Tretinoin/Hyaluronic Acid/Ascorbic Acid

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.

Hyaluronic acid (hyaluronan; sodium hyaluronate as the salt) is a naturally occurring glycosaminoglycan made of repeating units of glucuronic acid and N-acetylglucosamine. FDA regulates hyaluronic acid products mainly as medical devices: injectable dermal fillers, intra-articular viscosupplements, ophthalmic viscosurgical devices and some topical wound dressings. It is also a common cosmetic ingredient. Compounding pharmacies use it as a humectant component of topical preparations.

Device uses cleared or approved by FDA include correction of facial wrinkles and folds and lip augmentation (dermal fillers), knee osteoarthritis pain (intra-articular viscosupplements) and protection of eye tissues during ophthalmic surgery. In compounded topical preparations, prescribers include hyaluronic acid as a humectant to support skin hydration, often alongside retinoids.

Hyaluronic acid binds large amounts of water, forming a viscoelastic film on the skin surface and holding moisture in the stratum corneum. In tissues it contributes to the extracellular matrix, lubrication and tissue hydration and interacts with cell-surface receptors such as CD44. Effects depend on molecular weight: high-molecular-weight forms stay mainly on the skin surface, while lower-molecular-weight fragments penetrate the outer skin layers to a limited degree.

Topically applied high-molecular-weight hyaluronic acid has minimal systemic absorption. Endogenous hyaluronan turns over rapidly, with a half-life of about one day in skin, and is degraded by hyaluronidases and reactive oxygen species; fragments are cleared through the lymphatics and metabolized in the liver. Cross-linked injectable devices persist for months because cross-linking slows enzymatic breakdown.

• Hypersensitivity to hyaluronic acid or any component of the preparation.
• For avian-derived hyaluronic acid (some devices), allergy to avian proteins, feathers or eggs; most current products are made by bacterial fermentation.

• Topical use is generally well tolerated; irritation is more often caused by other actives in a combination, such as tretinoin.
• Do not apply to infected or broken skin unless directed.
• Injectable dermal fillers carry device warnings, including unintentional injection into blood vessels that can cause skin necrosis, vision loss and stroke. FDA has warned against use of needle-free devices to inject hyaluronic acid fillers.
• Intra-articular products: use caution with infection or skin disease at the injection site.

No clinically important drug interactions are known for topical use. Hyaluronidase degrades hyaluronic acid and is used to dissolve hyaluronic acid fillers. Quaternary ammonium disinfectants such as benzalkonium chloride can precipitate sodium hyaluronate, which matters for formulation and device labeling.

Topical: rare mild irritation, redness or itching. Dermal fillers: swelling, bruising, tenderness, nodules, delayed inflammatory reactions and rare vascular occlusion. Intra-articular injection: injection-site pain, joint swelling and effusion.

No data exist for compounded topical use in pregnancy or lactation. Hyaluronic acid is an endogenous substance and topical systemic exposure is expected to be minimal. In combination products, the other actives (for example tretinoin) usually determine pregnancy guidance.

• Topical use: local tolerability.
• No laboratory monitoring is required.

• European Pharmacopoeia monograph: Sodium Hyaluronate.
• Martindale: The Complete Drug Reference (hyaluronic acid).
• USP General Chapter <795> Pharmaceutical Compounding: Nonsterile Preparations.

Ascorbic acid (vitamin C) is an essential water-soluble vitamin and antioxidant. FDA-approved forms include ascorbic acid injection (Ascor). Oral vitamin C is widely sold as a dietary supplement, and L-ascorbic acid is used in topical skin preparations. Lake Hills Pharmacy uses ascorbic acid as an ingredient in compounded preparations, as a 503A pharmacy on patient-specific prescriptions.

Ascor (ascorbic acid injection) is FDA labeled for short-term (up to 1 week) treatment of scurvy in adults and pediatric patients 5 months and older when oral administration is not possible, insufficient or contraindicated. Prescribers use topical ascorbic acid in compounded skin preparations, often with other depigmenting agents, as an antioxidant and tyrosinase-modulating ingredient. There is no FDA-labeled topical indication.

Ascorbic acid is an electron donor. It is a cofactor for enzymes including prolyl and lysyl hydroxylases needed for collagen synthesis, and for enzymes in carnitine and catecholamine synthesis. It scavenges reactive oxygen species and regenerates vitamin E. In skin it reduces dopaquinone and interacts with copper at the tyrosinase active site, which lowers melanin formation.

Oral absorption occurs by saturable sodium-dependent transport (SVCT1), so the fraction absorbed falls as the dose rises, and plasma concentrations plateau with high oral intake. Intravenous dosing bypasses this limit. Ascorbic acid is oxidized to dehydroascorbic acid and metabolized in part to oxalate; amounts above the renal threshold are excreted in urine. Topical L-ascorbic acid penetrates skin most readily at low pH and is unstable in air and light, oxidizing and discoloring over time.

• Known hypersensitivity to ascorbic acid or any component of the preparation.

• Oxalate nephropathy and kidney stones: high doses, particularly intravenous, increase urinary oxalate. Use caution in renal impairment, prior oxalate stones or hyperoxaluria.
• Hemolysis: high doses can cause hemolysis in patients with G6PD deficiency. Screen at-risk patients before high-dose systemic use.
• Laboratory interference: high plasma concentrations can falsely raise point-of-care glucose meter readings and interfere with other assays, including some urine glucose and fecal occult blood tests.
• Iron overload: ascorbic acid increases nonheme iron absorption; use caution in hemochromatosis and other iron overload states.
• Topical use: stinging, erythema and dryness can occur, especially at low pH or on sensitized skin.

• Deferoxamine: in iron-overloaded patients, adding ascorbic acid has been associated with impaired cardiac function; deferoxamine labeling advises limiting the dose and timing.
• Iron: oral ascorbic acid enhances absorption of nonheme iron.
• Urinary acidification with large doses may alter renal excretion of some weakly acidic or basic drugs.
• No clinically important interactions are established for topical use.

Systemic: nausea, abdominal cramps and diarrhea with large oral doses; injection-site pain; dizziness and flushing with infusion; kidney stones and oxalate nephropathy at high doses; hemolysis in G6PD deficiency. Topical: stinging, redness, dryness and, rarely, contact dermatitis or yellow discoloration of skin or hair.

Ascorbic acid crosses the placenta and passes into breast milk. Intake at nutritional levels is considered compatible with pregnancy and breastfeeding. Data on high-dose systemic use are limited; it is a prescriber decision. Topical use is not expected to change systemic levels meaningfully.

For systemic high-dose use: renal function, G6PD status where indicated, and awareness of glucose meter interference. For topical use: skin tolerability at intervals set by the prescriber.

• Ascor (ascorbic acid injection) Prescribing Information, McGuff Pharmaceuticals.
• Desferal (deferoxamine mesylate) for Injection Prescribing Information, Novartis.
• Lexicomp Drug Information, Wolters Kluwer.