Azelaic acid

Azelaic acid is an Antiacne Agent belonging to pharmacology class of Retinoic Acid Derivative

Azelaic acid can be used in the treatment of Acne Vulgaris and Rosacea.

Azelaic acid is approx 4% absorbed systemically and Penetrates all layers of the skin and is Metabolised via β-oxidation into short-chained dicarboxylic acids (C₇, C₅) and get excreted Via urine (mainly as unchanged drug and some as dicarboxylic acids) with Half-life of 12 hr.

The common side effects associated with Azelaic acid include Burning, erythema, stinging, pruritus, dryness and scaling, peeling, irritation, dermatitis.

Azelaic acid is available in the form of Cream, foam, gel.

Azelaic acid is a dietary constituent normally found in whole grain cereals; can be formed endogenously. Exact mechanism is not known. In vitro, azelaic acid possesses antimicrobial activity against Cutibacterium acnes and Staphylococcus epidermidis. May decrease microcomedo formation.

Onset of action: Within 4 weeks.

Azelaic acid is available in Cream, foam, gel

Topical: Apply a thin film and gently massage into clean, dry skin; wash hands following application. Avoid the use of occlusive dressings or wrappings. For external use only; not intended for intravaginal, ophthalmic, or oral use.

Foam, gel: Shake foam well before use. Use only mild soaps or soapless cleansing lotion for facial cleansing; avoid use of abrasives, alcoholic cleansers, astringents, peeling agents, and tinctures. Cosmetics may be applied after foam or gel has dried.

Azelaic acid can be used in the treatment of Acne Vulgaris and Rosacea.

Azelaic acid is a naturally-occurring aliphatic dicarboxylic acid that inhibits the growth of Propionibacterium acnes and reduces keratinization, thus restricts the development of comedones.

Azelaic acid is approved for use in the following clinical indications

Acne vulgaris (cream): Treatment of mild to moderate inflammatory acne vulgaris.

The American Association of Dermatology (AAD) acne guidelines support azelaic acid use as an adjunctive treatment option and, in particular, recommend its use in the treatment of post-inflammatory dyspigmentation.

Rosacea (foam, gel): Treatment of inflammatory papules and pustules of mild to moderate rosacea.

Limitations of use: Efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated.

Acne vulgaris (alternative agent):

Note: Reserve for patients who are not able to use a topical retinoid.

Topical: Cream 20%; foam, gel 15%: Apply a thin film to the affected area(s) twice daily, in the morning and evening; may reduce to once daily if persistent skin irritation occurs. For moderate to severe acne, may be used as part of an appropriate combination regimen . Improvement is usually seen within 4 weeks.

Rosacea: Topical: Gel 15% and foam 15%: Apply a thin layer to the affected area(s) of the face twice daily, in the morning and evening; reassess diagnosis if no improvement after 12 weeks of therapy.

Cream, foam, gel

• 20%, 50%

Cream, Gel

Dose Adjustment in Pediatric Patient:

Acne vulgaris: Children ≥12 years and Adolescents: Cream (Azelex 20%): Topical: Apply a thin film to affected area(s) twice daily, in the morning and evening; may reduce to once daily if persistent skin irritation occurs.

Avoid spicy foods, alcoholic beverages and hot drinks that might provoke erythema, flushing and blushing during treatment of rosacea.

Azelaic acid may be contraindicated in the following conditions:

Hypersensitivity to Azelaic acid or any component of the formulation.

Concerns related to adverse effects:

• Hypersensitivity: Hypersensitivity reactions (eg, angioedema, dyspnea, eye swelling, facial swelling, skin reactions, urticaria) have been reported; discontinue use if signs/symptoms occur.

• Hypopigmentation: A few cases of hypopigmentation after use have been reported; monitor for changes in skin color, especially in patients with dark complexions.

• Skin irritation: Skin irritation (eg, pruritus, burning, stinging) may occur, usually during the first few weeks of therapy. Discontinue use if severe skin irritation or sensitivity occurs.

Disease-related concerns:

• Asthma: Exacerbation of asthma has been reported.

Dosage form specific issues:

• Foam: Contains flammable propellants. Avoid fire, flame and smoking during and immediately following use.

• Gel: Reassess use if no improvement is seen after 12 weeks of therapy.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

There is no sufficient scientific evidence traceable regarding use and safety of Azelaic acid in concurrent use with alcohol.

It is not known if Azelaic acid is present in breast milk.

There are no adequate and well-controlled studies of topically administered azelaic acid in pregnant women. The experience with AZEALIC ACID Gel, 15%, when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy.

Dermal embryofetal developmental toxicology studies have not been performed with azelaic acid, 15%, gel. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits, and cynomolgus monkeys. Azelaic acid was administered during the period of organogenesis in all three animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses of azelaic acid that generated some maternal toxicity. Embryotoxicity was observed in rats given 2500 mg/kg/day (162 times the maximum recommended human dose based on body surface area), rabbits given 150 or 500 mg/kg/day (19 or 65 times the maximum recommended human dose based on body surface area) and cynomolgus monkeys given 500 mg/kg/day (65 times the maximum recommended human dose based on body surface area) azelaic acid. No teratogenic effects were observed in the oral embryofetal developmental studies conducted in rats, rabbits and cynomolgus monkeys.

An oral peri- and post-natal developmental study was conducted in rats. Azelaic acid was administered from gestational day 15 through day 21 postpartum up to a dose level of 2500 mg/kg/day. Embryotoxicity was observed in rats at an oral dose that generated some maternal toxicity (2500 mg/kg/day; 162 times the maximum recommended human dose based on body surface area). In addition, slight disturbances in the postnatal development of fetuses was noted in rats at oral doses that generated some maternal toxicity (500 and 2500 mg/kg/day; 32 and 162 times the maximum recommended human dose based on body surface area). No effects on sexual maturation of the fetuses were noted in this study.

Because animal reproduction studies are not always predictive of human response, this drug should be used only if clearly needed during pregnancy.

The adverse reactions related to Azelaic acid can be categorized as

Common Adverse effects:

Burning, Erythema, Stinging, Pruritus, Dryness and Scaling, Peeling, Irritation, Dermatitis

Less Common Adverse effects:

Irritation, Dermatitis, Hypopigmentation, Rash, and Photosensitivity.

Rare Adverse effects:

Exacerbation of Asthma.

The most common side effects of Azelaic acid includes: Burning, Erythema, Stinging, Pruritus, Dryness and Scaling, Peeling, Irritation, Dermatitis.

Pregnancy Category B

There are no adequate and well-controlled studies of topically administered azelaic acid in pregnant women. The experience with Azealic Acid Gel, 15%, when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy.

Dermal embryofetal developmental toxicology studies have not been performed with azelaic acid, 15%, gel. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits, and cynomolgus monkeys. Azelaic acid was administered during the period of organogenesis in all three animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses of azelaic acid that generated some maternal toxicity. Embryotoxicity was observed in rats given 2500 mg/kg/day (162 times the maximum recommended human dose based on body surface area), rabbits given 150 or 500 mg/kg/day (19 or 65 times the maximum recommended human dose based on body surface area) and cynomolgus monkeys given 500 mg/kg/day (65 times the maximum recommended human dose based on body surface area) azelaic acid. No teratogenic effects were observed in the oral embryofetal developmental studies conducted in rats, rabbits and cynomolgus monkeys.

An oral peri- and post-natal developmental study was conducted in rats. Azelaic acid was administered from gestational day 15 through day 21 postpartum up to a dose level of 2500 mg/kg/day. Embryotoxicity was observed in rats at an oral dose that generated some maternal toxicity (2500 mg/kg/day; 162 times the maximum recommended human dose based on body surface area). In addition, slight disturbances in the postnatal development of fetuses was noted in rats at oral doses that generated some maternal toxicity (500 and 2500 mg/kg/day; 32 and 162 times the maximum recommended human dose based on body surface area). No effects on sexual maturation of the fetuses were noted in this study.

Because animal reproduction studies are not always predictive of human response, this drug should be used only if clearly needed during pregnancy.

• Labor and Delivery

There is no FDA guidance on use of Azelaic acid during labor and delivery.

• Nursing Mothers

Equilibrium dialysis was used to assess human milk partitioning in vitro. At an azelaic acid concentration of 25 μg/mL, the milk/ plasma distribution coefficient was 0.7 and the milk/buffer distribution was 1.0, indicating that passage of drug into maternal milk may occur. Since less than 4% of a topically applied dose of azelaic acid cream, 20%, is systemically absorbed, the uptake of azelaic acid into maternal milk is not expected to cause a significant change from baseline azelaic acid levels in the milk. However, caution should be exercised when Azealic Acid Gel, 15%, is administered to a nursing mother.

• Pediatric Use

Safety and effectiveness of Azealic Acid Gel, 15%, in pediatric patients have not been established.

• Geriatic Use

Clinical studies of Azealic Acid Gel, 15%, did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

• Gender

There is no FDA guidance on the use of Azelaic acid with respect to specific gender populations.

• Race

There is no FDA guidance on the use of Azelaic acid with respect to specific racial populations.

• Renal Impairment

There is no FDA guidance on the use of Azelaic acid in patients with renal impairment.

• Hepatic Impairment

There is no FDA guidance on the use of Azelaic acid in patients with hepatic impairment.

• Females of Reproductive Potential and Males

There is no FDA guidance on the use of Azelaic acid in women of reproductive potentials and males.

• Immunocompromised Patients

There is no FDA guidance one the use of Azelaic acid in patients who are immunocompromised.

Acute Overdose

Signs and Symptoms

Azealic acid Gel, 15%, is intended for cutaneous use only. If pronounced local irritation occurs, patients should be directed to discontinue use and appropriate therapy should be instituted.

Chronic Overdose

There is limited information regarding Chronic Overdose of Azelaic acid in the drug label.

Pharmacodynamics:

Azelaic acid is a saturated dicarboxylic acid found naturally in wheat, rye, and barley. It is a natural substance that is produced by Malassezia furfur (also known as Pityrosporum ovale), a yeast that lives on normal skin. It is effective against a number of skin conditions, such as mild to moderate acne, when applied topically in a cream formulation of 20%. It works in part by stopping the growth of skin bacteria that cause acne, and by keeping skin pores clear. Azelaic acid's antimicrobial action may be attributable to inhibition of microbial cellular protein synthesis.

Pharmacokinetics:

Absorption: Approx 4% absorbed systemically.

Distribution: Penetrates all layers of the skin.

Metabolism: Metabolized via β-oxidation into short-chained dicarboxylic acids (C₇, C₅).

Excretion: Via urine (mainly as unchanged drug and some as dicarboxylic acids). Half-life: 12 hr.

1. https://www.uptodate.com/contents/Azelaic acid -drug-information?search=Azelaic acid &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Azelaic acid _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Azelaic acid ?type=full&mtype=generic#mechanism-of-action