HQ/Kojic/Niacinamide/Ascorbic/Tranexamic

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.

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.

Niacinamide, also called nicotinamide, is the amide form of vitamin B3. It is sold as a dietary supplement and is widely used in cosmetic skin products. It is distinct from niacin (nicotinic acid), which is FDA-approved for dyslipidemia and causes flushing. Lake Hills Pharmacy uses niacinamide bulk substance in compounded topical preparations.

As a vitamin, nicotinamide is used to prevent and treat niacin deficiency (pellagra). Prescribers use topical niacinamide in compounded dermatology preparations for acne, rosacea, hyperpigmentation and skin barrier support, and oral nicotinamide in patients at high risk of nonmelanoma skin cancer.

Niacinamide is a precursor of NAD+ and NADP+, cofactors for cellular redox reactions, energy metabolism and DNA repair. In skin it reduces transfer of melanosomes from melanocytes to keratinocytes, increases synthesis of ceramides and other stratum corneum lipids to strengthen the barrier and reduce water loss, and has anti-inflammatory effects, including reduced cytokine release and neutrophil chemotaxis. It may also reduce sebum production. It does not cause the prostaglandin-mediated flushing seen with niacin.

Orally, niacinamide is rapidly absorbed and widely distributed. It is metabolized in the liver, chiefly to N-methylnicotinamide and pyridone derivatives, which are excreted in the urine; more unchanged drug appears in the urine at high doses. Topically, it penetrates the stratum corneum, and systemic exposure from topical use is small relative to dietary intake.

• Hypersensitivity to niacinamide or any component of the preparation.

• Topical: irritation, burning and itching can occur. In some formulations niacinamide can hydrolyze to nicotinic acid, which may cause transient flushing or redness.
• Oral high doses (grams per day): liver toxicity has been reported at very high doses; use caution in liver disease. Gastrointestinal upset is common at high doses.
• Thrombocytopenia has been reported with oral nicotinamide in patients on dialysis.

• Oral nicotinamide may raise concentrations of carbamazepine and primidone by reducing their clearance.
• No clinically relevant interactions are known for topical use.

Topical: mild burning, stinging, itching, redness and dryness; contact dermatitis is uncommon. Oral: nausea, diarrhea, flatulence, dizziness, headache and rash; liver enzyme elevation at very high doses.

Nicotinamide is a normal nutrient, and topical use is not expected to raise systemic exposure meaningfully above dietary intake. Safety of high-dose oral supplementation in pregnancy and lactation has not been established.

Topical: skin tolerability and clinical response. High-dose oral use: periodic liver tests, and blood counts in patients on dialysis.

• Martindale: The Complete Drug Reference, nicotinamide monograph.
• Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline, Institute of Medicine (National Academies).
• Niacin Fact Sheet for Health Professionals, NIH Office of Dietary Supplements.

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.

Tranexamic acid is a synthetic lysine analog antifibrinolytic (trans-4-aminomethylcyclohexanecarboxylic acid). US products are Lysteda 650 mg tablets, Cyklokapron 100 mg/mL injection and generic equivalents. Lake Hills Pharmacy uses tranexamic acid in compounded topical preparations.

• Lysteda (oral): treatment of cyclic heavy menstrual bleeding.
• Cyklokapron (intravenous): short-term use in patients with hemophilia to reduce or prevent hemorrhage and reduce the need for replacement therapy during and after tooth extraction.
• Prescribers use tranexamic acid off-label in surgical and trauma bleeding, and in compounded topical preparations for melasma and other hyperpigmentation disorders. No FDA-labeled topical product exists.

Tranexamic acid competitively blocks the lysine-binding sites on plasminogen, preventing plasminogen from binding to fibrin and being converted to plasmin, which inhibits fibrinolysis; at high concentrations it also inhibits plasmin directly. In skin, plasmin activity in keratinocytes promotes release of arachidonic acid and growth factors that stimulate melanocytes. By limiting this pathway, tranexamic acid reduces melanogenesis and may reduce the dermal vascular component of melasma.

Oral bioavailability is about 45%, with peak levels about 3 hours after a dose and an elimination half-life of about 11 hours (Lysteda). Protein binding is low (about 3%, mainly to plasminogen). More than 95% is excreted unchanged in the urine by glomerular filtration, so systemic doses are reduced in renal impairment. It crosses the placenta and enters breast milk. Systemic absorption after topical application is expected to be low but has not been well characterized.

• Lysteda: active thromboembolic disease; history or intrinsic risk of thrombosis or thromboembolism, including retinal vein or artery occlusion; hypersensitivity to tranexamic acid.
• Cyklokapron: subarachnoid hemorrhage; active intravascular clotting; hypersensitivity to tranexamic acid.

• Thromboembolic risk: higher with combined hormonal contraceptives, especially in women who are obese or smoke, and with procoagulant concentrates.
• Route errors: inadvertent intrathecal or neuraxial injection of tranexamic acid has caused seizures, cardiac arrhythmias and death; the injection is for intravenous use only.
• Seizures have occurred with high intravenous doses, particularly during cardiovascular surgery.
• Visual disturbances, including changes in color vision and retinal venous or arterial occlusion, have been reported; patients with visual changes need ophthalmologic evaluation and should stop the drug.
• Hypersensitivity reactions, including anaphylaxis, can occur. Dizziness may impair driving.

• Combined hormonal contraceptives: increased risk of thrombosis.
• Factor IX complex concentrates and anti-inhibitor coagulant concentrates: increased thrombotic risk.
• All-trans retinoic acid (oral tretinoin) in acute promyelocytic leukemia: may worsen the procoagulant effect.
• No clinically relevant interactions are established for topical use.

Oral: headache, nasal and sinus symptoms, back and abdominal pain, musculoskeletal pain, arthralgia, muscle cramps, anemia, fatigue, nausea, vomiting and diarrhea. Intravenous: hypotension with rapid injection, seizures, visual disturbances and thromboembolic events. Topical: erythema, irritation, dryness and scaling.

Tranexamic acid crosses the placenta, with cord blood levels similar to maternal levels; human data have not shown a clear risk, but data are limited, and Lysteda is not indicated in pregnancy. It is present in breast milk at about one hundredth of the maternal serum concentration. Systemic exposure from topical use is expected to be low.

For systemic use: symptoms of venous or arterial thrombosis, visual symptoms and renal function for dose adjustment. For topical use: skin tolerability and response, with attention to thrombotic history in patients with risk factors.

• Lysteda (tranexamic acid) Tablets Prescribing Information.
• Cyklokapron (tranexamic acid) Injection Prescribing Information, Pfizer.
• Martindale: The Complete Drug Reference, tranexamic acid monograph.