Topical 3% Diclofenac in 2.5% Hyaluronic Acid Gel

Topical 3% diclofenac in 2.5% hyaluronic acid (HA) gel (diclofenac HA gel; Solaraze™¹) is an NSAID approved for the treatment of actinic keratoses (AK).

The efficacy of diclofenac HA gel (0.5g applied twice daily to each 5cm × 5cm treatment area) in patients with AK has been evaluated in three randomized, double-blind, HA gel vehicle-controlled trials. In each trial, efficacy was assessed 30 days after the end of treatment because an earlier study revealed that resolution of lesions was greater when measured after a 4 week interval, rather than at the end of treatment.

In two fully published multicenter trials, there was no difference in baseline characteristics of the study groups. In a further single center study (not yet published), patients randomized to diclofenac HA gel had a significantly higher mean number of target lesions at baseline compared with HA gel vehicle.

In the two published studies, the efficacy of diclofenac HA gel increased with increased treatment duration. When compared with HA gel vehicle recipients, significant improvements in total lesion number scores (TLNS), cumulative lesion number scores (CLNS), patient global improvement indices (PGII) and investigator global improvement indices (IGII) were obtained in patients treated for 60 and 90 but not 30 days with diclofenac HA gel. Fifty percent of patients treated for 90 days with diclofenac HA gel (vs 20% in HA gel vehicle recipients) and 33% of those treated for 60 days (vs 10%) had TLNS and CLNS of zero at the end of follow-up.

In the third trial, in which treatment was applied for 90 days, there was no statistically significant difference in the proportion of patients with TLNS or CLNS of zero at the end of follow-up. However, when controlling for the significant difference in mean baseline target lesion scores by calculating the mean change from baseline in lesion counts, TLNS and CLNS were significantly lower in recipients of diclofenac HA gel than HA gel vehicle at the end of follow-up.

Pruritus was the most frequently reported adverse event in all trials and the incidence was generally similar or lower in patients treated with diclofenac HA gel than HA gel vehicle.

In conclusion, diclofenac HA gel produces significant reductions in the number of AK lesions, and can produce complete clearance of lesions when applied twice daily for 60 or 90 days. The product is well tolerated and did not produce serious adverse cosmetic effects in clinical trials. Thus, diclofenac HA gel represents a useful addition to the array of pharmacologic treatments available for AK.

Diclofenac is a nonsteroidal anti-inflammatory agent that has a greater affinity for the inducible form of cyclooxygenase (COX-2), than the constitutive (COX-1) form of this enzyme. The drug also has a high affinity for nuclear peroxisome proliferator-activated receptor-γ, at which it appears to be a partial agonist.

Although the precise mode of action still remains to be elucidated, hyaluronic acid (HA) has the potential to enhance delivery of diclofenac to sites of inflammation and/or neoplasia. Hyaluronic acid retards the passage of diclofenac through skin resulting in depot formation in the epidermis.

Diclofenac formulated in an HA-containing gel had angiostatic properties in a mouse model of chronic granulomatous inflammation. The extent of vascular development in the granulomatous mass was significantly (p < 0.05) inhibited by 0.018% diclofenac in 2.5% HA gel compared with an aqueous cream vehicle, diclofenac in aqueous cream or HA gel vehicle alone. The preparation was also effective when applied after granuloma formation, producing significant (p < 0.05) regression in the mass of granulomatous tissue and vascular volume compared with HA alone.

Topical diclofenac, applied in an HA-containing gel, is absorbed into the epidermis. Approximately 10% of the drug contained in a 2g dose of diclofenac HA gel, applied four times daily for 7 days over a 100 cm² area, was absorbed systemically in both normal and compromised epidermis in patients with mainly atopic dermatitis or other dermatitic conditions. Similarly, after application of topical diclofenac HA gel (2g three times daily for 6 days) to the calf of healthy volunteers, diclofenac was detected in plasma. Mean maximum plasma concentration (C_max), area under the plasma concentration-time curve (AUC), and time to C_max were 4 μg/L, 9 μg • h/L, and 4.5 hours. In comparison, a single oral dose of diclofenac 75mg produced an AUC of 1600 μg • h/L, confirming that the systemic bioavailability of the drug is considerably higher after oral administration than after topical application of diclofenac HA gel.

Mean serum diclofenac concentrations were ≤20 μg/L at the end of treatment in 60 patients with AK enrolled in clinical trials of diclofenac HA gel.

No data are available regarding the metabolism and elimination of topical diclofenac HA gel. Oral diclofenac is metabolized by oxidation and conjugation after which the parent drug and metabolites are excreted in urine. The terminal elimination half-life of diclofenac is 1–2 hours.

The efficacy of topical diclofenac HA gel in patients with actinic keratoses (AK) has been demonstrated in three randomized, double-blind, HA gel vehicle-controlled, phase III trials. In each trial, efficacy was assessed 30 days after the end of treatment because an earlier study revealed that resolution of lesions was greater when measured after a 4 week interval, rather than at the end of treatment. In one multicenter study, patients (n = 195) were treated for 30 or 60 days; in a second such study, 117 patients were treated for 90 days. In the third trial, 112 patients were enrolled at a single center and treated for 90 days. The dosage in these trials was 0.5g applied twice daily to each of one to three 5 x 5 cm treatment areas.

In two multicenter trials that have been published, there was no difference in baseline characteristics of the study groups. In the single center study, patients randomized to diclofenac HA gel had a significantly higher mean number of target lesions at baseline compared with recipients of HA gel vehicle.

In the two published studies, the efficacy of diclofenac HA gel increased with increased duration of treatment. When compared with HA gel vehicle recipients, significant improvements in total lesion number scores (TLNS), cumulative lesion number scores (CLNS), patient global improvement indices (PGII) and investigator global improvement indices (IGII) were obtained in patients treated for 60 and 90 days with diclofenac HA gel. Approximately 50% of patients treated for 90 days with diclofenac HA gel (vs ≈20% in HA gel vehicle recipients) and ≈33% of those treated for 60 days (vs ≈10%) had TLNS or CLNS of zero. Thirty days’ treatment with diclofenac HA gel produced no significant difference in the proportion of patients with TLNS or CLNS of zero compared with HA gel vehicle recipients (14% vs 4%).

In the third randomized, double-blind trial, in which treatment was applied for 90 days, there was no statistically significant difference in the proportion of patients with TLNS (34% in recipients of diclofenac HA gel vs 20% of HA gel vehicle recipients) or CLNS of zero (34% vs 18%) at the end of follow-up. However, when the significant difference in mean baseline target lesion scores was controlled for by calculating the mean change from baseline in lesion counts, TLNS and CLNS were significantly lower in recipients of diclofenac HA gel than HA gel vehicle at the end of follow-up.

Skin-related phenomena, mainly at the site of application, were the most common adverse events in patients with AK treated with diclofenac HA gel in phase III clinical trials. These were generally mild to moderate in severity and resolved upon discontinuation of therapy. Pruritus was the most frequently reported adverse event in all trials and the incidence was generally similar or lower in patients treated with diclofenac HA gel than with HA gel vehicle. In a pooled analysis of adverse event data from pivotal trials, contact dermatitis, rash, dry skin and exfoliation (scaling) were reported significantly more often in recipients of diclofenac HA gel than HA gel vehicle (p-values not reported).

Diclofenac HA gel is indicated for the topical treatment of AK. The gel should be applied to lesion areas twice daily, ensuring that enough gel is applied to adequately cover each lesion; normally approximately 0.5g of gel is used to cover a 5cm × 5cm area. The recommended duration of treatment is 60–90 days.

As other topical diclofenac preparations are available that have not been shown to be effective in AK and are not approved for the treatment of the condition, the specific formulation of topical diclofenac should be specified when prescribing.