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 Solaraze® is applied topically, diclofenac is absorbed into the epidermis. In a study in patients with com-promised 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 cm²) of diclofenac was absorbed systemically in both nor-mal and compromised epidermis after seven days, with four times daily applications.

After topical application of 2 g Solaraze® 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 AUC_0-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 (Voltaren™) produced an AUC of 1600 ng.hr/mL. Therefore, the systemic bioavailability after topical application of Solaraze® is lower than after oral dosing.

Blood drawn at the end of treatment from 60 patients with AK lesions treated with Solaraze® in three adequate and well-controlled clinical trials was assayed for diclofenac levels. Each patient was administered 0.5 g of Solaraze® 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 Solaraze® is much lower than that occurring after oral daily dosing of diclofenac sodium.

No information is available on the absorption of diclofenac when Solaraze® 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 (mean±SD). The terminal plasma half-life is 1-2 hours. Four of the metabolites also have short terminal half-lives of 1-3 hours.

CLINICAL STUDIES

Clinical trials were conducted involving a total of 427 patients (213 treated with Solaraze® and 214 with a gel vehi-cle). 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 prob-lems outside of the AK lesions and had undergone a 60-day washout period from disallowed medications (maso-procol, 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-inflamma-tory 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 per-mitted. Patients were instructed to apply a small amount of Solaraze® Gel (approximately 0.5 g) onto the affect-ed 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 pri-mary efficacy variable. No long-term patient follow-ups, after the 30-day assessments, were performed for the detection of recurrence.

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