A Summary of Approved Topical Treatments for Rosacea

G. Webster, MD, PhD

Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA

Rosacea’s cause is unknown, however genetic, environmental, vascular and inflammatory factors have been identified as possible triggers (see Table 1).

Symptoms

• facial erythema and/or visibly dilated blood vessels
• papules and pustules
• burning or stinging (may be triggered by topical agents)
• swelling
• ocular and phymatous changes.

Rosacea Subtypes

1. Vascular (erythematotelangiectatic)
   • prolonged flushing or permanent vasodilation and telangiectasia.¹
2. Papulopustular
   • Persistent central facial erythema; associated inflammatory lesions (papules and pustules)
3. Phymatous
   • sebaceous hyperplasia with fibrosis. The nose is the predominant affected area.
4. Ocular (Underrecognized)
   • affects nearly 60% of rosacea patients.²
   • sensation of dry eye or irritation or photophobia
   • interpalpebral conjunctival hyperemia.³

Quality of Life

More than 14 million people in the United States are affected, and 60% are adults under the age of 50.

• Nearly 70% of patients report low self-esteem; 41% avoid public contact due to their condition.
• 70% of severely affected patients report that it adversely affects their professional relationships.
• 30% report that they would miss work because of their condition.⁴

Treatment

There is presently no cure, so management and treatment focus on symptom reduction. The National Rosacea Society stresses the importance of early diagnosis and treatment.5 Subtypes 1 and 2 (as seen in Figures 1 and 2, which are online at www.skintherapyletter.com) are often treated with topical agents, whereas subtypes 3 and 4 require more intensive therapies like systemic antibiotics and sometimes surgery. Laser or light may be needed for reduction of the vascular component.

Avoid Trigger Factors

• Patients diagnosed with subtypes 1 and 2 are most susceptible to these factors.
• Avoidance alone will not cure the condition, but it may help to alleviate rosacea flare-ups.
• While not all trigger factors apply to every patient, most are affected at least by some of them.

Metronidazole

Metronidazole is the only topical agent validated by multiple well-controlled trials.^6-15

• It is a broad spectrum imidazole agent that exhibits antimicrobial and anti-inflammatory effects.
• It may interfere with neutrophil release of reactive oxygen species.¹⁴
• It is available in a 0.75% cream (MetroCream™), 0.75% lotion (MetroLotion™), 1% cream (Noritate®) and 1% gel (MetroGel™), which replaced the no longer available 0.75% gel.
• Metronidazole is widely recognized as the gold standard for treating rosacea.¹⁶
• Usage
  • 0.75% formulations are twice-daily regimens.
  • 1% formulations are once-daily, which may lead to better patient compliance.

Adverse effects
Mild-to-moderate adverse effects, such as stinging, burning, drying, and itching.¹⁷ A cumulative irritation study demonstrated that metronidazole gel 1% is milder than metronidazole gel 0.75% and azelaic acid gel 15%.¹⁸

A comparative trial with metronidazole gel 1% used once daily and azelaic acid gel 15% used twice daily showed equal efficacy in inflammatory lesions, global severity, and erythema. Patients reported that they were less bothered by side-effects with metronidazole gel 1% than with azelaic acid 15%.¹⁹

Azelaic Acid

It is a naturally occurring dicarboxylic acid with antioxidant and anti-inflammatory effects.²⁰

• It is available in a twice-daily, 15% gel (Finacea®).
• Inflammatory lesion counts were reduced 51%-58% and improvement in erythema was 44%-46% in two 12-week studies with a combined total of 664 patients.²⁰

Adverse Effects
Local skin irritations, such as facial burning, stinging and pruritus have been reported.²¹

Sodium Sulfacetamide 10% and Sulfur 5%

This formulation is available as a cream (Suphera™ and Rosac®), lotion (Sulfacet-R® and Klaron®), gel (Rosula®), suspension (Plexion®), cleanser (Rosanil®); Used as monotherapy or in combination therapy with other agents, like metronidazole. The typical treatment regimen is twice-daily.^2,22,23

Adverse Effects
Allergic reactions appear to be related to the sulfa drug and include swollen eyes, facial dryness, pruritus, hives, and increased erythema. Most adverse events are mild.

Role of Cleansers and Moisturizers

Skin maintenance is an important part of controlling rosacea. General skin care involves the use of:

• Therapeutic non-soap cleansers to minimize the potential irritation, while improving hydration.²⁴
• Moisturizers, which hydrate the stratum corneum and restore its ability to retain moisture.²⁵
• Broad spectrum sunscreens are important to avoiding triggering long-term photodamage.²⁶

Conclusion

Today, diagnosing and treating rosacea remains a challenge. More studies are necessary to provide additional insight on drugs currently available as well as possible future agents. The ultimate goal is to provide each patient with a treatment regimen best suited for his or her individual needs.

Editor’s Comment:

As recently noted by Landow, the etiology of rosacea remains an enigma and, as such, the disorder poses a frustrating challenge for both patients and health care providers alike.¹ Aside from cosmetic distress, untreated disease can lead to permanent disfigurement in the form of soft tissue hypertrophy, vision-disturbing ocular symptoms and even severe mental aberrations such as major depression.² Thus, timely diagnosis and prompt administration of therapy is imperative. Triggering factors, as listed in this synopsis, are quite idiosyncratic. Several, one or none of the many “triggers” listed may apply to any given patient. The relevance of any potential trigger factor may be elucidated by a detailed history; conversely, it may be discovered only by trial and error, as factors are sequentially eliminated.

Topical therapy requires daily application of one or more agents to the entire face. For some patients, this may be difficult to integrate into a hectic or erratic schedule. For others, topical therapy may result in transient or persistent adverse events (such as stinging and burning). However, the wide spectrum of therapeutic options available, including the many different types of formulations, almost always insures that some available medication will be tolerable. Moreover, for other patients, topical therapy is preferable to any systemic medication. Mild-to-moderate vascular and papulopustular rosacea is most amenable to topical therapy.³

The Editor believes that topical therapy should always be entertained and at least offered to most patients. Recent development of phototherapeutic systems which may eliminate residual erythema represent an exciting forefront in rosacea management.⁴

We will discuss systemic therapies, including new advancements, in a future issue of Skin Therapy Letter – Family Practice Edition.

References

1. Lonne-Rahm SB, Fischer T, Berg M. Stinging and rosacea. Acta Derm Venereol. 79(6):460-1 (1999).
2. Bikowski JB. The pharmacologic therapy of rosacea: a paradigm shift in progress. Cutis. 75(3 Suppl):27-32 (2005).
3. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 46(4):584-7 (2002).
4. http://www.rosacea.org. Accessed on May 16, 2006, National Rosacea Society.
5. http://www.rosacea.org/press/archive/20050421.html. Accessed on May 23, 2006, National Rosacea Society.
6. Draelos ZD. The rationale for advancing the formulation of azelaic acid vehicles. Cutis. 77(2 Suppl):7-11 (2006).
7. Thiboutot D, Thieroff-Ekerdt R, Graupe K. Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea: results from two vehicle-controlled, randomized phase III studies. J Am Acad Dermatol 48(6):836-45 (2003).
8. Elewski BE, Fleischer AB, Jr., Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol 139(11):1444-50 (2003).
9. Aronson IK, Rumsfield JA, West DP, et al. Evaluation of topical metronidazole gel in acne rosacea. Drug Intell Clin Pharm. 21(4):346-51 (1987).
10. Bleicher PA, Charles JH, Sober AJ. Topical metronidazole therapy for rosacea. Arch Dermatol. 123(5):609-14 (1987).
11. Espagne E, Guillaume JC, Archimbaud A, et al. Double-blind study versus excipient of 0.75% metronidazole gel in the treatment of rosacea. Ann Dermatol Venereol. 120(2):129-33 (1993).
12. Breneman D, Bucko A, Friedman D, et al. Evaluation of topical metronidazole lotion in rosacea. Presented at: the American Academy of Dermatology 55th Annual Meeting; Orlando, Florida: February 27-March 4, 1998. Abstract P289.
13. Drake L, Leyden J, Lucky A, et al. Evaluation of topical metronidazole cream in rosacea. Presented at: the American Academy of Dermatology 55th Annual Meeting; San Francisco, California: March 21-26, 1998. Abstract P65.
14. Bitar A, Bourgouin J, Dore N, et al. A double-blind randomised study of metronidazole (Flagyl) 1% cream in the treatment of acne rosacea: a placebo-controlled study. Drug Invest 2:242-8 (1990).
15. Bjerke J, Nyfors A, Austad J, et al. Metronidazole (Elyzol) 1% cream v. placebo cream in the treatment of rosacea. Clin Trials J 26:187-94 (1989).
16. Breneman DL, Stewart D, Hevia O, et al. A double-blind, multicenter clinical trial comparing efficacy of once-daily metronidazole 1 percent cream to vehicle in patients with rosacea. Cutis. 61(1):44-7 (1998).
17. Jorizzo JL, Lebwohl M, Tobey RE. The efficacy of metronidazole 1% cream once daily compared with metronidazole 1% cream twice daily and their vehicles in rosacea: a double-blind clinical trial. J Am Acad Dermatol 39(3):502-4 (1998).
18. Nielsen PG. A double-blind study of 1% metronidazole cream versus systemic oxytetracycline therapy for rosacea. Br J Dermatol 109(1):63-5 (1983).
19. Freeman CD, Klutman NE, Lamp KC. Metronidazole. A therapeutic review and update. Drugs 54(5):679-708 (1997 Nov).
20. McClellan KJ, Noble S. Topical metronidazole. A review of its use in rosacea. Am J Clin Dermatol 1(3):191-9 (2000).
21. Data on file Galderma Laboratories, L.P. CSR C05-D176.
22. Wolf J. Efficacy and Safety of once-daily metronidazole 1% gel compared with twice-daily azelaic acid 15% gel in the treatment of rosacea. Cutis 77:3-11 (2006).
23. Mackley CL, Thiboutot DM. Diagnosing and managing the patient with rosacea. Cutis 75(4 Suppl):25-9 (2005).
24. Nally JB, Berson DS. Topical therapies for rosacea. J Drugs Dermatol 5(1):23-6 (2006).
25. Ananthapadmanabhan KP, Moore DJ, Subramanyan K, et al. Cleansing without compromise: the impact of cleansers on the skin barrier and the technology of mild cleansing. Dermatol Ther 17(Suppl 1):16-25 (2004).
26. Johnson AW. Overview: fundamental skin care–protecting the barrier. Dermatol Ther. 17(Suppl 1):1-5 (2004).
27. Baranda L, Gonzalez-Amaro R, Torres-Alvarez B, et al. Correlation between pH and irritant effect of cleansers marketed for dry skin. Int J Dermatol 41(8):494-9 (2002).

References (for Editor’s Comment)

1. Landow K. Rosacea: the battle goes on. Compr Ther. 200531:145-58
2. Gupta MA, Gupta AK, Chen SJ, Johnson AM. Comorbidity of rosacea and depression: an analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey–Outpatient Department data collected by the U.S. National Center for Health Statistics from 1995 to 2002. Br J Dermatol. 2005;153:1176-81
3. Dahl MV. Rosacea subtypes: a treatment algorithm. Cutis. 2004;74(3 Suppl):21-7, 32-4
4. Ceilley RI. Advances in the topical treatment of acne and rosacea. J Drugs Dermatol. 2004;3(5 Suppl):S12-22