Topical Ivermectin 10 mg/g and Oral Doxycycline 40 mg Modified-Release: Current Evidence on the Complementary Use of Anti-Inflammatory Rosacea Treatments

Abstract

Rosacea is a common, chronic inflammatory skin disease that can present with a variety of signs and symptoms. The potentially simultaneous occurrence of different signs and symptoms is due to different underlying inflammatory pathways, emphasizing the need for complementary treatment approaches. Topical ivermectin cream (10 mg/g) and systemic, oral anti-inflammatory doxycycline (40 mg modified-release) are both approved for the treatment of papulopustular rosacea (PPR). Whether or not a combined therapeutic approach may be more beneficial than monotherapy for patients with PPR remains to be tested. Here, we summarize underlying inflammatory pathways implicated in rosacea and clarify the impact of these two agents on selective pathways during inflammation, due to specific characteristics of their individual mechanisms of action (MoA). Based on the complementary MoA of doxycycline modified-release and ivermectin, a scientific rationale for a combined therapy targeting inflammatory lesions in rosacea is given. We propose that topical ivermectin cream is a promising new candidate as first-line treatment to target the inflammatory lesions of rosacea, which can be used in combination with systemic doxycycline modified-release to provide an optimal treatment approach considering all inflammatory pathways involved in PPR.Funding Galderma.

Erythematotelangiectatic rosacea may be associated with a subclinical stage of demodicosis: a case–control study

“…In our experience, such treatment can lead to improvement and even disappearance of erythema and subjective complaints, such as burning sensation, so that sometimes no supplementary treatment (such as laser) is necessary. Several topical treatments have been used to kill the mites, including sulfur or selenium (di)sulfide, salicylic acid, ammoniated mercury, permethrin, lindane, crotamiton, benzyl benzoate, tea tree oil and, more recently, ivermectin . In our practice, we have successfully used a 20% benzyl benzoate cream (with 10% crotamiton) for more than 20 years; however, the development of ivermectin has provided an effective alternative with good tolerance and this is now our treatment of choice.…”

“…Several topical treatments have been used to kill the mites, including sulfur or selenium (di)sulfide, 8,62,63 salicylic acid, 8 ammoniated mercury, 8 permethrin, 10,64,65 lindane, 9,10,65,66 crotamiton, 20,67-70 benzyl benzoate, 12,13,66,69 tea tree oil 71,72 and, more recently, ivermectin. [73][74][75][76] In our practice, we have successfully used a 20% benzyl benzoate cream (with 10% crotamiton) for more than 20 years; 69 however, the development of ivermectin has provided an effective alternative with good tolerance 75,76 and this is now our treatment of choice. Clearly, the effectiveness of treating subclinical demodicosis with an acaricide needs to be confirmed in prospective clinical trials.…”

Real‐life experience on effectiveness and tolerability of topical ivermectin in papulopustular rosacea and antiparasitic effect on Demodex mites

“…Moreover, we assume that ivermectin is useful to achieve an effective result (IGA ≤ 1) in the IGA 3‐4 patient group, but it should be associated with other treatments in order to reach IGA = 0, as recommended in guidelines (Anzengruber et al, ; Asai et al, ; Reinholz et al, ). In fact, clinical evidence and guidelines support that an intensified initial treatment with two agents would be more effective in patients with severe disease than others (Steinhoff et al, ). Furthermore, achieving IGA = 0 would be desirable in every stage of rosacea as the final goal, since it means a greater reduction in inflammatory lesions, an improved subject self‐assessment and a better quality of life (Webster et al, ).…”

“…Papulopustular rosacea (PPR) is defined as multiple small dome‐shaped erythematous papules and pustules on the background of erythema in a centrofacial distribution (Wilkin et al, ). Topical ivermectin cream is a drug characterized by both anti‐inflammatory and antiparasitic effects, especially on Demodex mites (Moran, Foley, & Powell, ; Schaller et al, ; Stein Gold, Kircik, Fowler, Jackson, et al, ; Stein Gold, Kircik, Fowler, Tan, et al, ), which gained the Food and Drug Administration (FDA) approval for the treatment of PPR in December 2014, and by European Medicines Agency (EMA) in March 2015 (Steinhoff, Vocanson, Voegel, Hacini‐Rachinel, & Schäfer, ). Up to now, ivermectin has only been tested in moderate‐to‐severe PPR, and studies concerning its use on almost clear mild forms are lacking (Sahni, Feldman, & Taylor, ).…”

Efficacy of topical ivermectin and impact on quality of life in patients with papulopustular rosacea: A systematic review and meta‐analysis

“…In addition, it has the potential to be utilized as a single or combined therapy. In addition, the doxycycline 40 mg can be a helpful partner due to the inflammatory activity at subantimicrobial dosage as suggested by Steinhoff et al (Steinhoff, Vocanson, Voegel, Hacini-Rachinel, & Schäfer, 2016): These authors propose that the different underlying inflammatory pathways in PPR can be confronted selectively with these two medications because of their each specific mechanism of action; therefore, they can act complementary to get a more effective, faster and longer-acting approach. In addition, the doxycycline 40 mg can be a helpful partner due to the inflammatory activity at subantimicrobial dosage as suggested by Steinhoff et al (Steinhoff, Vocanson, Voegel, Hacini-Rachinel, & Schäfer, 2016): These authors propose that the different underlying inflammatory pathways in PPR can be confronted selectively with these two medications because of their each specific mechanism of action; therefore, they can act complementary to get a more effective, faster and longer-acting approach.…”