Drug Monograph

Azelaic Acid/Brimonidine Tartrate/Niacinamide
18/0.4/4% Clarifying Cream

DESCRIPTION

All in one combination product composed of azelaic acid, brimonidine and niacinamide combined in a clarifying base with ingredients scientifically studied to treat rosacea in patients with erythematotelangiectatic and papulopustular rosacea.

HOW SUPPLIED

Azelaic Acid/Brimonidine tartrate/Niacinamide is commonly compounded as a 18/0.4/4% Clarifying Cream.

CLINICAL PHARMACOLOGY
Azelaic acid

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.

Brimonidine tartrate (BT)

Brimonidine is a relatively selective alpha-2 adrenergic agonist. The topical application of brimonidine cream may reduce erythema through direct vasoconstriction.

Niacinamide

Niacinamide helps 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.

CLINICAL EVIDENCE
Azelaic Acid 15%

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
Brimonidine 0.33%

Brimonidine topical gel was evaluated for the treatment of moderate to severe, persistent (non-transient) facial erythema of rosacea in two randomized, double-blind, vehicle-controlled clinical trials, which were identical in design. The trials were conducted in 553 subjects aged 18 years and older who were treated once daily for 4 weeks with either brimonidine topical gel or vehicle. Overall, 99% of subjects were Caucasian and 76% were female.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

The primary efficacy endpoint in both pivotal trials was 2-grade Composite Success, defined as the proportion of subjects with a 2-grade improvement on both CEA and PSA measured at hours 3, 6, 9, and 12 on Day 29. Table 2 presents the efficacy results. In addition to Day 29, efficacy was evaluated on Day 15 and Day 1, and the results are presented in Figures 1 and 2 for Studies 1 and 2, respectively.2

IGA Success Rate and Nominal Change in Inflammatory Lesion Count from Baseline to End of 12 Week Treatment Period
  TRIAL 1   TRIAL 2  
Time Point (hr) Brimonidine (n=129) Vehicle Gel (n=131) Brimonidine (n=148) Vehicle Gel (n=145)
3 31% 11% 25% 9%
6 30% 10% 25% 9%
9 26% 10% 18% 11%
12 23% 9% 22% 10%
Niacinamide 2%

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.3

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.4

INDICATIONS AND USAGE
Azelaic Acid

Azelaic acid has been studied in the treatment of inflammatory lesions (papules and pustules) associated with mild to moderate rosacea.1

Brimonidine

Brimonidine has been studied for treatment of erythematotelangiectatic (flushing & facial redness) rosacea.2

Niacinamide

Niacinamide has been studied for the treatment of cosmetic xerosis in patients with rosacea.3,4

DOSING AND ADMINISTRATION

It is recommended that a pea sized amount of Azelaic Acid/Brimonidine Tartrate/Niacinamide 18/0.4/4% Clarifying Cream be applied once daily to each of the five areas of the face: central forehead, chine, nose, and each cheek.

The cream should be applied smoothly and evenly as a thin layer across the entire face avoiding the eyes and lips.

The cream should not be applied to irritated skin or open wounds.

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.

DRUG INTERACTIONS
Blood pressure and heart medication

Alpha-2 agonists, as a class, may reduce blood pressure. Patients on concomitant beta-blockers, anti-hypertensives and/or cardiac glycosides should be carefully monitored.

Central nervous system depressants

Although specific drug-drug interactions studies have not been conducted with topical brimonidine, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.

Monoamine oxidase inhibitors

Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine and potentially result in increased systemic side-effects such as hypotension.

ADVERSE EFFECTS

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.

In a long-term study, where patients used brimonidine topical gel for up to 12 months, the most common adverse events included flushing (10%), erythema (8%), rosacea (5%), nasopharyngitis (5%), skin burning sensation (4%), increased intraocular pressure (4%), and headache (4%).

Post-marketing reports for brimonidine suggest that rebound flare of redness and discomfort may be more common that was predicted by clinical trials.

Allergic contact dermatitis was reported in approximately 1% of patients in clinical studies with brimonidine. Of the 2 patients who underwent patch testing with individual product ingredients, 1 patient was found to be sensitive to brimonidine tartrate, and the other patient was sensitive to phenoxyethanol, a preservative (not found in this cream formulation).

WARNINGS AND PRECAUTIONS

Allergies: 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.

Worsening of vascular insufficiency: Topical brimonidine should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud phenomenon, orthostatic hypotension, thromboangiitis obliterans, scleroderma/systemic sclerosis, or Sjögren syndrome.

Severe heart disease: Alpha-2 adrenergic agonists can lower blood pressure. Topical brimonidine should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease.

Serious adverse reactions after oral intake: Two young children experienced serious adverse reactions following accidental ingestion of brimonidine topical gel. Adverse reactions experienced included lethargy, respiratory distress with apnoeic episodes (requiring intubation), sinus bradycardia, confusion, psychomotor hyperactivity, and diaphoresis. Both children were hospitalized overnight and discharged the following day without sequelae.

USE IN SPECIFIC POPULATION
Pregnancy

There are no adequate and well-controlled studies of the use of Azelaic acid/brimonidine/niacinamide topical cream in pregnant women.

Lactation

It is not known whether it is safe for breastfeeding mothers. In animal studies, brimonidine tartrate has been shown to be excreted in breast milk.

Pediatric/Geriatric

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

PHARMACOKINETICS
Azelaic Acid

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.

Brimonidine

Brimonidine is extensively metabolized by the liver. Urinary excretion is the major route of elimination of brimonidine and its metabolites.

Niacinamide

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.

STORAGE

Store at room temperature.

REFERENCES
  1. Finacea (azelaic acid) topical gel [prescribing information]. Montiville, NJ: Berlex Laboratories; Jan 2013.
  2. Mirvaso (brimonidine) topical gel [prescribing information]. Fort Worth, TX: Galderma Laboratories, LP; August 2013.
  3. 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.
  4. 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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