HQ/Tret/Azelaic/Kojic/Hydrocortisone

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.

Azelaic acid is a saturated nine-carbon dicarboxylic acid that occurs naturally in wheat, rye and barley and is produced by the skin yeast Malassezia. US products are Finacea Gel 15% (and generic azelaic acid gel 15%), Finacea Foam 15% and Azelex Cream 20%. Lake Hills Pharmacy uses azelaic acid in compounded topical preparations.

• Finacea Gel 15% and Foam 15%: topical treatment of the inflammatory papules and pustules of mild to moderate rosacea.
• Azelex Cream 20%: topical treatment of mild to moderate inflammatory acne vulgaris.
• Prescribers use compounded azelaic acid, alone or combined with other agents, for acne, rosacea, melasma, post-inflammatory hyperpigmentation and other hyperpigmentation disorders.

Azelaic acid has several actions: it is antibacterial against Cutibacterium acnes and Staphylococcus epidermidis by inhibiting microbial protein synthesis; it normalizes keratinization and reduces follicular hyperkeratosis; it reduces reactive oxygen species from neutrophils and dampens the kallikrein-cathelicidin pathway implicated in rosacea; and it competitively inhibits tyrosinase and has an antiproliferative effect on hyperactive melanocytes, with little effect on normal melanocytes. The exact mechanism in rosacea is not fully known.

A small fraction, a few percent, of a topical dose is absorbed through the skin. Absorbed azelaic acid is excreted mainly unchanged in the urine, with some undergoing beta-oxidation. Its apparent half-life after topical application is longer than after oral dosing because absorption is rate-limiting. Plasma levels after topical use remain within the range seen from normal dietary intake.

Azelex Cream labeling contraindicates use in patients with hypersensitivity to any of its components; Finacea labeling lists no contraindications. Compounded preparations should not be used in patients with hypersensitivity to azelaic acid or any component.

• Skin reactions: burning, stinging, itching, dryness and erythema are common, mostly early in treatment; stop if severe or persistent.
• Hypopigmentation has been reported; monitor patients with darker complexions for early signs.
• Avoid contact with the eyes, mouth and other mucous membranes; rinse with water if contact occurs.
• Worsening of asthma has been reported in patients using azelaic acid products.
• Finacea Foam contains a flammable propellant; avoid fire, flame and smoking during and right after application.

No formal interaction studies exist and no clinically relevant systemic interactions are expected with topical use. Irritation can be additive with retinoids, benzoyl peroxide, abrasive or drying cleansers and alcohol-containing products.

Burning, stinging, tingling, itching, dryness, erythema, scaling and contact dermatitis. Less often: hypopigmentation, hypersensitivity reactions including angioedema and urticaria, eye irritation after accidental contact, and worsening of asthma.

Systemic absorption after topical use is minimal. In animal studies, oral doses far above human topical exposure caused embryotoxicity only at maternally toxic levels, with no teratogenicity. Human data are limited. Azelaic acid is not expected to raise milk levels meaningfully above those from diet after topical use; avoid application to the breast area while nursing.

Tolerability and skin irritation, pigmentary changes in patients with darker skin, asthma symptoms in patients with asthma, and clinical response at follow-up.

• Finacea (azelaic acid) Gel 15% Prescribing Information, LEO Pharma.
• Finacea (azelaic acid) Foam 15% Prescribing Information, LEO Pharma.
• Azelex (azelaic acid) Cream 20% Prescribing Information.
• Guidelines of Care for the Management of Acne Vulgaris (2024), American Academy of Dermatology.

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.

Hydrocortisone (cortisol) is the principal endogenous glucocorticoid. FDA-approved products include oral tablets (Cortef), oral granules (Alkindi Sprinkle), injection (Solu-Cortef, hydrocortisone sodium succinate), rectal enema and foam, and topical creams, ointments and lotions (Rx strengths up to 2.5%; 0.5% and 1% available OTC). Topical hydrocortisone is a low-potency corticosteroid. Compounded topical preparations combine hydrocortisone with other actives, such as in pigmentation formulas, to reduce irritation.

• Topical (for example hydrocortisone cream 2.5%): relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.
• Oral and injectable: replacement therapy in primary or secondary adrenal insufficiency and congenital adrenal hyperplasia, and a range of endocrine, rheumatic, allergic, dermatologic, hematologic, respiratory and other inflammatory conditions. Rectal: ulcerative colitis and proctitis.
• Prescribers use hydrocortisone in compounded topical combinations, including with hydroquinone, tretinoin and kojic acid. Dosing is as prescribed.

Hydrocortisone binds the intracellular glucocorticoid receptor; the complex moves to the nucleus and alters gene transcription, increasing anti-inflammatory proteins such as lipocortins and suppressing cytokines, prostaglandins and leukotrienes. Topically, it has anti-inflammatory, antipruritic and vasoconstrictive actions. Hydrocortisone also has mineralocorticoid activity at systemic doses.

Oral bioavailability is high (about 95%). Hydrocortisone is extensively bound to corticosteroid-binding globulin and albumin, metabolized in the liver mainly by CYP3A4 and by 11-beta-hydroxysteroid dehydrogenases, and excreted as metabolites in the urine. The plasma half-life is about 1.5 to 2 hours; biologic effects last 8 to 12 hours.

Percutaneous absorption depends on the vehicle, skin integrity, anatomic site, area treated and occlusion; absorption is low through intact forearm skin and higher on the face, scrotum, intertriginous areas and inflamed skin, and in children.

• Known hypersensitivity to hydrocortisone or any ingredient of the product.
• Systemic products: systemic fungal infections (Cortef) and, for immunosuppressive doses, administration of live or live-attenuated vaccines.

• Topical: reversible HPA-axis suppression, Cushing syndrome, hyperglycemia and glucosuria can occur with extensive, prolonged or occlusive use, especially in children. Local skin atrophy, striae, telangiectasia, perioral dermatitis, acneiform eruptions and hypopigmentation can occur. Avoid the eyes; ocular use risks cataract and glaucoma. Topical steroids can mask or worsen skin infections.
• Systemic: adrenal suppression and acute adrenal insufficiency on abrupt withdrawal; increased risk and masking of infections; hyperglycemia; hypertension, sodium and fluid retention and hypokalemia; osteoporosis; myopathy; psychiatric effects; peptic ulcer; cataract and glaucoma; growth suppression in children; Kaposi sarcoma.

• Systemic use: strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin) increase and CYP3A4 inducers (rifampin, phenytoin, carbamazepine, phenobarbital) decrease hydrocortisone exposure. Estrogens raise corticosteroid-binding globulin.
• Systemic use also interacts with NSAIDs and aspirin (GI risk), warfarin (altered INR), antidiabetic drugs (higher glucose), potassium-depleting diuretics and amphotericin B (hypokalemia), digoxin (arrhythmia with hypokalemia) and vaccines (reduced response). Clinically significant interactions are not expected with limited topical use.

Topical: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, skin atrophy, striae and miliaria. Systemic: fluid retention, weight gain, hyperglycemia, hypertension, mood changes and insomnia, increased appetite, impaired wound healing, infections, bone loss and cushingoid features.

Systemic corticosteroids have shown teratogenic effects in animal studies; human data do not show a consistent increase in major malformations, though some studies suggest a small increase in oral clefts with first-trimester use. Infants exposed to high maternal doses should be watched for adrenal suppression. Low-potency topical hydrocortisone on limited areas is generally considered acceptable. Hydrocortisone is present in breast milk; avoid applying topical products to the nipple area.

Topical: response, local skin changes and, with extensive or prolonged use (especially in children), signs of HPA-axis suppression; morning cortisol or ACTH stimulation testing if suspected. Systemic: blood pressure, weight, blood glucose, electrolytes, signs of infection, bone density with long-term use, eye examinations, growth in children, and adrenal function when tapering.

• Cortef (hydrocortisone tablets) Prescribing Information, Pfizer.
• Solu-Cortef (hydrocortisone sodium succinate for injection) Prescribing Information, Pfizer.
• Hydrocortisone Cream USP 2.5% Prescribing Information.