2
|
0
|
4
|
1
|
|
Eye Pain
|
0
|
2
|
2
|
0
|
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UROGENITAL SYSTEM
|
0
|
0
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4
|
5
|
|
Hematuria
|
0
|
0
|
2
|
1
|
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OTHER
|
0
|
0
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0
|
3
|
|
Procedure
|
0
|
0
|
0
|
3
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Skin and Appendages Adverse Events Reported for Solaraze at less than 1%
Incidence in the phase 3 studies: skin hypertrophy, paresthesia, seborrhea,
urticaria, application site reactions (skin carcinoma, hypertonia, skin
hypertrophy lacrimation disorder, maculopapular rash, purpuric rash, vasodilation).
Adverse Reactions Reported for Oral Diclofenac Dosage Form
(not topical Solarazeä
Gel):
*Incidence greater than 1% marked with asterisk.
Body as a Whole: abdominal pain or cramps*, headache*,
fluid retention*, abdominal distention*, malaise, swelling of lips and tongue,
photosensitivity, anaphylaxis, anaphylactiod reactions, chest pain.
Cardiovascular: hypertension, congestive heart failure,
palpitations, flushing, tachycardia, premature ventricular contractions, myocardial
infarction, hypotension.
Digestive: diarrhea*, indigestion*, nausea*, constipation*,
flatulence*, liver test abnormalities*, PUB*, i.e., peptic ulcer, with or without
bleeding and/or perforation, or bleeding without ulcer, vomiting, jaundice,
melena, esophageal lesions, aphthous stomatitis, dry mouth and mucous membranes,
bloody diarrhea, hepatitis, hepatic necrosis, cirrhosis, hepatorenal syndrome,
appetite change, pancreatitis with or without concomitant hepatitis, colitis,
intestinal perforation.
Hemic and Lymphatic: hemoglobin decrease, leukopenia,
thrombocytopenia, eosinophilia, hemolytic anemia, aplastic anemia, agranulocytosis,
purpura, allergic purpura, bruising.
Metabolic and Nutritional Disorders: azotemia, hypoglycemia,
weight loss.
Nervous System: dizziness*, insomnia, drowsiness, depression,
diplopia, anxiety, irritability, aseptic meningitis, convulsions, paresthesia,
memory disturbance, nightmares, tremor, tic, abnormal coordination, disorientation,
psychotic reaction.
Respiratory: epistaxis, asthma, laryngeal edema, dyspnea,
hyperventilation, edema of pharynx.
Skin and Appendages: rash*, pruritus*, alopecia, urticaria,
eczema, dermatitis, bullous eruption, erythema multiforme major, angioedema,
Stevens-Johnson syndrome, excess perspiration, exfoliative dermatitis.
Special Senses: tinnitus*, blurred vision, taste disorder,
reversible and irreversible hearing loss, scotoma, vitreous floaters, night
blindness, amblyopia.
Urogenital: nephrotic syndrome, proteinuria, oliguria,
interstitial nephritis, papillary necrosis, acute renal failure, urinary frequency,
nocturia, hematuria, impotence, vaginal bleeding.
DRUG INTERACTIONS
Although the systemic absorption of SolarazeÔ
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. (Note: Solaraze™ contains 3% diclofenac sodium.) When administered
orally for 2 years, diclofenac showed no evidence of carcinogenic potential
in rats given diclofenac sodium at up to 2 mg/kg/day (3 times the estimated
systemic human exposure*), or in mice given diclofenac sodium at up to 0.3 mg/kg/day
in males and 1 mg/kg/day in females (25% and 83%, respectively, of the estimated
systemic human exposure).
A photococarcinogenicity study with up to 0.035% diclofenac
in the Solarazeä 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 lymphoma 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.
* Based on body surface area and assuming 10% bioavailability
following topical application of 2 g Solarazeä gel
per day (1 mg/kg diclofenac sodium).
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 Solarazeä 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 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 uterine
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. SolarazeÔ should
not be used by children.
Geriatric Use
Of the 211 subjects treated with Solaraze™ in controlled
clinical studies, 143 subjects were 65 and over. Of those 143 subjects, 55 subjects
were 75 and over. No overall differences in safety or effectiveness were observed
between these 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.
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
SolarazeÔ
(diclofenac sodium) Gel should be used with caution in patients with active
gastrointestinal ulceration or bleeding and severe renal or hepatic impairments.
SolarazeÔ 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 SolarazeÔ
is unknown.
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