SOLARAZE^® GEL
Diclofenac Sodium-3%

Solaraze^® (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. The structural formula is represented below:

Solaraze^® Gel also contains benzyl alcohol, hyaluronate sodium, polyethylene glycol monomethyl ether, and purified water.

1 g of Solaraze^® (diclofenac sodium) Gel contains 30 mg of the active substance, diclofenac sodium.

The mechanism of action of diclofenac sodium in the treatment of actinic keratoses (AK) is unknown.

The contribution to efficacy of individual components of the vehicle has not been established.

Solaraze^® (diclofenac sodium) Gel is indicated for the topical treatment of actinic keratoses (AK). Sun avoidance is indicated during therapy.

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 × 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^® ingredient, pregnancy, allergies to aspirin or other nonsteroidal anti-inflammatory 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 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.

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.

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.

Solaraze^® (diclofenac sodium) Gel should be used with caution in patients with active gastrointestinal 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.

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.

Patients should understand the importance of monitoring and follow-up evaluation, the signs and symptoms of dermal adverse reactions, and the possibility of irritant or allergic contact dermatitis. 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.

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.

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 exposureBased on body surface area and assuming 10% bioavailability following topical application of 2 g Solaraze^® Gel per day (1 mg/kg diclofenac sodium).), 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 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 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.

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 uterine contractions and delay parturition.

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.

Actinic keratoses is not a condition seen within the pediatric population. Solaraze^® should not be used by children.

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.

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 discontinuation 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.

Table 1 below presents the AEs reported at an incidence of >1% for patients treated with either Solaraze^® Gel or vehicle (60- and 90-day treatment groups) during the phase 3 studies.

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 Solaraze^® Gel):

Body as a Whole: abdominal pain or crampsIncidence greater than 1%., headache, fluid retention, abdominal distention, malaise, swelling of lips and tongue, photosensitivity, anaphylaxis, anaphylactoid 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.

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, resulting 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. The effect of dialysis or hemoperfusion in the elimination of diclofenac (99% protein-bound) remains unproven. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of diclofenac. Supportive and symptomatic treatment should be given for complications such as renal failure, convulsions, gastrointestinal irritation and respiratory depression.

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 × 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.

Available in tubes of 50 g (NDC 10337-803-05) and 100 g (NDC 10337-803-01). Each gram of gel contains 30 mg of diclofenac sodium.

Store at controlled room temperature 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F). Protect from heat. Avoid freezing.