{"format":"citation-manifest/v1","page":"https://azelaicrx.com/monograph","claim_count":78,"claims":[{"id":"clm-001","text":"Azelaic acid is nonanedioic acid, a naturally occurring saturated nine-carbon dicarboxylic acid, molecular formula C9H16O4, molecular weight 188.22, CAS 123-99-9. It is a white, odorless crystalline solid, poorly soluble in water at 20 C.","source_url":"https://pubchem.ncbi.nlm.nih.gov/compound/2266","grade":"chemical-reference","grade_label":"Chemical reference"},{"id":"clm-002","text":"Azelaic acid 15% gel (originally approved as Finacea, NDA 021470) is an FDA-approved prescription drug indicated for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-003","text":"The 15% gel label limits its claim to papules and pustules: efficacy for treating erythema of rosacea in the absence of papules and pustules has not been evaluated.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-004","text":"Azelex (azelaic acid cream) 20%, NDA 020428, is an FDA-approved prescription drug indicated for the topical treatment of mild-to-moderate inflammatory acne vulgaris.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ebdfcaf7-b5d6-47e1-be87-ccaba4b97e75","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-005","text":"Finacea Foam 15%, NDA 207071, is an FDA-approved prescription foam indicated for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9fabd24e-4c3b-49a0-aa5f-c8d75ae67572","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-006","text":"Generic azelaic acid 15% gel is approved and marketed: Drugs@FDA lists multiple approved ANDAs for azelaic acid gel with Prescription marketing status (including ANDA 204637, ANDA 210549, ANDA 208724 and ANDA 208011).","source_url":"https://api.fda.gov/drug/drugsfda.json?search=products.active_ingredients.name:%22azelaic%20acid%22&limit=20","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-007","text":"Under United States law, cosmetic products and ingredients do not need FDA premarket approval, with the exception of color additives. An azelaic acid serum sold as a cosmetic has not been reviewed by FDA for safety or effectiveness before sale.","source_url":"https://www.fda.gov/cosmetics/cosmetics-laws-regulations/fda-authority-over-cosmetics-how-cosmetics-are-not-fda-approved-are-fda-regulated","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-008","text":"Azelaic acid is not an ingredient in FDA's over-the-counter acne monograph. The eCFR acne rule (21 CFR 333 subpart D) permits benzoyl peroxide 2.5 to 10 percent, salicylic acid 0.5 to 2 percent, sulfur, and sulfur-resorcinol combinations; azelaic acid does not appear anywhere in the rule. There is therefore no lawful over-the-counter DRUG route for azelaic acid in the United States.","source_url":"https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-333/subpart-D","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-009","text":"Products labeled as 10% to 14% azelaic acid acne creams appear in FDA's label database registered under over-the-counter monograph codes, even though azelaic acid is not an OTC monograph ingredient. These registrations are self-submitted listings, not FDA approvals.","source_url":"https://api.fda.gov/drug/label.json?search=openfda.generic_name:%22azelaic%20acid%22&limit=10","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-010","text":"Compounded drugs are not FDA-approved: FDA does not verify the safety, effectiveness or quality of compounded drugs before they are marketed. This applies to compounded azelaic acid formulations sold by pharmacies and telehealth services.","source_url":"https://www.fda.gov/drugs/human-drug-compounding/compounding-and-fda-questions-and-answers","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-011","text":"The 15% gel is applied as a thin layer, gently massaged into the affected areas on the face twice daily, morning and evening, after cleansing with only very mild soap or a soapless cleansing lotion and patting dry. Hands are washed after application, and cosmetics may be applied once the gel has dried. If there is no improvement after 12 weeks, the label says to reassess the diagnosis.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-012","text":"All three labels instruct patients to avoid alcoholic cleansers, tinctures and astringents, abrasives and peeling agents while using azelaic acid, and to avoid occlusive dressings or wrappings. These are the only product-interaction cautions the labels contain; none of the three labels has a drug-drug interactions section.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-013","text":"The foam is applied twice daily to the entire facial area (cheeks, chin, forehead, and nose), shaking the can well first and dispensing the smallest amount of foam necessary to cover the affected areas with a thin layer, continuously over 12 weeks.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9fabd24e-4c3b-49a0-aa5f-c8d75ae67572","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-014","text":"Azelex 20% cream is applied as a thin film, gently but thoroughly massaged into the affected areas twice daily, morning and evening, after the skin is thoroughly washed and patted dry. The label states that improvement occurs in the majority of patients with inflammatory lesions within four weeks.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ebdfcaf7-b5d6-47e1-be87-ccaba4b97e75","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-015","text":"In the foam pharmacokinetic study, the mean applied dose covering the whole face was 0.94 grams of foam, containing 141 mg of azelaic acid, applied twice daily. This is the only per-application quantity stated in any azelaic acid label.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9fabd24e-4c3b-49a0-aa5f-c8d75ae67572","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-016","text":"Pack sizes: the 15% gel is supplied in a 50 g tube, Azelex 20% cream in 30 g and 50 g tubes, and the foam in a pressurized 50 g can.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-017","text":"Storage: the gel and foam are stored at 25 C with excursions permitted between 15 and 30 C; Azelex cream is protected from freezing and stored on its side at 15 to 30 C. The foam is flammable and pressurized: avoid fire, flame and smoking during and immediately after application, do not puncture or incinerate the can, and do not store above 120 F (49 C).","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-018","text":"A fingertip unit (FTU) is the amount of product expressed from a tube with a 5 mm nozzle applied from the distal skin-crease to the tip of the index finger. In the defining study, treating the face and neck took 2.5 FTU (standard deviation 0.8), one hand 1.2 FTU, and one FTU covered a mean of 286 square centimeters of skin.","source_url":"https://europepmc.org/article/MED/1806320","grade":"human-trial","grade_label":"Human trial"},{"id":"clm-019","text":"The companion rule of hand states that 4 hand areas = 2 FTU = 1 g, which makes one adult fingertip unit approximately 0.5 grams of product.","source_url":"https://europepmc.org/article/MED/1497374","grade":"human-trial","grade_label":"Human trial"},{"id":"clm-020","text":"In the 15% gel rosacea trials (safety population 788 subjects), the most common treatment-related adverse events were burning, stinging or tingling in 29% of gel users, pruritus 11%, scaling or dry skin 8%, and erythema or irritation 4%. In the active-controlled trial, overall adverse reactions were 19.4% with the gel versus 7.1% with the comparator gel at 15 weeks.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-021","text":"In the foam pivotal trials, application site pain (a term covering burning, stinging, paraesthesia and tenderness) occurred in 6.2% of foam users versus 1.5% with vehicle; application site pruritus 2.5% versus 0.3%; dryness and erythema 0.7% each.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9fabd24e-4c3b-49a0-aa5f-c8d75ae67572","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-022","text":"With Azelex 20% cream, adverse reactions were generally mild and transient; the most common, in approximately 1 to 5% of patients, were pruritus, burning, stinging and tingling, with erythema, dryness, rash, peeling, irritation and contact dermatitis each below 1%. The label attributes initial stinging in part to the low pH of azelaic acid and notes the irritation commonly subsides with continued treatment.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ebdfcaf7-b5d6-47e1-be87-ccaba4b97e75","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-023","text":"Skin irritation with azelaic acid usually occurs during the first few weeks of treatment; the labels advise discontinuing and seeking care if sensitivity or severe irritation develops and persists.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-024","text":"Isolated cases of hypopigmentation have been reported after azelaic acid use. Because azelaic acid has not been well studied in patients with dark complexions, the labels instruct monitoring these patients for early signs of hypopigmentation and reporting abnormal color changes.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-025","text":"Azelaic acid can irritate the eyes; the labels require avoiding contact with eyes, mouth and other mucous membranes, washing with large amounts of water on contact, and seeking care if irritation persists. Iridocyclitis on accidental eye exposure has been reported post-marketing with the gel.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-026","text":"Worsening of asthma has been reported in patients using azelaic acid formulations; the gel label carries a dedicated warning to consult a physician if asthma is exacerbated. Post-marketing reports also include hypersensitivity reactions such as angioedema, eye and facial swelling, dyspnea, urticaria and wheezing.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-027","text":"Rarely reported events in azelaic acid users include vitiligo depigmentation, small depigmented spots, hypertrichosis, reddening described as signs of keratosis pilaris, and exacerbation of recurrent herpes labialis.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-028","text":"The 15% gel has no contraindications listed on its label; Azelex is contraindicated only in people with hypersensitivity to any of its components. The gel label also warns to avoid use in known hypersensitivity to any gel component.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-029","text":"In human dermal safety studies the 15% gel caused significantly more irritation than its vehicle in a cumulative irritation study, and no phototoxicity or photoallergenicity was reported.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"human-trial","grade_label":"Human trial"},{"id":"clm-030","text":"The current 15% gel label states that azelaic acid is minimally absorbed systemically after topical administration and that maternal use is not expected to result in fetal exposure to the drug. In oral animal studies, embryofetal toxicity appeared only at maternally toxic doses 162, 19 and 65 times the maximum recommended human dose in rats, rabbits and monkeys, and no malformations were observed.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-031","text":"The older-format Azelex label is more conservative: there are no adequate and well-controlled studies in pregnant women, animal reproduction studies are not always predictive of human response, and the drug should be used during pregnancy only if clearly needed. No teratogenic effects were observed in the animal studies.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ebdfcaf7-b5d6-47e1-be87-ccaba4b97e75","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-032","text":"A peer-reviewed review of acne treatment in pregnancy recommends topical azelaic acid or benzoyl peroxide as baseline therapy, while oral retinoids are teratogenic and absolutely contraindicated.","source_url":"https://europepmc.org/article/MED/26957383","grade":"review","grade_label":"Review or guideline"},{"id":"clm-033","text":"Azelaic acid is naturally present in human milk. The gel label states that when used as prescribed it is unlikely to be absorbed in clinically relevant amounts that would change milk concentration or milk production; the Azelex label reports an in vitro milk-plasma distribution coefficient of 0.7 and, since less than 4% of a topical dose is absorbed, expects no significant change from baseline milk levels, while still advising caution in nursing mothers.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-034","text":"Hydroquinone, the comparison drug for melasma, has a relatively high systemic absorption rate; a pregnancy-safety review singles out hydroquinone and tretinoin as the exceptions among topical skin products, while products that act locally produce minimal systemic levels.","source_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC3114665/","grade":"review","grade_label":"Review or guideline"},{"id":"clm-035","text":"Pediatric use: safety and effectiveness of the 15% rosacea gel have not been established in pediatric patients, and Azelex has not been established under age 12.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-036","text":"Approximately 4% of topically applied azelaic acid is systemically absorbed. After a single application of the 20% cream to human skin in vitro, roughly 3 to 5% of the dose penetrates the stratum corneum and up to 10% is found in the epidermis and dermis.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ebdfcaf7-b5d6-47e1-be87-ccaba4b97e75","grade":"human-pk","grade_label":"Human PK"},{"id":"clm-037","text":"The observed half-lives of azelaic acid in healthy subjects are approximately 45 minutes after oral dosing and about 12 hours after topical dosing, indicating percutaneous absorption rate-limited kinetics. Elimination is mainly as unchanged drug in urine.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ebdfcaf7-b5d6-47e1-be87-ccaba4b97e75","grade":"human-pk","grade_label":"Human PK"},{"id":"clm-038","text":"Azelaic acid is a normal part of human physiology and diet: it is a dietary constituent found in whole grain cereals and animal products, can be formed endogenously, and normal plasma concentrations run 20 to 80 ng/mL with daily urinary excretion of 4 to 28 mg, highly dependent on diet.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ebdfcaf7-b5d6-47e1-be87-ccaba4b97e75","grade":"human-pk","grade_label":"Human PK"},{"id":"clm-039","text":"Twice-daily 15% gel does not raise plasma azelaic acid beyond the normal dietary and endogenous range: on-treatment levels of 42 to 63.1 ng/mL sit inside the 24.0 to 90.5 ng/mL range observed in vehicle-treated rosacea subjects.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"human-pk","grade_label":"Human PK"},{"id":"clm-040","text":"Foam pharmacokinetics in 21 rosacea patients: steady state by day 5 of twice-daily whole-face dosing; day 7 maximum plasma azelaic acid ranged 22.2 to 90.1 ng/mL with mean 51.8 +/- 18.5 ng/mL, values overlapping the endogenous range.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9fabd24e-4c3b-49a0-aa5f-c8d75ae67572","grade":"human-pk","grade_label":"Human PK"},{"id":"clm-041","text":"After a single topical application of 20% cream in nine adults, azelaic acid concentrations measured in follicular casts reached levels comparable to the concentrations that inhibit Propionibacterium acnes and Staphylococcus epidermidis growth in vitro, supporting follicular delivery of antimicrobial concentrations despite low systemic absorption.","source_url":"https://europepmc.org/article/MED/8217752","grade":"human-pk","grade_label":"Human PK"},{"id":"clm-050","text":"The FDA labels are candid that the mechanism is not established: the rosacea gel label says the mechanisms by which azelaic acid interferes with the pathogenic events in rosacea are unknown, and the Azelex label says the exact mechanism of action is not known and that its in vitro data are of unknown clinical significance.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"regulatory","grade_label":"Regulatory record"},{"id":"clm-051","text":"Azelaic acid has in vitro antimicrobial activity against Propionibacterium acnes (Cutibacterium acnes) and Staphylococcus epidermidis, possibly through inhibition of microbial cellular protein synthesis.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ebdfcaf7-b5d6-47e1-be87-ccaba4b97e75","grade":"in-vitro","grade_label":"In vitro"},{"id":"clm-052","text":"A proposed antibacterial mechanism is disruption of bacterial intracellular pH: 30 mM azelaic acid dissipated the transmembrane proton gradient of P. acnes and S. epidermidis in vitro, with rapid loss of viability at pH 4 and little effect at pH 6, tying activity to the acidic skin-surface environment.","source_url":"https://europepmc.org/article/MED/7829407","grade":"in-vitro","grade_label":"In vitro"},{"id":"clm-053","text":"Azelaic acid normalizes keratinization: biopsies from Azelex-treated patients showed reduced stratum corneum thickness, fewer and smaller keratohyalin granules, and reduced filaggrin, consistent with an anticomedonal effect that reduces microcomedo formation.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ebdfcaf7-b5d6-47e1-be87-ccaba4b97e75","grade":"human-trial","grade_label":"Human trial"},{"id":"clm-054","text":"The tyrosinase story begins with pityriasis versicolor: dicarboxylic acids isolated from Pityrosporum (Malassezia) cultures were shown in 1978 to act as competitive inhibitors of tyrosinase in vitro, which is the origin of azelaic acid's use in hyperpigmentation and of its known anti-tyrosinase activity.","source_url":"https://europepmc.org/article/MED/99481","grade":"in-vitro","grade_label":"In vitro"},{"id":"clm-055","text":"Azelaic acid suppresses inflammatory signaling in human keratinocytes in vitro at concentrations achievable after topical 15% gel: 20 mM azelaic acid suppressed UVB-induced interleukin-1beta, interleukin-6 and TNF-alpha, reduced NF-kB p65 nuclear translocation, and acted through PPARgamma activation.","source_url":"https://europepmc.org/article/MED/20545756","grade":"in-vitro","grade_label":"In vitro"},{"id":"clm-056","text":"Azelaic acid is a potent inhibitor of 5 alpha-reductase in human skin IN VITRO, detectable at 0.2 mmol/l and complete at 3 mmol/l. The authors themselves conditioned any clinical use on in vivo confirmation, and no clinical trial has confirmed a DHT-mediated benefit.","source_url":"https://europepmc.org/article/MED/3207614","grade":"in-vitro","grade_label":"In vitro"},{"id":"clm-057","text":"Azelaic acid is naturally produced by the yeast Malassezia, and modern reviews summarize its pharmacology as antibacterial, anti-keratinizing, antimelanogenic, antioxidant and anti-inflammatory.","source_url":"https://europepmc.org/article/MED/39464747","grade":"review","grade_label":"Review or guideline"},{"id":"clm-060","text":"Two identical multicenter, randomized, double-blind, vehicle-controlled 12-week phase III trials in 664 subjects established the 15% gel for papulopustular rosacea: mean inflammatory lesion reductions of 57.9% versus 39.9% (study one) and 50.0% versus 38.2% (study two), and investigator global success (clear, minimal or mild) in 61% versus 40% and 61% versus 48%.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=66178511-5c1a-4ecd-bc98-2ceb54e710ac","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-061","text":"In the published report of the two pivotal gel trials, patients on azelaic acid also had higher rates of erythema improvement than vehicle (44% versus 29% and 46% versus 28%), and no serious treatment-related adverse events were reported.","source_url":"https://europepmc.org/article/MED/12789172","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-062","text":"Head-to-head against metronidazole 0.75% gel in 251 patients over 15 weeks, 15% azelaic acid gel was superior: 72.7% versus 55.8% mean reduction in inflammatory lesions, erythema improved in 56% versus 42%, and metronidazole's effect appeared to plateau after week 8 while azelaic acid kept improving through week 15.","source_url":"https://europepmc.org/article/MED/14623704","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-063","text":"In a 40-patient double-blind split-face trial, azelaic acid 20% cream and metronidazole 0.75% cream produced equal reductions in inflammatory lesions over 15 weeks, with a significantly higher physician rating of global improvement for azelaic acid and a trace of stinging on application.","source_url":"https://europepmc.org/article/MED/10365928","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-064","text":"The foam was approved on two vehicle-controlled 12-week trials in 1362 subjects: IGA success 32.1% versus 23.4% (trial 1) and 43.4% versus 32.5% (trial 2), with mean inflammatory lesion count changes of -13.2 versus -10.3 and -13.3 versus -9.5.","source_url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9fabd24e-4c3b-49a0-aa5f-c8d75ae67572","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-065","text":"The 2015 Cochrane review of rosacea interventions (106 studies, 13,631 participants) rated the evidence that azelaic acid beats placebo in papulopustular rosacea as HIGH quality, with participant-assessed improvement RR 1.46 (95% CI 1.30 to 1.63); metronidazole's evidence was rated moderate quality.","source_url":"https://europepmc.org/article/MED/25919144","grade":"meta-analysis","grade_label":"Meta-analysis"},{"id":"clm-066","text":"The 2019 GRADE-assessed update (152 studies, 20,944 participants) concluded there is high-certainty evidence for topical azelaic acid (and topical ivermectin) for reducing papules and pustules in rosacea, with moderate-certainty evidence for topical metronidazole.","source_url":"https://europepmc.org/article/MED/30585305","grade":"systematic-review","grade_label":"Systematic review"},{"id":"clm-067","text":"A 2025 network meta-analysis of 19 randomized trials (8208 participants) in moderate-to-severe papulopustular rosacea ranked azelaic acid 20% highest for IGA improvement (OR 8.54, 95% CI 2.48 to 29.45; P-score 0.97), and also found azelaic acid 15% was the only topical with a statistically significant adverse event signal (OR 1.95, 95% CI 1.30 to 2.93). It works, and it stings, and both facts are in the same dataset.","source_url":"https://europepmc.org/article/MED/40213532","grade":"meta-analysis","grade_label":"Meta-analysis"},{"id":"clm-070","text":"In the 20% cream's controlled acne studies, azelaic acid beat vehicle in 92 patients with moderate inflammatory acne over 3 months, and equaled tretinoin 0.05% cream in 289 patients with comedonal acne over 6 months while causing fewer local side effects.","source_url":"https://europepmc.org/article/MED/2528257","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-071","text":"Mechanistic acne trial data: versus placebo, 20% azelaic acid cream reduced inflamed lesions after 1 month and non-inflamed lesions after 2 months, cut skin-surface free fatty acids from 15.9 to 10.5%, and reduced follicular Micrococcaceae 2,500-fold and Propionibacterium species 44-fold, without changing sebum excretion rate.","source_url":"https://europepmc.org/article/MED/2528256","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-072","text":"Against oral tetracycline in a 6-month double-blind study of 45 men, both treatments helped; tetracycline was more effective, but the differences were only just significant.","source_url":"https://europepmc.org/article/MED/2938615","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-073","text":"The 15% gel matched the two standard topicals in two randomized blinded trials: median inflamed-lesion reductions of 70% versus benzoyl peroxide 5% (n=351) and 71% versus clindamycin 1% (n=229) over 4 months of twice-daily use, with local irritation distinctly less than benzoyl peroxide but more than clindamycin.","source_url":"https://europepmc.org/article/MED/16281587","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-074","text":"In a 60-patient double-blind vehicle-controlled trial, azelaic acid gel reduced total acne lesion count by 60.6% versus 19.9% for vehicle and acne severity index by 65.2% versus 21.3% over 45 days.","source_url":"https://europepmc.org/article/MED/17456913","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-075","text":"For adult female acne, azelaic acid 15% gel was non-inferior to adapalene 0.1% gel over 9 months in a 55-woman randomized investigator-blind trial, with significantly less dryness and scaling, and continued use through the maintenance phase controlled lesions better than stopping at 3 months.","source_url":"https://europepmc.org/article/MED/25399481","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-076","text":"A 1996 overview of the European clinical program concluded 20% azelaic acid cream is an effective monotherapy in mild to moderate acne with overall efficacy comparable to tretinoin 0.05%, benzoyl peroxide 5% and topical erythromycin 2%, is non-teratogenic, and does not induce resistance in Propionibacterium acnes.","source_url":"https://europepmc.org/article/MED/8654128","grade":"review","grade_label":"Review or guideline"},{"id":"clm-080","text":"The largest melasma head-to-head: in a 24-week double-blind study of 329 women, 20% azelaic acid cream (with sunscreen) produced good or excellent results in 65%, with NO significant differences versus 4% hydroquinone on overall rating, reduction in lesion size, or pigmentary intensity, and no allergic sensitization or exogenous ochronosis on azelaic acid.","source_url":"https://europepmc.org/article/MED/1816137","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-081","text":"Against the weaker 2% hydroquinone concentration, 20% azelaic acid was clearly superior: 73% versus 19% good-to-excellent results over 24 weeks in 155 patients of Indo-Malay-Hispanic origin.","source_url":"https://europepmc.org/article/MED/2528260","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-082","text":"A small 2-month open trial (29 women) found 20% azelaic acid reduced MASI more than hydroquinone 4% at month 2 (3.8 versus 6.2 from similar baselines); its own authors flagged the open design and small size and called for larger studies.","source_url":"https://europepmc.org/article/MED/22151936","grade":"human-trial","grade_label":"Human trial"},{"id":"clm-083","text":"For post-inflammatory hyperpigmentation, the direct evidence is a 16-week open-label baseline-controlled pilot: azelaic acid 15% gel twice daily reduced both acne and PIH in patients with darker skin types. There is no randomized vehicle-controlled PIH trial of azelaic acid.","source_url":"https://europepmc.org/article/MED/21637899","grade":"human-trial","grade_label":"Human trial"},{"id":"clm-084","text":"Azelaic acid is not the top-ranked melasma therapy in modern evidence syntheses: a 2021 network meta-analysis of 59 randomized trials ranked it mid-field (behind laser therapies, triple combination cream, oral tranexamic acid and others), and a 2019 systematic review gave its strong clinical recommendations to cysteamine, triple combination therapy and tranexamic acid rather than azelaic acid.","source_url":"https://europepmc.org/article/MED/34660626","grade":"meta-analysis","grade_label":"Meta-analysis"},{"id":"clm-085","text":"A 2023 systematic review of 43 randomized trials found azelaic acid more effective than vehicle for rosacea, acne and melasma, more effective than metronidazole 0.75% on erythema and inflammatory lesions, often equivalent to comparators elsewhere, and found NO eligible trials for skin aging.","source_url":"https://europepmc.org/article/MED/37550898","grade":"systematic-review","grade_label":"Systematic review"},{"id":"clm-090","text":"Alopecia areata (an autoimmune patchy hair loss, distinct from pattern hair loss): one 31-person pilot randomized 20% azelaic acid against 0.5% anthralin for 12 weeks; complete regrowth response was similar (53.3% versus 56.2%, not significant). There was no vehicle arm, so the trial cannot show either drug beat doing nothing.","source_url":"https://europepmc.org/article/MED/16343028","grade":"human-rct","grade_label":"Human RCT"},{"id":"clm-091","text":"For androgenetic (pattern) hair loss, no randomized trial of azelaic acid alone exists: a PubMed search for azelaic acid trials in androgenetic alopecia or hair loss returns only reviews, a case report, an alopecia areata pilot and a minoxidil combination product study. The popular DHT-blocker claim rests on the 1988 in vitro enzyme result.","source_url":"https://pubmed.ncbi.nlm.nih.gov/?term=azelaic+acid+AND+%28androgenetic+alopecia+OR+hair+loss%29+AND+%28randomized+OR+trial%29","grade":"review","grade_label":"Review or guideline"},{"id":"clm-092","text":"For Malassezia (pityrosporum) folliculitis, the condition skincare marketing calls fungal acne, there are no clinical trials of azelaic acid: our PubMed searches for azelaic acid with Malassezia or pityriasis versicolor return in vitro work, reviews and unrelated case reports, not treatment trials. The connection is real but preclinical: azelaic acid was discovered in Malassezia cultures and the yeast produces it.","source_url":"https://pubmed.ncbi.nlm.nih.gov/?term=azelaic+acid+AND+Malassezia","grade":"review","grade_label":"Review or guideline"},{"id":"clm-093","text":"The only randomized, vehicle-controlled human data at the 10% cosmetic strength is an 8-week split-face study of 23 completers testing a COMBINATION product (0.1% retinal plus 10% azelaic acid) for blemish-prone skin. It measured cosmetic endpoints (texture, surface irregularities, redness, pores) by imaging, not acne, rosacea or melasma outcomes, and its own authors note no prior clinical study of the combination existed. The azelaic acid contribution cannot be isolated.","source_url":"https://europepmc.org/article/MED/42572367","grade":"human-trial","grade_label":"Human trial"},{"id":"clm-094","text":"We could not locate any published randomized controlled trial of a 10% azelaic acid cosmetic serum used alone for rosacea, acne or melasma. The PubMed search for 10% azelaic acid trials returns a 20% peel-solution comparison and the 10% combination cosmetic study; every azelaic acid monotherapy trial in this monograph used 15% or 20%.","source_url":"https://pubmed.ncbi.nlm.nih.gov/?term=%22azelaic+acid+10%25%22+AND+%28randomized+OR+trial%29","grade":"review","grade_label":"Review or guideline"},{"id":"clm-100","text":"This site's study-results table contains 29 rows, of which 24 are human evidence and 5 are laboratory (in vitro) mechanism studies, each labeled in its species column.","source_url":"https://europepmc.org/article/MED/12789172","grade":"internal-measurement","grade_label":"Internal measurement"},{"id":"clm-101","text":"This site cites 52 sources, of which 37 are peer-reviewed journal articles and 15 are FDA, eCFR, PubChem or archived-search government records, giving 100.0% peer-reviewed or governmental material.","source_url":"https://europepmc.org/article/MED/25919144","grade":"internal-measurement","grade_label":"Internal measurement"},{"id":"clm-102","text":"Of the 17 interventional human studies in this site's study table (randomized trials, open trials and pharmacokinetic studies, excluding reviews and meta-analyses), 16 tested the prescription strengths of 15% or 20%. Exactly 1 tested the 10% strength the cosmetic market sells, and it was an 8-week combination-product cosmetic study in 23 people.","source_url":"https://europepmc.org/article/MED/42572367","grade":"internal-measurement","grade_label":"Internal measurement"}]}