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usually resolve within 1 to 2 weeks and can be lessened with appropriate use of a gentle cleanser and a moisturizer. The mechanism of action appears to be decreased expression of KLK5 and cat- helicidin. 7,25 Effectiveness appears to be the same whether azelaic acid is adminis- tered once or twice daily. 23 In 2 of 3 stud- ies comparing metronidazole and azelaic acid, investigators were more satisfied with azelaic acid treatment outcomes. 27,28 The use of azelaic acid produced a great- er percentage of patients who achieved excellent improvement or complete remission of their condition. 27,28 Sodium Sulfacetamide Topical sodium sulfacetamide is a sec- ond-line agent that is most useful in patients who have rosacea in combina- tion with seborrheic dermatitis. It is thought to work as an anti-inflammatory. Common administration is twice-daily application of 10% sodium sulfacetamide and 5% sulfur. Several formulations are available, including lotions, creams, and cleansers. Studies have shown the prod- uct to be effective for PPR by decreasing erythema and inflammatory lesions. It is also effective in combination with topical metronidazole. Common transient AEs include dry or irritated skin, redness, and product odor from some older formula- tions. Use should be avoided in patients with a sulfa allergy. 18,23,29 Brimonidine Topical brimonidine gel 0.33%, an alpha- 2 adrenergic agonist, is the only FDA- approved agent for treatment of persis- tent erythema. 7,30 It has been shown to effectively reduce persistent erythema by vasoconstriction of blood vessels in the dermis. Brimonidine has no significant effect on inflammatory lesions or telan- giectasias, although blood vessels may become more visible when erythema is reduced. In trials, the effect of once-daily application of brimonidine tartrate gel 0.5% on erythema was fairly rapid, with an onset as quick as 30 minutes and a duration of effect up to 12 hours. 18,31,32 Mild, transient skin irritation was the primary AE noted. Approximately 10% of patients experienced temporary wors- ening of redness, which resolved without additional therapy. No tachyphylaxis or rebound effect, which is commonly seen in nasal administration of alpha agonists, was evident in trials; however, a return of the redness occurred when the drug effect wore off. 32 Subsequent case reports of rebound or exaggerated recurrence of erythema have emerged. 33,34 Recent panel recommendations on the use of brimonidine reinforce the use of appropriate lifestyle and skin care measures in addition to the following suggestions. 30 Initial application of bri- monidine should be a pea-sized drop spread thin, possibly starting on a test site; the amount applied can be gradu- ally increased to achieve the maximum benefit. In order to prevent additional disruption of the cutaneous barrier, avoid initiation of brimonidine at the same time as beginning a topical retinoid. 35 Make patients aware that 10% to 20% of patients may have worsening facial redness in the first 2 weeks of therapy, which usually resolves within 12 to 24 hours of discontinuing drug use. Facial redness and burning may be treated with aspirin or a nonsteroidal anti-inflamma- tory drug, cool compresses, a topical steroid, or a calcineurin inhibitor. 30 Brimonidine can be used in combi- nation with anti-inflammatory topical agents to treat patients with PPR who exhibit both persistent erythema and pap- ules/pustules. 35 Other alpha-adrenergic agonists have shown effectiveness in trials for treating persistent erythema. Oxymetazoline, an alpha-1 agonist/alpha- 2 partial agonist, is in phase 3 trials. 18,35 When discussing use of brimo- nidine for facial redness with patients who are starting this topical agent, what counseling information is most important to discuss to ensure optimum effectiveness with the least risk of AEs? Ivermectin Ivermectin 1% cream was recently approved for once-daily application to treat inflammatory lesions of rosacea. The mechanism of action is unknown 6 ; however, ability to decrease coloniza- tion of D folliculorum may play a role in its effectiveness. In clinical trials, sub- jects treated with 1% ivermectin reported good or excellent improvement of rosa- cea and an improved quality of life. 36 The primary AEs reported are mild stinging and burning of the skin. 6 Topical Products Used Off-Label A number of topical products, including retinoids, calcineurin inhibitors, mac- rolides, benzoyl peroxide, and perme- thrin, are used off-label for rosacea treat- ment. Before they can be considered for approval to treat rosacea, all of these agents require additional study; they should not be recommended for routine use in rosacea at this time. Due to its ability to downregulate TLR2 expression and reverse the effects of UV radiation, topical tretinoin, a reti- noid, has been proposed for use in rosa- cea. It has been used alone or in combi- nation with approved topical agents to treat symptoms of PPR. 18 Topical calcineurin inhibitors pimecro- limus and tacrolimus have been tested in both ETR and PPR with mixed results. These anti-inflammatory agents inhibit T-cell activation and prevent release of inflammatory mediators from T- and mast cells. 18 Due to its ability to decrease coloniza- tion by Demodex mites, permethrin has been proposed for rosacea treatment. It has shown some effectiveness in reduc- ing redness and papules. 18 Oral Therapy Tetracyclines Tetracyclines have been used for treat- ment of PPR as anti-inflammatory and antimicrobial agents for more than 50 years. The only oral agent FDA-approved for rosacea therapy is doxycycline 40 mg in a once-daily, delayed-release cap- sule (30 mg immediate release and 10 mg delayed release). Doxycycline has been shown to improve PPR symptoms through anti-inflammatory actions at this subantimicrobial dose. The mechanism appears to be decreased expression of AMPs, thereby preventing KLK5 from being converted to its active form. Other elements of its action are to downregulate inflammatory cytokines, reduce vasodilation via inhibition of nitric oxide, and reduce levels of ROS. Anti-inflammatory doses of doxycycline can be used in combination with a topical STAR 114 PharmacyTimes.org December 2015 CONTINUING EDUCATION