IngredientsAzelaic acid (AZA) is classified as a dicarboxylic acid composed of 9 carbon atoms, 16 hydrogen atoms, and 4 oxygen atoms, with the molecular formula C9H16O4 (HOOC(CH2)7COOH). Its IUPAC name is nonanedioic acid, and it exists as a white crystalline solid with a melting point of 106.5 °C. It belongs to a class of chemicals called dicarboxylic acids. As a saturated dicarboxylic acid, it is soluble in alcohol and very slightly soluble in water, with a molecular weight of 188.22 g/mol.
In humans, azelaic acid is synthesized by omega-oxidation from fatty acids and occurs as a physiological component in human urine. It is found in small amounts in healthy individuals and in excess in the urine of patients with ketosis and those with congenital or acquired inability to β-oxidize monocarboxylic acids — a condition described as dicarboxylic acidosis. AZA is metabolized by β-oxidation, ending in the formation of malonyl-CoA or acetyl-CoA. Azelaic acid is also a dietary constituent found in whole grain cereals and animal products, and can be formed endogenously from longer-chain dicarboxylic acids, metabolism of oleic acid, and ψ-oxidation of monocarboxylic acids.
Azelaic acid occurs naturally in grains such as wheat, rye, and barley. It is also produced naturally by Malassezia furfur (also known as Pityrosporum ovale), a yeast that lives on normal skin. In plants, azelaic acid functions as an endogenous signaling molecule that plays a central role in systemic defense responses after infection.
Industrially, azelaic acid is synthesized via ozonolysis of oleic acid, yielding both azelaic acid and pelargonic acid (nonanoic acid). Diverse topical formulations of AZA exist in commerce, and it is mainly produced via chemical synthesis. Commercially available topical formulations with cosmetic and drug status contain 5% to 20% AZA in the form of gels and creams. Azelaic acid is available as a 20% cream, a 15% foam, and a 15% gel, typically administered twice daily.
Azelaic acid has no formal history of use within classical herbal or traditional medicine systems such as Ayurveda or Traditional Chinese Medicine in the way that botanical extracts do. Its recognition as a bioactive compound is relatively recent and emerged from scientific observation rather than ethnobotanical tradition. The discovery of AZA in dermatology dates back to the 1970s, when significant depigmentation was found in the lesions of pityriasis versicolor by a dermatologist in Rome.
These properties were initially discovered by Drs. Marcella Nazzaro-Porro and Siro Passi of the S. Gallicano Dermatological Institute, Rome, and applied clinically with benefit to some cutaneous hyperpigmentary disorders. Their interest arose from studies on pityriasis versicolor, when they observed that the fungus Pityrosporum, the etiological agent of the disease, is capable — in culture — of oxidizing oleic acid to azelaic acid, and that azelaic acid is a competitive inhibitor of tyrosinase. Because of this inhibitory effect on tyrosinase, the key enzyme for melanogenesis, it seemed possible that azelaic acid could be involved in the hypochromia of pityriasis versicolor, and after studies on metabolism and toxicology, a cream was prepared to see if it could act as a depigmenting agent.
It soon became evident that the cream had no depigmenting or other deleterious effects on normal skin. The hypochromia in pityriasis versicolor, therefore, was not found to be caused by azelaic acid alone. Nonetheless, the compound's potent anti-tyrosinase activity redirected research toward its use in pathological hyperpigmentation such as melasma and lentigo maligna. Subsequent collaborative laboratory and clinical studies in Rome, Turin, and London, and later at other centres, established that azelaic acid is an inhibitor of tyrosinase, mitochondrial enzymes of the respiratory chain, and of DNA synthesis, and that it has an anti-proliferative and cytotoxic effect on a variety of tumoural cells in culture, with normal cells being practically unaffected.
Azelaic acid has become increasingly relevant in modern dermatology due to its multifaceted therapeutic applications, including acne vulgaris, rosacea, melasma, and other inflammatory or pigmentary skin disorders. Its broad spectrum of clinical efficacy and favorable safety profile have led to its incorporation into numerous treatment algorithms and guidelines.
AZA is a non-phenolic, saturated dicarboxylic acid with nine carbon atoms, naturally produced by the yeast Malassezia. It has diverse physiological activities, including antibacterial, anti-keratinizing, antimelanogenic, antioxidant, and anti-inflammatory effects. The exact mechanism of action of azelaic acid is not fully understood. However, several distinct molecular mechanisms have been identified in laboratory studies.
AZA competitively inhibits thioredoxin reductase, resulting in reduced ribonucleotide reductase activity, which in turn leads to decreased DNA synthesis and repair, as well as reduced mitochondrial DNA replication in multiple microorganisms, thereby exhibiting antibacterial properties. Azelaic acid has a dose-dependent antimicrobial effect on S. epidermidis and P. acnes.
Azelaic acid works by killing acne bacteria that infect skin pores and also decreases the production of keratin, which is a natural substance that promotes the growth of acneic bacteria. Azelaic acid can inhibit DNA synthesis of keratinocytes and is comedolytic.
AZA acts as a competitive inhibitor of tyrosinase and competes with L-tyrosine for the α-carboxylate binding site on the enzyme's active site. AZA selectively targets hyperactive and malignant melanocytes without affecting normal cells. This may be related to the increased permeability of the membrane of abnormal melanocytes to AZA. In vitro studies have shown that AZA can penetrate the cell membrane, disrupt mitochondrial respiration, induce rough endoplasmic reticulum expansion, and inhibit DNA synthesis, thereby suppressing the proliferation and differentiation of melanocytes. Due to its chemical structure, AZA is capable of inhibiting tyrosinase and, to a much greater extent, thioredoxin.
AZA inhibits cytokines biosynthesis through interference with the NF-κB axis. Key molecular targets include peroxisome proliferator-activated receptor gamma (PPARγ), reactive oxygen species (ROS), and NF-κB itself. AZA also inhibits NADPH oxidase in neutrophils, kallikrein 5 (KLK5), and the cathelicidin antimicrobial peptide gene (CAMPG), thereby reducing the generation of reactive oxygen species. AZA is used for the treatment of rosacea due to its anti-inflammatory and antioxidant properties, by inhibiting the production of reactive oxygen species and lowering cathelicidin levels through kallikrein-5 inhibition.
In addition, AZA is an inhibitor of many other oxidoreductive enzymes, including enzymes involved in DNA synthesis such as DNA polymerase and mitochondrial respiratory chain oxidoreductases. It is a scavenger of harmful free radicals, and inhibits generation of reactive oxygen species by neutrophils, and has broad-spectrum bactericidal activity towards a range of microorganisms.
AZA has been extensively evaluated in randomized controlled trials for the treatment of acne vulgaris due to its antibacterial, anti-inflammatory, and anti-keratinizing properties. AZA is an effective anti-acne medication with good therapeutic effects on both non-inflammatory and inflammatory acne, especially the latter, commonly used in concentrations of 15% and 20%. It is now recommended by most physicians as a second-line treatment option.
Randomized controlled trial (RCT) vs. placebo: A double-blinded, randomized clinical trial assessed the effectiveness of topical azelaic acid gel in treating mild-to-moderate acne vulgaris in 60 participants randomly divided into two groups: one receiving 20% azelaic acid gel and the other receiving a placebo gel. Azelaic acid gel was significantly more effective than placebo in reducing total lesion count (TLC) and improving acne severity. Specifically, AZA gel reduced the mean TLC by 60.6% compared to a 19.9% reduction with the placebo (P = 0.002). The Acne Severity Index (ASI) was decreased by 65.2% with AZA gel compared to a 21.3% reduction with placebo (P = 0.001).
Comparative RCT vs. adapalene: A parallel-group study comparing AZA 15% gel to adapalene 0.1% gel in female adult acne patients over a 9-month period found comparable efficacy in lesion reduction, with significantly lower irritation scores in the AZA group.
Comparative RCT vs. tretinoin: A double-blind clinical trial comparing 20% AZA cream with 0.05% tretinoin cream and a placebo vehicle reported that AZA reduced both inflammatory and non-inflammatory lesion counts with fewer local side effects compared to tretinoin.
Summary of evidence strength: Across indications, 15–20% AZA formulations produced clinically meaningful improvements with mild, transient local irritation. For acne vulgaris, reductions in inflammatory and noninflammatory lesions were comparable to those of topical retinoids/adapalene, and tolerability was superior in some studies. In topical pharmaceutical preparations and scientific research, AZA is typically used at concentrations of 15%–20%, but some studies show that in certain vehicle formulations, the pharmaceutical effects of 10% AZA can be fully comparable to those of 20% creams. Azelaic acid is effective for mild to moderate acne when applied topically at 15%–20%.
A randomized, double-blind, placebo-controlled trial enrolled 72 patients with mild to moderate acne. Patients in the AZA group applied 15% AZA gel twice daily for 12 weeks, and those in the placebo group applied AZA-free gel. At 8 and 12 weeks, patients in the AZA group showed significantly reduced post-acne hyperpigmentation index (PAHPI) for post-inflammatory erythema (PIE) lesions compared to baseline and patients receiving placebo (P < 0.05). Hemoglobin content decreased significantly in AZA-treated PIE lesions compared to those treated with placebo at week 12 (P < 0.05).
A single-blinded randomized clinical trial assessed the efficacy of twice-daily administration of 20% AZA cream versus 5% tranexamic acid (TA) solution for the treatment of post-inflammatory hyperpigmentation (PIH) in patients with acne vulgaris over 12 weeks. The rate of healing was assessed by scoring photographs based on the post-acne hyperpigmentation index (PAHI) at baseline, 4th, 8th, and 12th weeks. PAHI score in both AZA and TA groups improved significantly during the study course (Ptime < 0.001 for both groups), and topical administration of 20% AZA was found efficient in the treatment of PIH.
AZA is widely used in dermatology and is FDA-approved for treating papulopustular rosacea (PPR). Azelaic acid is used as a topical gel treatment for rosacea, due to its ability to reduce inflammation, and it clears the bumps and swelling caused by rosacea.
Large multicenter RCT: In the largest study conducted by Draelos et al., 961 patients with the papulopustular variety of rosacea used a foam with 15% AZA twice a day for 12 weeks. Compared to placebo, the foam with 15% AZA was significantly more effective (32.0% vs. 23.5%; p < 0.001).
Comparative study vs. metronidazole: A study compared the efficacy of topical AZA 20% cream and topical metronidazole 0.75% cream in 40 patients with rosacea. After 15 weeks of treatment, both treatment groups showed equal reductions in the number of inflammatory lesions (pustules and papules) and equal reductions of signs and symptoms of dryness, burning, telangiectasia, and itching. A trace amount of stinging on application was reported with AZA; however, patients' overall impression of AZA was superior to that of metronidazole.
Regulatory status: In the US, the FDA has approved 15% gel for rosacea and 20% cream for acne.
Azelaic acid is used to treat skin pigmentation, including melasma and post-inflammatory hyperpigmentation, particularly in patients with darker skin types. It has been recommended as an alternative to hydroquinone. Hydroquinone (HQ) is the gold standard for melasma treatment; however, its repeated use can lead to permanent discoloration and ochronosis. Therefore, safer alternative topical treatments for melasma are needed. AZA is considered an effective and safer alternative to HQ, commonly used at concentrations of 15–25%.
Large RCT vs. hydroquinone: A study included 329 participants with epidermal or mixed epidermo-dermal type of melasma who were not pregnant or breastfeeding. Participants were randomly assigned to two groups: one using 20% AZA cream and the other using 4% hydroquinone cream, applied twice daily along with broad-spectrum sunscreen, for 24 months.
Randomized, double-masked, multicenter study (darker skin types): A randomized, double-masked, multicenter study evaluated AZA 20% cream in darker-skinned individuals (Fitzpatrick phototypes IV to VI) with facial hyperpigmentation. Over a 24-week period, AZA significantly reduced pigmentary intensity compared to vehicle, as measured by both the investigator's subjective scale (p = 0.021) and objective chromometer analysis (p = 0.039). Global improvement scores were also significantly higher with AZA (p = 0.008). Patients reported smoother skin, greater satisfaction, and improved perceptions of efficacy compared to past treatments.
Systematic review and meta-analysis vs. hydroquinone: A systematic review and meta-analysis assessed the efficacy and safety of azelaic acid versus hydroquinone in treating melasma patients across six included studies. The analysis revealed that azelaic acid outperformed hydroquinone in terms of improving Melasma Area and Severity Index (MASI) scores. However, there was no discernible difference between the two treatment groups in objective response scale and pigmentation decrease, despite a trend toward more favorable responses in the azelaic acid group. The two interventions were comparable regarding adverse events reported.
Combination therapy: A study by Dayal et al. found a greater reduction in MASI when using a combination of 20% AZA and glycolic acid, rather than AZA alone.
Regulatory status for melasma: While melasma treatment is off-label in Europe, it is widely used based on supporting evidence.
Promising results have been observed in lentigo melanoma as AZA selectively inhibited hyperactive or malignant melanocytes. In a study of 23 patients with malignant melanoma, including some with metastasis and patients in terminal condition, topical and oral (10–15 g daily) administration of AZA for 1–12 weeks prior to surgical excision of the lesions resulted in arrest and subsequent regression of the progressive edges of the lesions. A reduction in the size and flattening of the nodular areas, as well as a gradual lightening of pigmentation, was also observed. A study by Nazzaro-Porro et al. showed that topical AZA led to complete clinical and histological resolution of lentigo maligna in more than 50 patients. The therapeutic results were reported as durable, with 27 of the 50 patients being disease-free for 5–10 years after treatment. There was a relapse in 11 cases, but in all cases it resolved after resumption of treatment.
These data are preliminary and derive from older, non-randomized clinical series. They are of significant scientific interest but cannot be considered definitive evidence for clinical use in oncology without confirmation from rigorous controlled trials.
In a clinical trial involving 45 patients with follicular keratosis, they used 20% AZA cream on one arm, cheek or leg for 3 months and Cetaphil cream on the same areas on the opposite side of the body. 92% of the skin treated with AZA showed improvement. Evidence in this indication is limited to small studies and requires replication.
The efficacy of AZA has been confirmed in clinical studies on male pattern baldness. In a study conducted by Gugle et al., 46 patients with male pattern baldness were divided into two groups: 23 patients were treated with a topical 5% minoxidil lotion, while the others were treated with a lotion containing 5% minoxidil, 1.5% AZA, and 0.01% tretinoin. There was statistically significant hair growth and thickening in both groups, while no significant statistical differences were observed between the groups. This evidence suggests AZA may support minoxidil-based regimens without adding additional benefit over minoxidil alone; the study size was small and findings are preliminary.
AZA is FDA-approved for treating PPR, and research supports its use in melasma and as a second-line treatment for acne vulgaris. However, its application in conditions like psoriasis, alopecia areata, and folliculitis is less explored, indicating a need for further studies.
In topical pharmaceutical preparations and scientific research, AZA is typically used at concentrations of 15%–20%, but some studies show that in certain vehicle formulations, the pharmaceutical effects of 10% AZA can be fully comparable to those of 20% creams.
Pharmacokinetics of topical forms: Approximately 4% of the topically applied azelaic acid is systemically absorbed. Azelaic acid is mainly excreted unchanged in the urine but undergoes some β-oxidation to shorter chain dicarboxylic acids. The observed half-lives in healthy subjects are approximately 45 minutes after oral dosing and 12 hours after topical dosing, indicating percutaneous absorption rate-limited kinetics. After the application of a single dose of topical AZA cream, approximately 3–5% of the drug is retained in the stratum corneum. However, when using a gel formulation, the percutaneous absorption rate can increase to 8%.
AZA is classified as pregnancy category B for topical use and is suitable for individuals aged 12 and above. Local application of 15% or 20% AZA is well tolerated in humans, with the main adverse effects being mild and transient sensations of stinging, burning, or itching. There are no significant systemic adverse reactions or photosensitivity reported. In clinical trials with Azelex cream, adverse reactions were generally mild and transient in nature. The most common adverse reactions occurring in approximately 1–5% of patients were pruritus, burning, stinging, and tingling.
Skin irritation — including pruritus, burning, or stinging — may occur during use of azelaic acid gel, usually during the first few weeks of treatment. If sensitivity or severe irritation develops and persists, treatment should be discontinued and appropriate therapy instituted.
Azelaic acid may cause loss of skin pigmentation. Clinicians are advised to monitor for early signs of hypopigmentation, particularly in patients with dark complexions. This side effect arises from AZA's anti-tyrosinase mechanism, which selectively affects hyperactive melanocytes but can occasionally affect normal pigmentation at higher concentrations or with prolonged use.
This medicine may cause allergic reactions, including angioedema, which can be life-threatening and require immediate medical attention. Signs include itching skin, trouble breathing, or large hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs. Uncommon reactions (0.1% to 1%) include application site dermatitis, discomfort, edema, and paresthesia. Rare reactions (0.01% to 0.1%) include application site eczema, ulcer, and vesicle formation.
Systemic side effects are exceedingly rare due to minimal percutaneous absorption. No systemic toxicity has been reported with topical AZA use, and it is considered safe during pregnancy, supporting its favorable safety profile in reproductive-age women.
As an alternative to hydroquinone (FDA category C), azelaic acid is preferred in pregnancy with US FDA category B. Topical use of this tyrosinase inhibitor leads to 3 to 8 percent systemic absorption. An animal study revealed no harmful effect on fetuses and newborns even when administered in high dosages during pregnancy. Until the present, controlled studies of azelaic acid usage in humans during pregnancy are still lacking, but no adverse events have been reported in parenteral usage. Therefore, azelaic acid should only be used on small skin surfaces and preferably not in the first trimester.
Azelaic acid is minimally absorbed systemically following topical route of administration, and maternal use is not expected to result in fetal exposure to the drug. In animal reproduction studies, embryofetal toxicity was noted when azelaic acid was administered orally during the period of organogenesis at doses 162, 19, and 65 times the maximum recommended human dose (MRHD) in rats, rabbits, and monkeys, respectively. Maternal toxicity was noted at these doses but no malformations were observed in these embryofetal developmental studies.
Because only 4% of a dose is absorbed after topical application and it is a chemical that appears in foods, bloodstream, and breastmilk normally, azelaic acid is considered a low risk to the nursing infant. If azelaic acid is required by the mother, it is not a reason to discontinue breastfeeding. Direct application to the breast or nipple should be avoided, and the infant's skin should not come into direct contact with treated areas. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking.
Based on available prescribing information and published clinical data, topically applied azelaic acid has a very low interaction potential. A randomized trial comparing AZA 20% plus hydroquinone 5% versus hydroquinone alone in melasma found burning and stinging to be more frequent in the combination group (50% vs. 35%; p = 0.034), though symptoms were mostly mild and well tolerated. In the active-controlled rosacea trial, overall adverse reactions — including burning, stinging/tingling, dryness/tightness/scaling, itching, and erythema/irritation/redness — were 19.4% (24/124) for azelaic acid gel compared to 7.1% (9/127) for the active comparator gel at 15 weeks. No clinically significant systemic drug interactions have been identified in published literature for topical formulations.
AZA has demonstrated therapeutic potential in various dermatological conditions due to its multifaceted mechanisms of action, which remain not entirely understood. This incomplete understanding represents a significant limitation, as elucidating the molecular and cellular pathways involved may not only optimize its current clinical applications but also facilitate the identification of novel therapeutic indications. Many clinical trials are of moderate size; large-scale, long-term, placebo-controlled studies for some indications such as follicular keratosis, alopecia, and lentigo maligna remain sparse or methodologically dated.
Health conditions that Azelaic acid may help support.
Azelaic acid (20% cream, 15% gel) is an FDA-indicated topical treatment for acne vulgaris with antibacterial, anti-inflammatory, and keratolytic mechanisms. A 2023 systematic review of 43 RCTs confirmed its efficacy in reducing both inflammatory and non-inflammatory lesions. Efficacy is comparable to topical retinoids with superior tolerability.
Azelaic acid, a dicarboxylic acid, has been specifically evaluated and patented in topical gel formulations for removing corns and calluses. It acts as a keratolytic by inducing keratinocyte differentiation and solubilizing the intercellular matrix of hyperkeratotic lesions. In vitro keratinocyte assays confirm its keratolytic action on corn tissue.
Azelaic acid is a naturally occurring dicarboxylic acid with tyrosinase-inhibiting and anti-melanogenic properties relevant to periorbital hyperpigmentation. It is included in a PMC systematic review (PMC5843359) and JCAD (2018) among natural ingredients with clinical study evidence for treating hyperpigmentation. It is listed among topical depigmenting agents studied for periorbital dark circles.
Azelaic acid is a naturally occurring dicarboxylic acid (found in grains) with demonstrated 5-alpha reductase inhibitory activity. It reduces DHT production in follicles and has been used in topical formulations for androgenetic alopecia. It is also synergistic with zinc and B6 in inhibiting 5-alpha reductase in vitro.
Azelaic acid inhibits tyrosinase activity, mitochondrial oxidoreductase, and DNA synthesis in melanocytes, producing documented depigmentation in melasma and post-inflammatory hyperpigmentation (PIH). Two RCTs confirmed its efficacy against both melasma and PIH. A 15% gel formulation was evaluated in a 16-week baseline-controlled study for PIH and acne.
Azelaic acid is recognized as an additional topical treatment for KP, particularly for its anti-inflammatory, antioxidant, and mild keratolytic properties. One clinical study reported 92% of KP participants showed significant improvement in hyperkeratosis erythema after three months. Medscape and a 2020 systematic review list azelaic acid among effective topical treatments for KP appearance.
FDA-approved at 15% prescription strength for inflammatory rosacea papules and pustules. Multiple clinical studies and a review of 20 trials confirm it reduces redness, bumps, and skin clarity better than vehicle. Works by directly inhibiting kallikrein-5 and cathelicidin (LL-37) inflammatory pathways central to rosacea pathogenesis.
Body systems that Azelaic acid may help support.
Go back