Azelaic acid

Azelaic acid is a naturally occurring substance derived from cereal grains. It was first investigated in Europe in the 1970s for the treatment of pigmented lesions such as melasma and tinea versicolor. One researcher noted that patients treated with azelaic acid cream for benign hyperpigmented disorders also had significant improvement of acne lesions within the treated areas.[1] Further study confirmed the serendipitous observation and, as a result, a 20 percent cream formulation of azelaic acid (Azelex) has recently been marketed. It is labeled for use in the treatment of mild to moderate inflammatory acne vulgaris.

Mechanism of Action

Acne is a chronic inflammatory disorder of the hair follicle and associated structures. The development of acne is related to increased production of sebum and abnormal cell turnover in the hair follicle, most frequently as a result of increased production of testosterone during adolescence. This combination plugs the follicle, causing a closed comedo (blackhead). Bacterial growth, usually Propionibacterium acnes, produces enzymes that break down the sebum. The products of this breakdown stimulate an inflammatory reaction involving the follicle and surrounding structures, resulting in an open comedo (whitehead).[2]

The mechanism by which azelaic acid exerts its therapeutic effect is not known. Chemically, azelaic acid is not related to other acne treatments such as tretinoin (Retin-A) or benzoyl peroxide, or to antibiotics such as tetracycline or erythromycin. Unlike isotretinoin (Accutane), azelaic acid does not decrease the production of sebum or reduce the size of sebaceous glands. Also, it does not affect levels of testosterone.

Azelaic acid shares some of the properties of other effective acne therapies. Like antibiotics and benzoyl peroxide, azelaic acid is bacteriostatic against several anaerobic and aerobic microorganisms, including P. acnes and Staphylococcus epidermidis. It also is a cytostatic agent similar to tretinoin, in that it decreases the thickness of the stratum corneum and decreases production of keratin. An anti-inflammatory effect of azelaic acid may also play a role in acne therapy. Azelaic acid is an oxygen free radical scavenger, which may provide the anti-inflammatory effect.

Evaluation of Azelaic Acid Using the STEP Approach

A useful way to evaluate the value of a new drug is STEP,[3] an acronym for safety, tolerability, effectiveness and price. Safety describes the long-term, serious adverse affects associated with the drug. Tolerability refers to the minor side effects that can be bothersome and may affect compliance. Effectiveness indicates the clinical usefulness of azelaic acid compared with other treatment choices, and price ifs the cost to the patient for continuous therapy.

We will review the attributes and cost of azelaic acid in comparison with other available agents.

SAFETY

Serious side effects resulting from the topical use of azelaic acid have not been demonstrated. After topical administration, only 4 percent of the drug is absorbed into the system. Since no clinical trials have been performed in pregnant women, azelaic acid falls within U.S. Food and Drug Administration pregnancy category B. If used in nursing mothers, azelaic acid would not be expected to affect the infant. Use of azelaic acid in children under 12 years of age has not been studied.

Azelaic acid has been used to treat hyperpigmenting conditions, and isolated reports of hypopigmented spots have also been reported. Patients with dark complexions should be monitored for early signs of hypopigmentation.

TOLERABILITY

The most frequent side effect of azelaic acid is mild transient erythema and cutaneous irritation, characterized by scaling (2 to 5 percent of patients), pruritus (5 to 10 percent) and a mild burning sensation (5 to 9 percent).[4,5] These symptoms are less likely to occur with azelaic acid than with either 0.05 percent tretinoin cream[5] or with 5 percent benzoyl peroxide gel.[6] These symptoms are transient and usually subside after two to four weeks of treatment. Unlike benzoyl peroxide, azelaic acid does not bleach clothes or hair.

A useful indicator of tolerability is the overall dropout rate of patients in clinical studies. The dropout rate of patients with acne is not known. In studies of the use of azelaic acid in the treatment of melasma, the dropout rate attributed to adverse effects ranges from 2.4 to 3.7 percent.[7]

EFFECTIVENESS

Trials to determine the effectiveness of azelaic acid in the treatment of acne are limited, and most have been performed in Europe. Azelaic acid has been compared with 0.05 percent tretinoin cream,[5] 5 percent benzoyl peroxide gel,[6] 2 percent erythromycin cream and 0.5 to 1.0 g daily of oral tetracycline[8,9] in the treatment of comedonal and mild to moderate inflammatory acne of the face. In both types of acne, azelaic acid produced response rates similar to those achieved with the other agents. After six months of treatment, approximately 65 to 85 percent of patients had at least a 50 percent decrease in the number of lesions. benzoyl peroxide produced a more rapid initial effect than azelaic acid, although the therapeutic effect was similar after three to four months. The time necessary to reduce the number of lesions was similar for azelaic acid, tretinoin, erythromycin and oral tetracycline. One study found that oral tetracycline was more effective than azelaic acid in the treatment of acne of the chest and back.[9]

A study of azelaic acid used in combination with minocycline (Minocin) is currently under way, but the results of this study have not been published. Azelaic acid has not been studied in combination with other acne agents.

PRICE

A 30-g tube of 20 percent azelaic acid (approximately a one-month supply when applied to the face twice daily) will cost the patient about $30. The comparative prices of various acne therapies are listed in Table 1.

(*)--Estimated cost to the pharmacist based on average wholesale prices (rounded to the nearest half-dollar) in Red book. Montvale, N.J.: Medical Economics Data, 1996. Cost to the patient will be greater, depending on prescription filling fee.

([dagger]) -- No generic available.

Use-of Azelaic Acid

Azelaic acid should be applied twice daily to freshly washed skin. A one-inch ribbon of cream should be used to treat the entire face. A thin film should be gently rubbed into the skin until the cream vanishes. Overzealous rubbing will increase the development of erythema and pain. Following application, the hands should be washed.

As with all acne products, patient counseling should focus on appropriate use of and expectations for the product. Azelaic acid does not eradicate existing lesions but does prevent the development of new lesions. As a result, patients should be aware that about a four-week period of continuous therapy is necessary before demonstrable results are seen. More frequent application of the cream will not hasten the response. Also, side effects such as burning and redness are not necessary for the cream to be effective, and patients should be told that the dictum of "no pain, no gain" does not apply to this acne preparation.

REFERENCES

[1.] Nazzaro-Porro M, Passi S, Picardo M, Breathnach A, Clayton R, Zina G. Beneficial effect of 15% azelaic acid cream on acne vulgaris. Br J Dermatol 1983;109:45-8.

[2.] Seaton TL. Acne. In: Young LL, Koda-Kimble MA, eds. Applied therapeutics: the clinical use of drugs. 6th ed. Vancouver, Wash: Applied Therapeutics, 1995.

[3.] Preskorn SH. Advances in antidepressant therapy: the pharmacologic basis. San Antonio: Dannemiller Memorial Educational Foundation, 1994.

[4.] Cunliffe WJ, Holland KT. Clinical and laboratory studies on treatment with 20% azelaic acid cream for acne. Acta Derm Venereol 1989;143(Suppl):31-4.

[5.] Katsambas A, Graupe K, Stratigos J. Clinical studies of 20% azelaic acid cream in the treatment of acne vulgaris. Comparison with vehicle and topical tretinoin. Acta Derrn Venereol 1989;143(Suppl):35-9.

[6.] Cavicchini S, Caputo R. Long-term treatment of acne with 20% azelaic acid cream. Acta Derm Venereol 1989;143(Suppl):40-4.

[7.] Graupe K, Cunliffe WJ, Gollnick HP, Zaumseil RP. Efficacy and safety of topical azelaic acid (20 percent cream): an overview of results from European clinical trials and experimental reports. Cutis 1996;57(Suppl 1S):20-35.

[8.] Hjorth N, Graupe K. Azelaic acid for the treatment of acne. A clinical comparison with oral tetracycline. Acta Derm Venereol 1989;143(Suppl):45-8.

[9.] Bladon PT, Burke BM, Cunliffe WJ, Forster RA, Holland KT, King K. Topical azelaic acid and the treatment of acne: a clinical and laboratory comparison with oral tetracycline. Br J Dermatol 1986;114:493-9.

PAULA S. MACKRIDES, D.O. is a faculty member at the Harrisburg Family Practice Residency Program, Harrisburg, Pa., and a clinical assistant professor in the Department of Family Medicine at Allegheny University of the Health Sciences, Philadelphia. Dr. Mackrides is a graduate of the Philadelphia College of Osteopathic Medicine and completed a residency in family practice and a fellowship in primary care sports medicine at Harrisburg Hospital.

ALLEN F. SHAUGHNESSY, PHARM.D. is the director of research of the Harrisburg Family Practice Residency Program and a clinical associate professor in the Department of Family Medicine at Allegheny University of the Health Sciences. Dr. Shaughnessy is a graduate of Temple University School of Pharmacy, Philadelphia, and received a doctorate from the Medical University of South Carolina College of Medicine, Charleston.

Address correspondence to Allen F. Shaughnessy, Pharm.D., Harrisburg Family Practice Residency Program, PO. Box 8700, 205 5. Front St., Harrisburg, PA 17105-8700.

COPYRIGHT 1996 American Academy of Family Physicians
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