Azelaic acid, oxymetazoline and niacinamide have been clinically studied in the treatment of patients with various forms of rosacea.1-7
Azelaic acid, niacinamide and oxymetazoline may be compounded individually, combined in parts, or completely combined. Generally, this combination is commonly compounded at the following strengths 18/4/1% in a clarifying cream base.
The manifestation of rosacea often includes facial erythema, visible blood vessels and swollen red acne-like bumps. Although the pathophysiology is not completely understood, it is thought to be an inflammatory disorder characterized by neurovascular dysregulation and inflammation that produce physiochemical and structural changes in the skin.
Azelaic acid is a saturated dicarboxylic acid. Azelaic acid inhibits the production of ROS and upregulation of pro‐inflammatory cytokines as IL‐1, IL‐6 and TNF‐α. Also, phosphorylation of ERK1/2 and p38 as well as UV‐induced NF‐κB activation is downregulated. PPARγ inhibits inflammatory responses and is induced by azelaic acid.
Oxymetazoline is an alpha-1A adrenoceptor agonist. The topical application of oxymetazoline cream may reduce erythema through direct vasoconstriction.
Niacinamide helps to improve the integrity of the stratum corneum and thus reduce cosmetic xerosis over time. Anti-inflammatory action affecting neutrophil chemotaxis has also been reported for niacinamide. Additionally, due to its inhibition of ADP-ribosylation, niacinamide has been shown to suppress cytokine mediated induction of nitric oxide synthase in a number of cells, thus effecting interleukin-1-exposed chondrocytes, resulting in decreased inflammation.
Azelaic acid has been studied in the treatment of inflammatory lesions (papules and pustules) associated with mild to moderate rosacea.1
Oxymetazoline HCL 1% cream has been studied for persistent facial erythema associated with rosacea in adults.2-5
Niacinamide has been studied for the treatment of cosmetic xerosis in patients with rosacea.6,7
The efficacy and safety of azelaic acid foam was evaluated in two multicenter, randomized, double-blind, vehicle-controlled, 12-week clinical trials (Trials 1 and 2) in subjects with papulopustular rosacea, with a mean lesion count of 21.3 (range 12 to 50) inflammatory papules and pustules. A total of 1362 (active: 681; vehicle: 681) subjects aged 19 to 92 years (mean age = 50.6 years), 95.7% Caucasian, and 73.4% female participated in the trials. The following subjects were excluded: a) those with ocular rosacea, phymatous rosacea or plaque type rosacea lesions; b) those with rosacea that requires systemic treatment; c) those who are known non-responders to azelaic acid, and d) those with a known hypersensitivity to any ingredients of the study drug.1
Azelaic acid foam or its vehicle were to be applied twice daily for 12 weeks; no other topical or systemic medication affecting the course of rosacea and/or evaluability was to be used during the studies. Subjects were instructed to avoid any food and beverages that, by their own experience, may provoke erythema, flushing and blushing, including spicy food, hot drinks and alcoholic beverages during the study. Subjects were also instructed to avoid use of products which may cause local irritation such as soaps, alcohol-containing cleansers, tinctures and astringents, abrasives and peeling agents during the study.1
The efficacy endpoints were 1) nominal change in inflammatory lesion count from baseline and 2) success defined as a score of “clear” or “minimal” with at least 2-step reduction from baseline on a 5-point Investigator’s Global Assessment (IGA).1
| TRIAL 1 | TRIAL 2 | |||
|---|---|---|---|---|
| Azelaic Acid (N=483) | VEHICLE (N=478) | Azelaic Acid (N=198) | VEHICLE (N=203) | |
| IGA SUCCESS | 32.1% | 23.4% | 43.4% | 32.5% |
| Mean nominal change in inflammatory lesion count from baseline | -13.2 | -10.3 | -13.3 | -9.5 |
Oxymetazoline HCl 1% cream was evaluated for the treatment of persistent erythema associated with rosacea in two identical, randomized, double-blind, vehicle-controlled, parallel-group clinical trials. The trials enrolled 885 subjects aged 18 years and older. Overall, 90% of subjects were Caucasian and 79% were female. Subjects applied either oxymetazoline or vehicle once daily for 29 days.2
Baseline disease severity was graded using a 5-point Clinical Erythema Assessment (CEA) scale and a 5-point Patient Self-Assessment (PSA) scale, on which subjects scored either “moderate” or “severe” on both scales.2
CEA and SSA were measured over a 12-hour period at equally-spaced time points (hours 3, 6, 9, and 12) post- dose on Days 1, 15, and 29. The primary efficacy endpoint was defined as the proportion of subjects with at least a 2-grade reduction in erythema (improvement) from baseline (pre-dose on Day 1) on both the CEA and SSA measured at hours 3, 6, 9, and 12 on Day 29. The results from both trials on the composite endpoint for Day 29 are represented below.
Proportion of Subjects Achieving Composite Success* on Day 29
| TRIAL 1 | TRIAL 1 | TRIAL 2 | TRIAL 2 | |
|---|---|---|---|---|
| Time Point (hr) | Oxymetazoline cream (n=222) | Vehicle Cream (n=218) | Oxymetazoline Cream (n=224) | Vehicle Cream (n=221) |
| 3 | 12% | 6% | 14% | 7% |
| 6 | 16% | 8% | 13% | 5% |
| 9 | 18% | 6% | 16% | 9% |
| 12 | 15% | 6% | 12% | 6% |
*Composite success is defined as the proportion of subjects achieving at least a 2-grade improvement on both CEA and SSA.
Two 35-day studies were performed to evaluate the ability of body moisturizers containing various levels of oils/lipids, humectants, as well as other ingredients (e.g. niacinamide) to improve stratum corneum integrity. 63 and 58 female subjects were enrolled in an incomplete block design to six of nine products (8 moisturizers, no control), respectively. The two niacinamide/glycerin moisturizers demonstrated an overall better solution towards rapid and prolonged improvement of cosmetic xerosis due to functional improvement on stratum corneum barrier function compared to no treatment and other moisturizers.6
Another clinical trial (n=50) was designed to assess whether a niacinamide-containing facial moisturizer would improve the stratum corneum barrier. Subjects applied the test moisturizer to their face and to one forearm twice daily for 4 weeks. The dermatologist investigator found that the niacinamide-containing facial moisturizer improved the skin barrier and benefits subjects with rosacea.7
- It is recommended that a pea sized amount of Azelaic Acid/Niacinamide/Oxymetazoline 18/4/1% Clarifying Cream be applied once daily to each of the five areas of the face: central forehead, chin, nose, and each cheek.
- The cream should be applied smoothly and evenly as a thin layer across the entire face avoiding the eyes, mouth and lips.
- The cream should not be applied to irritated skin, open wounds, or vaginal region.
- Hands need to be washed thoroughly after applying the topical cream.
- Recommended to avoid spicy foods, hot foods/drinks, alcoholic beverages, and other foods/beverages that may cause flushing or redness of skin during treatment.
- Safety and efficacy of azelaic acid >12 weeks has not been established.
- Patients should be reassessed in 12 weeks if there has been no improvement.
Alpha-adrenergic agonists, as a class, may reduce blood pressure. Patients on concomitant beta-blockers, anti-hypertensives and/or cardiac glycosides should be carefully monitored.
Caution should also be exercised in patients receiving alpha-1 adrenergic receptor antagonists such as in the treatment of cardiovascular disease, benign prostatic hypertrophy, or Raynaud's disease.
Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.
With azelaic acid, hypopigmentation is reported rarely, monitor patients with dark complexions for early signs of hypopigmentation during therapy.
Possible skin irritation (e.g., erythema, flushing. pruritus, burning, stinging) during initial weeks of therapy. If sensitivity or severe irritation develops, discontinue therapy, contact clinician, and institute appropriate therapy.
With oxymetazoline, the most common adverse reactions (incidents >1%) are application site dermatitis (2%), worsening inflammatory lesions of rosacea (1%), application site pruritis (1%), application site erythema (1%), and application site pain (1%).
Allergy: Niacinamide can make allergies more severe because they cause histamine, the chemical responsible for allergic symptoms, to be released.
Diabetes: Niacinamide might increase blood sugar. People with diabetes who take niacinamide should check their blood sugar carefully.
Gallbladder disease: Niacinamide, when taken orally, might make gallbladder disease worse.
Gout: Large amounts of niacinamide taken orally might bring on gout.
Kidney dialysis: Taking niacinamide orally seems to increase the risk of low blood-platelet levels in people with kidney failure who are on dialysis.
Liver disease: Niacinamide might increase liver damage when taken orally. Use with caution in patients with liver disease.
Stomach or intestinal ulcers: Niacinamide might make ulcers worse when taken orally. Use with caution in patients with liver disease.
Surgery: Niacinamide might interfere with blood sugar control during and after surgery. Stop taking niacinamide at least 2 weeks before a scheduled surgery.
Potential Impacts on Cardiovascular Disease: Alpha-adrenergic agonists may impact blood pressure. Oxymetazoline should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease, orthostatic hypotension, and uncontrolled hypertension or hypotension. Advise patients with cardiovascular disease, orthostatic hypotension, and/or uncontrolled hypertension/hypotension to seek immediate medical care if their condition worsens.
Potential Impacts on vascular insufficiency: Oxymetazoline should be used with caution in patients with cerebral or coronary insufficiency, Raynaud’s phenomenon, thromboangiitis obliterans, scleroderma, or Sjögren’s syndrome. Advise patients to seek immediate medical care if signs and symptoms of potentiation of vascular insufficiency develop.
Risk of Angle Closure Glaucoma: Oxymetazoline may increase the risk of angle closure glaucoma in patients with narrow-angle glaucoma. Advise patients to seek immediate medical care if signs and symptoms of acute angle closure glaucoma develop.
There are no adequate and well-controlled studies of the use of Azelaic acid/niacinamide/ oxymetazoline HCl topical cream in pregnant women. Therefore, this compound should not be used in pregnant women.
It is not known whether it is safe for breastfeeding mothers. In animal studies, oxymetazoline has been shown to be detected in breast milk. Therefore, this compound should not be used in lactating women who are breastfeeding.
There is Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults for these ingredients. Therefore, this compound should be used with caution in this population.
Safety and effectiveness of Oxymetazoline has not been established in pediatric patients below the age of 18 years. Therefore, this compound should not be used in this population.
The percutaneous absorption of azelaic acid after topical application of azelaic acid gel, 15%, could not be reliably determined. Mean plasma azelaic acid concentrations in rosacea patients treated with azelaic acid gel, 15%, twice daily for at least 8 weeks are in the range of 42 to 63.1 ng/mL. These values are within the maximum concentration range of 24.0 to 90.5 ng/mL observed in rosacea patients treated with vehicle only. This indicates that azelaic acid gel, 15%, does not increase plasma azelaic acid concentration beyond the range derived from nutrition and endogenous metabolism. In vitro and human data suggest negligible cutaneous metabolism of 3 H-azelaic acid 20% cream after topical application. Azelaic acid is mainly excreted unchanged in the urine, but undergoes some ß-oxidation to shorter chain dicarboxylic acids.
Absorption: Following the first dose application of Oxymetazoline, the mean ± standard deviation (SD) peak concentrations (Cmax) and area under the concentration-time curves from time 0 to 24 hours (AUC0-24hr) were 60.5 ± 53.9 pg/mL and 895 ±798 pg*hr/mL, respectively. Following once daily applications for 28 days, the mean ± SD Cmax and AUC0-24hr were 66.4 ± 67.1 pg/mL and 1050 ± 992 pg*hr/mL, respectively. Following twice daily applications (twice the recommended frequency of application) for 28 days, the mean ± SD Cmax and AUC0-24hr were 68.8 ± 61.1 pg/mL and 1530 ± 922 pg*hr/mL, respectively.
Metabolism: In vitro studies using human liver microsomes showed that oxymetazoline was minimally metabolized, generating mono-oxygenated and dehydrogenated products of oxymetazoline. The percentage of parent drug oxymetazoline remaining was 95.9% after a 120-minute incubation with human liver microsomes.2
The pharmacokinetics of niacinamide depend on dose, species, gender, and route of administration. Niacinamide is readily absorbed from all parts of the gastrointestinal tract. A negligible portion of niacinamide is metabolized to niacin, mostly due to bacterial activity. Peak serum concentrations are reached in humans within one hour of oral ingestion of standard preparations. Niacinamide is rapidly cleared from the circulation and distributed in all tissues. It has a high hepatic excretion ratio and plasma clearance can be reduced in patients with hepatic insufficiency.
Store at room temperature.
- Finacea (azelaic acid) topical gel [prescribing information]. Montiville, NJ: Berlex Laboratories; Jan 2013.
- Allergan [sponsor]. A long-term safety and efficacy study AGN-19920 in patients with persistent erythema associated with rosacea. Updated September 21, 2016. https://clinicaltrials.gov/ct2/show/NCT02095158. Accessed November 5, 2017.
- Baumann L, Goldberg DJ, Stein Gold L, et al. Pivotal trial of the efficacy and safety of oxymetazoline cream 1.0% for the treatment of persistent facial erythema associated with rosacea: findings from the second REVEAL trial. J Drugs Dermatol. 2018;17(3):290–298.
- Kircik LH, DuBois J, Draelos ZD, et al. Pivotal trial of the efficacy and safety of oxymetazoline cream 1.0% for the treatment of persistent facial erythema associated with rosacea: findings from the first REVEAL trial. J Drugs Dermatol. 2018;17(1):97–105.
- Allergan [sponsor]. Safety and efficacy of oxymetazoline HCl cream 1.0% in patients with persistent erythema associated with rosacea. Updated August 2, 2016. https://clinicaltrials.gov/ct2/show/NCT02132117?cond=oxymetazoline+cream&rank=1. Accessed November 5, 2017.
- Christman JC et al. Two randomized, controlled, comparative studies of the stratum corneum integrity benefits of two cosmetic niacinamide/glycerin body moisturizers vs. conventional body moisturizers. J Drugs Dermatol. 2012 Jan;11(1):22-9.
- Draelos ZD et al. Niacinamide-containing facial moisturizer improves skin barrier and benefits subjects with rosacea. Cutis. 2005 Aug;76(2):135-41.
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