Update on the Management of Rosacea: A Status Report on the Current Role and New Horizons With Topical Azelaic Acid

developed specifically to treat persistent non-transient facial erythema of rosacea through vasoconstriction of chronically enlarged and dilated superficial vasculature of the central face, which is commonly referred to as background erythema.^5,13-16

It is important that clinicians recognize that background erythema is a visible manifestation of rosacea which is both clinically and pathophysiologically distinct from papulopustular lesions and inflammatory erythema induced by pathways of inflammation that are activated during flares of rosacea.^1,5,13,15,16 Topical metronidazole, AzA 15% gel, and doxy- MR 40 mg QD are approved by the FDA for rosacea based on studies completed only in subjects with PPR; studies completed with these agents for cutaneous rosacea subsequent to FDA approval have also been performed only in patients with PPR.^3,5,13-18 The approved indication for all 3 of these agents, as stated in their current product labeling (package inserts), is for treatment of the inflammatory lesions (papules and pustules) of rosacea, with none of these agents evaluated in patients with rosacea who did not have papulopustular lesions. Topical metronidazole (all strengths and formulations), AzA 15% gel, and doxy-MR 40 mg QD are not FDA-approved specifically for facial erythema of rosacea as a “stand alone” indication. However, AzA 15% gel (n=333) demonstrated statistically significantly greater reduction in overall facial erythema scores compared with vehicle gel (n=331) in both Phase 3 pivotal trials (P=.0017 study 1; P=.0005 study 2) performed in subjects with PPR, compared with topical metronidazole formulations and doxy-MR 40 mg QD, which did not achieve statistically significant reduction in overall facial erythema in all Phase 3 studies in subjects with PPR.^19-21 It is important to recognize that overall facial erythema of rosacea in a patient with a flare PPR is distinct from background erythema, which is persistent, non-transient, and present between rosacea flares.^3-4,14,16

As a result of the statistical consistency of reduction in overall facial erythema in subjects with PPR treated with AzA 15% gel, the approved FDA indication statement is the following: “[AzA 15% gel] is indicated for topical treatment of inflammatory papules and pustules of mild to moderate rosacea. Efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated.”²² This labeling serves to distinguish facial erythema related to the augmented inflammation present in patients with active PPR from the persistent and non-transient background erythema related to fixed dilatation and enlargement of centrofacial superficial cutaneous vasculature.^{4,5,11,12,15,16,22,23} However, it is also important to recognize that AzA 15% gel markedly reduced both papulopustular lesions and overall facial erythema in pivotal Phase 3 studies, both of which are clinical signs associated with augmented inflammation present in rosacea patients with centrofacial erythema and papulopustular lesions.¹⁹

This supplement reviews the treatment of rosacea with emphasis on the track record of data with AzA 15% gel, which has been available in the US marketplace for over a decade. Also included are important considerations related to its formulation and optimal use, newer information on pharmacologic properties of AzA that appear to correlate with possible modes of therapeutic action in rosacea, and new horizons related to formulation development.

The formulation characteristics, efficacy, skin tolerability, and safety of AzA 15% gel have been thoroughly reviewed elsewhere. ^19,24-39 Nevertheless, a summary of data on AzA 15% gel serves to maintain a clinically relevant perspective of the therapeutic value of this agent in the management of rosacea.

Azelaic acid (1,7-heptanedicarboxylic acid) is a naturally occurring dicarboxylic acid, which exists as a white, odorless, large-particulate crystalline powder that is soluble in ethanol and not highly soluble in water.^25,40

Azelaic acid is a naturally occurring organic compound found in grains such as wheat, barley, and rye. Application of AzA 15% gel does not result in systemic accumulation of AzA, with plasma concentrations not increasing above levels reflective of usual nutritional ingestion and endogenous metabolism (formed from the metabolism of larger chain dicarboxylic acids, ie, oleic acid).^25,40,41

Azelaic acid 20% cream was the initial formulation approved by the FDA in 1995 for the topical treatment of inflammatory acne vulgaris.⁴² The decision to reformulate AzA in the 15% gel was due to improvements in the cutaneous delivery of AzA.²⁵

The vehicle gel formulation improved the pharmacologic characteristics of AzA through micronization of the AzA crystals to create a uniformly small particle size; incorporation into an aqueous-based gel (70% water) using polyacrylic acid and lecithin to form the gel matrix as dispersers and thickening agents; and using polysorbate 80 as an emulsifier and stabilizer of the aqueous formulation.^25,40,41