Tretinoin TAAN Cream

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Overview of Tretinoin TAAN Cream

Dosage Strengths of Tretinoin TAAN Cream

Tretinoin TAAN Sensitive Cream: (Tretinoin / Azelaic Acid / Niacinamide) 0.015/4/4% 30 mL Pump
Tretinoin TAAN Mild Cream: (Tretinoin / Azelaic Acid / Niacinamide) 0.03/4/4% 30 mL Pump
Tretinoin TAAN Strong Cream: (Tretinoin / Azelaic Acid / Niacinamide) 0.045/4/4% 30 mL Pump

General Information

Tretinoin

Also known as all-trans retinoic acid (ATRA), Tretinoin is one of the most bioactive forms of retinoids, which are vitamin A derivatives. Originally studied over 30 years ago, Tretinoin is commonly applied topically in the treatment of acne vulgaris and as a palliative in treating features of photoaging such as facial wrinkles, roughened skin, and liver spots.1 It has a comedolytic as well as anti-inflammatory effect and can be used by itself or synergistically with other medications to manage skin disorders.

In addition to its topical use, oral Tretinoin has also been found beneficial in the management of specific kinds of cancers such as refractory acute promyelocytic leukemia (APL), characterized by chromosomal translocation t(15, 17) or in patients who are unable to tolerate anthracycline-based chemotherapy.1

Azelaic Acid

Used topically in the management of acne vulgaris and other inflammatory skin conditions such as rosacea, azelaic acid is found naturally in wheat, rye, and barley. It is a straight-chain dicarboxylic acid and can also be produced by Malassezia furfur, otherwise known as Pityrosporum Ovale, which is a species of fungus that is naturally found on human skin. While not very clear, azelaic acid is believed to exert its effects through the inhibition of cellular synthesis in both aerobic and anaerobic bacteria. Its mechanism of action is not very clear but it is generally well tolerated with minimal side effects, however, some people have reported symptoms of mild to moderate pruritus as well as xerosis after topical administration of azelaic acid.2 3

Niacinamide

Niacinamide, also known as nicotinamide, is a derivative of the water-soluble B-complex vitamin niacin. It is a precursor of the cofactors niacinamide adenine dinucleotide (NAD) and niacinamide adenine dinucleotide phosphate (NADP). NAD and NADP are key components of many essential metabolic pathways in the human body. It is found in dietary sources such as meats, liver, yeast, dairy products, legumes, beans, nuts, seeds, green leafy vegetables, fortified bread, cereals, coffee, and tea. A deficiency in niacin results in the condition known as pellagra which comprises dementia, dermatitis, and diarrhea.

Clinically, topical niacinamide is used by dermatologists to manage a variety of skin conditions. Due to its ability to inhibit procytokine inflammatory pathways, niacinamide is used in the treatment of skin disorders such as bullous pemphigoid, IgA bullous dermatosis, acne vulgaris, as well as certain kinds of pruritus. It also has a synergistic effect when used with other topical anti-aging medications; studies have shown a reduction in facial spots and facial skin erythema when niacinamide is used in conjunction with kinetin topically.4 5

Mechanism of Action

Tretinoin

Tretinoin exerts its anti-inflammatory effects by binding with alpha, beta, and gamma retinoic acid receptors. Through this binding, Tretinoin increases cellular phagocytic responses as well as the modulation of other inflammatory events associated with acne vulgaris and related inflammatory skin disorders. Tretinoin administration suppresses the respiratory burst, with its consequent release of cytokines such as hydrogen peroxide, that characterizes inflammation. It also downregulates the production of nitric oxide, another key mediator of inflammation, by the inhibition of nitrous oxide synthase. Furthermore, Tretinoin has an inhibitory effect on the proteolytic enzymes released by neutrophils in the human body during phagocytosis.1 6

Tretinoin also exerts cytokine immunomodulating effects in managing the inflammatory effects of acne vulgaris and other inflammatory skin conditions. By upregulating the production of interleukin-2 (IL-2), Tretinoin helps activate T-helper cells which are of benefit in healing acne lesions. It also inhibits interleukin-6, interleukin-12, and TNF-a, which are all proinflammatory cytokines that are released during acne vulgaris.6

In addition to its anti-inflammatory effects, Tretinoin also has comedolytic properties. It modifies the abnormal follicular keratinization, a feature of acne, by loosening the connection between cells within the stratum corneum, enhancing corneocyte shedding from the follicles, and accelerating sebum removal from the ducts. All these actions serve to decrease the development of comedones, also known as blackheads, which are characteristic of acne.7 8

Azelaic Acid

While not fully understood, azelaic acid is known to have both bacteriostatic and bactericidal effects on bacteria on the skin such as Propionibacterium acne that predispose to the development of acne. The reduction of these effects serves to reduce the inflammation that typically occurs with acne. Additionally, azelaic acid also inhibits oxidoreductive enzymes such as tyrosinase, thioredoxin reductase, and 5-alpha reductase. Furthermore, by reducing the amount as well as distribution of filaggrin, azelaic acid reduces the thickness of the stratum corneum and shrinks the size of the keratohyalin granules, all which contribute to an improvement in symptoms associated with acne.2 9

Niacinamide

Given the widespread role that niacinamide plays in the human body, several mechanisms have been postulated through which it is beneficial in controlling acne vulgaris and other inflammatory skin disorders. One of the ways that niacinamide exerts its effect is through the inhibition of protein oxidation, also known as glycation. Glycation results in the production of yellowish-brown Amedori products that can accumulate in collagen and cause some of the changes in skin appearance such as sallowness that are associated with aging. Additionally, similar to Tretinoin, niacinamide inhibits the development of proinflammatory cytokines which as responsible for the features seen with acne.5 10

Contraindications/Precautions

Since Tretinoin is a retinoid, it should be avoided as much as possible in individuals with a demonstrated hypersensitivity to vitamin A due to the likelihood of cross-sensitivity. Tretinoin is contraindicated in individuals manifesting symptoms of retinoid toxicity such as headache, hyperhidrosis, alopecia, altered visual acuity, and pruritus, among others. The administration of Tretinoin in the face of retinoid toxicity may result in retinoic acid syndrome which may present as acute respiratory distress, fever, pleural and pericardial effusion, and multi-organ failure. In individuals who are hypersensitive to fish products, are photosensitive, or have eczema, Tretinoin should be administered with caution.1

Some azelaic acid products contain propylene glycol and so should be avoided in individuals who have propylene glycol hypersensitivity. In addition, care should be exercised when using azelaic acid on dark complexioned individuals due to the risk of hypopigmentation. Furthermore, azelaic acid should not be used with occlusive dressings.14

Pregnancy

Tretinoin is an FDA category C medication, meaning that there is a high risk of fetal malformation or loss if administered during pregnancy. As such, Tretinoin is contraindicated in first trimester pregnancy and during breastfeeding. Extreme care and close monitoring are essential if Tretinoin is to be administered in the second or third trimester as there is still the likelihood of fetal malformation. It is advisable that women of reproductive age use two forms of contraceptives prior to oral Tretinoin therapy. Contraception should be continued for at least one month after Tretinoin therapy has been discontinued.1

Azelaic acid is classified as an FDA category B medication, meaning that studies have not revealed any teratogenic effects in animals and sufficient research has not been performed on pregnant women. As such, azelaic acid can be administered when the benefits of its use clearly outweigh any risks of teratogenesis. It is generally safe to administer azelaic acid during breastfeeding as there is very negligible uptake into maternal breast milk.14

Niacinamide is an FDA category A medication, meaning that adequate studies have not revealed any teratogenic effects to maternal fetuses in the first trimester. It can therefore be safely administered at any point during pregnancy.

Breastfeeding

Azelaic acid can be administered when the benefits of its use clearly outweigh any risks of teratogenesis. It is generally safe to administer azelaic acid during breastfeeding as there is very negligible uptake into maternal breast milk.14

Adverse Reactions/Side Effects

Most of the adverse reactions that may occur during Tretinoin administration are as a result of hypersensitivity and may include pruritus, erythema, xerosis, and pharyngitis. At high doses, other adverse effects of Tretinoin that may manifest are cardiac arrhythmias, renal tubular necrosis, pseudotumor cerebri, pancreatitis, paresthesia, and hallucinations. In addition, retinoid toxicity may occur if Tretinoin is administered to patients with demonstrable features of hypervitaminosis A. Also, as earlier stated, Tretinoin is highly teratogenic and so should be avoided in pregnancy as much as possible, especially during the first trimester.

Azelaic acid is generally well tolerated but there have been some reported instances of severe angioedema, contact dermatitis, dyspnea, and erythema. Mild reactions that may also present after topical azelaic acid administration include pruritus, xerosis, skin hypopigmentation, and urticaria.14

Storage

Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

1. a. b. c. d. e. f. Yoham AL, Casadesus D, "Tretinoin". In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557478/
2. a. b. "Azelaic acid", Drug Bank.[Online]. Available: https://go.drugbank.com/drugs/DB00548
3. J. E. Frampton, A. J. Wagstaff, "Azelaic Acid 15% gel in the treatment of papulopustular rosacea", The American Journal of Clinical Dermatology, vol.5, issue 1, pp. 57 – 64, 2004.
4. PC Chiu, CC Chan , HM Lin, HC Chiu, "The clinical anti-aging effects of topical kinetin and niacinamide in Asians: a randomized, double-blind, placebo-controlled, split-face comparative trial", Journal of Cosmetic Dermatology vol.6, issue 4, pp. 243 -249, December 2007. Available: https://pubmed.ncbi.nlm.nih.gov/18047609/
5. a. b. E. Forbat, F. Al-Niaimi, FR. Ali, "Use of nicotinamide in dermatology", Clinical and Experimental Dermatology vol.42, issue 2, pp. 137 – 144, March 2017. Available: https://pubmed.ncbi.nlm.nih.gov/28052374/
6. a. b. N. Schmidt, G.H. Eugene, "Tretinoin: A Review of Its Anti-inflammatory Properties in the Treatment of Acne." The Journal of clinical and aesthetic dermatology vol. 4, issue 11, pp. 22 – 29, 2011. Available: https://www.ncbi.nlm.nih.gov/books/NBK557478/
7. M. Zasada, E. Budzisz, "Retinoids: active molecules influencing skin structure formation in cosmetic and dermatological treatments." Advances in Dermatology and Allergology vol 36 issue 4, pp. 392–397. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791161/
8. "Tretinoin", Drug Bank. [Online]. Available: https://go.drugbank.com/drugs/DB00755
9. A. Zalewska, "Azelaic acid hyperpigmented lesions treatment", Case Reports and Clinical Practice Review vol.3 issue 3 pp. 204 -207.
10. D.L. Bissett, K. Miyamoto, P. Sun, J. Li, C.A. Berge, "Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin1". International Journal of Cosmetic Science vol 26, pp. 231 – 238
14. a. b. c. d. "Azelaic acid – Drug Summary", Prescribers' Digital Reference. Available: https://www.pdr.net/drug-summary/Azelex-azelaic-acid-1111#:~:text=An%20occlusive%20dressing%20should%20not,physician%20if%20ocular%20irritation%20persists.