HQ/Tretinoin/Azelaic

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.