HQ/Tretinoin/Kojic Acid

Hydroquinone (1,4-dihydroxybenzene) is a topical depigmenting agent. In the US it is available on prescription in Tri-Luma cream (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%). Since the CARES Act OTC monograph reform of 2020, hydroquinone can no longer be marketed in nonprescription skin-lightening products without FDA approval. Lake Hills Pharmacy compounds topical hydroquinone preparations as a 503A pharmacy on patient-specific prescriptions.

Tri-Luma cream is FDA labeled for short-term treatment of moderate to severe melasma of the face, used with sun avoidance and sunscreen. Prescribers use compounded topical hydroquinone, alone or with other agents, for melasma, post-inflammatory hyperpigmentation, solar lentigines and other hyperpigmentation.

Hydroquinone inhibits tyrosinase, the enzyme that converts tyrosine to DOPA and then to melanin, reducing melanin synthesis. It also generates reactive oxygen species and quinones within melanocytes that damage melanosomes and melanocyte membranes. Its effect is reversible, and pigment can return with sun exposure or after stopping.

Hydroquinone is absorbed through the skin to a meaningful degree; studies of topical application have reported systemic absorption of a substantial fraction of the applied dose. Absorbed drug is conjugated to glucuronide and sulfate metabolites and excreted in urine. In formulation, hydroquinone oxidizes to p-benzoquinone, which turns the preparation brown; antioxidants and light protection slow this.

• Hypersensitivity to hydroquinone or any component of the preparation, including sulfites where present.

• Exogenous ochronosis: gradual blue-black darkening of treated skin with prolonged use, reported more often in darker skin types and with higher strengths. Discontinue if it appears; it may be persistent.
• Irritation and allergic contact dermatitis: test a small area first when the prescriber directs; stop if vesicles, marked erythema or itching develop.
• Sun exposure: UV exposure reverses depigmentation. Daily broad-spectrum sunscreen and sun avoidance are part of therapy.
• Sulfites: many hydroquinone products contain sodium metabisulfite, which can cause allergic and asthmatic reactions in sensitive people.
• Hypopigmentation and confetti-like depigmentation can occur, particularly with higher strengths or application beyond the target area. Avoid the eyes and mucous membranes.

• No clinically important systemic interactions are established for topical use.
• Use with benzoyl peroxide or hydrogen peroxide can cause transient dark staining of the skin.
• Additive irritation with other topical irritants, including retinoids, alpha-hydroxy acids and resorcinol.

Common: erythema, burning, stinging, dryness and pruritus. Less common: allergic contact dermatitis, hypopigmentation, nail discoloration. Rare with long-term use: exogenous ochronosis and colloid milium.

Adequate human pregnancy data are lacking. Because systemic absorption is meaningful, many prescribers defer hydroquinone during pregnancy. It is not known whether hydroquinone passes into breast milk; use during breastfeeding is a prescriber decision.

Assess response and tolerability at regular intervals set by the prescriber, watching for irritation, contact dermatitis, hypopigmentation and early signs of ochronosis, and reassess the need for continued use.

• Tri-Luma (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) Cream Prescribing Information, Galderma Laboratories.
• Coronavirus Aid, Relief, and Economic Security (CARES) Act of 2020, OTC monograph reform provisions.
• Lexicomp Drug Information, Wolters Kluwer.

Tretinoin (all-trans retinoic acid) is a retinoid. FDA-approved topical products include Retin-A cream and gel, Renova emollient cream, Atralin gel, Altreno lotion and Tri-Luma cream (with hydroquinone and fluocinolone). Oral tretinoin capsules are approved for acute promyelocytic leukemia. Lake Hills Pharmacy compounds topical tretinoin preparations as a 503A pharmacy on patient-specific prescriptions.

• Topical (Retin-A, Atralin, Altreno): acne vulgaris.
• Topical (Renova 0.02% and 0.05%): adjunct for mitigation of fine facial wrinkling, mottled hyperpigmentation and roughness associated with chronic sun exposure, with sun avoidance.
• Topical (Tri-Luma): short-term treatment of moderate to severe facial melasma, in combination.
• Oral capsules: induction of remission in acute promyelocytic leukemia (APL) with the t(15;17) translocation or PML/RARA gene.
• Prescribers use compounded topical tretinoin, alone or with other agents, for acne, photoaging and hyperpigmentation.

Tretinoin binds nuclear retinoic acid receptors (RAR-alpha, beta, gamma), altering gene transcription. In skin it increases epidermal cell turnover, reduces cohesion of follicular keratinocytes, normalizes follicular keratinization and promotes dispersion of melanin granules. In APL it induces differentiation of leukemic promyelocytes.

Topical: systemic absorption is minimal, and plasma retinoid levels stay within the endogenous range in labeled studies. Oral: peak levels occur in 1 to 2 hours, elimination half-life is short (about 0.5 to 2 hours), and metabolism through CYP26 and CYP3A4 induces its own clearance with continued dosing.

• Hypersensitivity to tretinoin, other retinoids or any component of the preparation (oral capsules: also parabens).

• Topical: local irritation (erythema, peeling, dryness, burning) is common; reduce frequency or stop if severe. Avoid eyes, mouth, nasal folds and mucous membranes, and do not apply to eczematous, sunburned or broken skin.
• Photosensitivity: minimize sun and UV exposure and use sunscreen and protective clothing. Weather extremes such as wind or cold may increase irritation.
• Oral: leukocytosis, pseudotumor cerebri (risk rises with tetracyclines), hyperlipidemia, elevated liver enzymes, and thrombosis risk.

• Topical: additive irritation with keratolytics (salicylic acid, sulfur, resorcinol), astringents, alcohol-containing products and abrasive cleansers; benzoyl peroxide can degrade some tretinoin formulations. Use caution with photosensitizing drugs such as thiazides, tetracyclines, fluoroquinolones, phenothiazines and sulfonamides.
• Oral: CYP3A4 inhibitors and inducers alter exposure; antifibrinolytics such as tranexamic acid increase thrombotic risk; tetracyclines increase the risk of pseudotumor cerebri; avoid vitamin A supplements.

Topical: erythema, peeling, dryness, burning, stinging, pruritus, temporary hyper- or hypopigmentation and photosensitivity. Oral: headache, fever, dry skin and mucous membranes, bone pain, nausea, hyperlipidemia, liver enzyme elevation and differentiation syndrome.

Oral tretinoin causes fetal harm and requires pregnancy exclusion and contraception. Topical tretinoin labeling reports limited human data; systemic absorption is low, but isolated reports of birth defects exist and many prescribers avoid topical retinoids in pregnancy. It is not known whether topical tretinoin passes into breast milk; oral labeling advises against breastfeeding during treatment and for 1 week after the last dose.

Topical: skin tolerability and photosensitivity at intervals set by the prescriber; confirm pregnancy status and plans. Oral: complete blood counts, coagulation, lipids, liver tests, pregnancy testing and signs of differentiation syndrome.

• Retin-A (tretinoin) Cream and Gel Prescribing Information.
• Renova (tretinoin) Cream 0.02% Prescribing Information.
• Tri-Luma (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) Cream Prescribing Information, Galderma Laboratories.
• Tretinoin Capsules, 10 mg, Prescribing Information (generic labeling).
• Lexicomp Drug Information, Wolters Kluwer.

Kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one) is a fungal metabolite produced during fermentation by Aspergillus and Penicillium species, including in rice fermentation for sake. Kojic acid is used in cosmetic skin-brightening products, typically at concentrations up to about 1%, and in compounded topical preparations, usually in combination with other actives.

• Prescribers use compounded topical preparations containing kojic acid, often with hydroquinone, tretinoin, a corticosteroid, tranexamic acid or niacinamide, for hyperpigmentation disorders such as melasma. Dosing is individualized by the prescriber.

Kojic acid inhibits tyrosinase, the rate-limiting enzyme of melanin synthesis, mainly by chelating the copper ions at the enzyme's active site. This reduces conversion of tyrosine to DOPA and dopaquinone. It also has antioxidant and free-radical scavenging activity, and chelates iron.

Percutaneous absorption of kojic acid from topical products is limited; human data are sparse. Safety assessments by the European Scientific Committee on Consumer Safety estimated systemic exposure from 1% cosmetic use and judged it acceptable for face and hand products. Absorbed kojic acid is excreted mainly in the urine, partly as glucuronide and sulfate conjugates. Exposure from higher compounded concentrations has not been characterized.

• Known hypersensitivity to kojic acid or any ingredient of the preparation. Avoid use on broken, irritated or infected skin.

• Kojic acid is a recognized contact sensitizer. Allergic and irritant contact dermatitis can occur, more often at higher concentrations; consider patch testing in patients with a history of contact allergy.
• High-dose oral studies in rodents reported thyroid effects and liver tumors; the relevance to topical human use is uncertain, and safety assessments have favored concentrations of 1% or less in cosmetics.
• Kojic acid is unstable with light, heat and air and darkens on oxidation; it also forms colored complexes with iron. Discolored product should not be used. Daily sun protection is part of treatment for hyperpigmentation.

• No systemic drug interactions have been established. Irritation can be additive when kojic acid is combined with other topical agents such as tretinoin, hydroquinone, alpha-hydroxy acids or benzoyl peroxide.

Reported effects include erythema, stinging, burning, itching, dryness and peeling at the application site, allergic contact dermatitis and, uncommonly, post-inflammatory hyperpigmentation after irritation. Systemic adverse effects have not been reported with topical use.

Human data in pregnancy and lactation are lacking. Systemic exposure from limited topical use is expected to be low, but safety has not been established; use during pregnancy or breastfeeding is a prescriber decision. Combination products may contain other actives, such as tretinoin or hydroquinone, with their own pregnancy considerations.

Monitor pigmentation response, local irritation and signs of allergic contact dermatitis. Reassess therapy if irritation persists or if pigmentation worsens.

• Scientific Committee on Consumer Safety (SCCS), European Commission: Opinion on Kojic Acid.
• Cosmetic Ingredient Review: Final Report of the Safety Assessment of Kojic Acid.
• USP General Chapter <795> Pharmaceutical Compounding, Nonsterile Preparations.