General Information: Hydroquinone, tretinoin (retinoic acid), kojic acid, and hydrocortisone can be used together in a topical preparation to lighten the appearance of melasma. Melasma is a condition characterized by a darkening of the skin on the face caused by a change in hormones, such as pregnancy or beginning oral contraceptive or hormone replacement therapy. With proper avoidance of sun exposure, the use of hydroquinone-tretinoin-kojic acid-hydrocortisone topical cream can resolve the treated melasma spots. This drug combination is not intended for long-term treatment of melasma and does not permanently cure skin melasma. Once this treatment is discontinued, repigmentation will occur in the affected areas, although patients can continue to be managed with other treatments.
Mechanism of Action: Topical hydroquinone-tretinoin-kojic acid-hydrocortisone cream can be effective at reducing hyperpigmentation associated with melasma of the face. Improvements are usually noticed within the first month of treatment. Brown spots begin to fade at around six to eight weeks. Discontinuation of treatment usually results in a loss of pharmacologic effect, with remission periods appearing to shorten between progressive courses of treatment.
- Hydroquinone: Hydroquinone inhibits melanin formation by blocking the enzymatic oxidation of tyrosine to 3,4-dihydroxyphenylalanine (DOPA) in melanocytes. Other melanocyte metabolic processes are also inhibited. Exposure to sunlight or ultraviolet light will cause re-pigmentation of bleached areas.
- Tretinoin: The mechanism of action of tretinoin as a depigmenting agent is unknown. Tretinoin is a retinoid and thus is a natural ligand for retinoic acid receptors (RARs). Available evidence strongly suggests that retinoid actions are mediated by RARs. Retinoic acid receptors bind to regulatory regions in DNA called retinoic acid response elements (RARE) or target sequences, and activate gene transcription. The skin effects of topical tretinoin must somehow occur through regulated gene expression, which then modulates skin growth and pigmentation. Increased shedding of melanin-laden keratinocytes from the retinoid-treated epidermis is likely to result in decreased melanin content within the epidermal layer. In melanocytes, tretinoin significantly reduces the size of the endoplasmic reticulum and the Golgi complex.1 In vitro, tretinoin inhibits tyrosinase and thus tretinoin may also reduce melanin production. Tretinoin does not inhibit resting or basal levels of tyrosinase activity. Therefore, topical tretinoin is unlikely to result in hypopigmentation of normal skin.1
- Kojic Acid: Kojic acid is a chelation agent. It is a mild inhibitor of the formation of pigment in plant and animal tissues, and is used in food and cosmetics to preserve or change colors of substances. It is often used in cosmetics to lighten skin.
- Hydrocortisone: Endogenous corticosteroids are secreted by the adrenal cortex, and their effects are believed to be due to enzyme modification rather than to a direct hormone-induced action. The antiinflammatory actions of corticosteroids are thought to involve induction of phospholipase A2 inhibitory proteins. Early anti-inflammatory effects of topical corticosteroids include the inhibition of macrophage and leukocyte movement and activity in the inflamed area by reversing vascular dilation and permeability. Later inflammatory processes such as capillary production, collagen deposition, keloid (scar) formation also are inhibited by corticosteroids.Corticosteroids are loosely classified into two categories, mineralocorticoids and glucocorticoids, depending on their primary pharmacological activity. Mineralocorticoids alter electrolyte and fluid balance by facilitating sodium resorption and hydrogen and potassium excretion at the level of the distal renal tubule, resulting in edema and hypertension. Glucocorticoids exert some mineralocorticoid effects but are also involved in a number of other metabolic pathways including gluconeogenesis, fat redistribution, protein metabolism, and calcium balance. Hydrocortisone possesses both mineralocorticoid actions and glucocorticoid actions. Early anti-inflammatory effects of topical corticosteroids include the inhibition of macrophage and leukocyte movement and activity in the inflamed area by reversing vascular dilation and permeability. Later inflammatory processes such as capillary production, collagen deposition, keloid (scar) formation also are inhibited by corticosteroids. Clinically, these actions correspond to decreased edema, erythema, pruritus, plaque formation and scaling of the affected skin.
- Hydroquinone: It is not known whether percutaneous absorption of hydroquinone occurs. Absorption of a topically applied drug may be affected by the conditions of the epidermis including overall pH, disease state, and genetically driven factors such as oiliness or dryness of the skin. The rate of absorption can affect the efficacy and tolerability of hydroquinone.
- Tretinoin: Following topical application, a minimal amount of drug is absorbed systemically. There is no expected difference in the systemic absorption of tretinoin from the microsphere formulation. Prolonged treatment or application to large body surface areas can enhance systemic absorption. Approximately 1—5% of a topically applied dose is excreted in the urine within 24 hours.
- Hydrocortisone: Systemic absorption after topical application of hydrocortisone is dependant on the vehicle, the state of the skin at the application site, the use of occlusive dressings, and the age of the patient. Absorption is increased in areas that have skin damage, inflammation, or occlusion, or where the stratum corneum is thin such as the eyelids, genitalia, and face. Factors that can increase systemic absorption of topical hydrocortisone include occlusive dressings, large surface area, frequent application, longer duration of treatment, increased humidity or temperature, and younger age.2 Topical preparations distribute throughout the area of application but are only minimally absorbed into the circulation. Topical preparations of hydrocortisone are metabolized in the skin.
- A proper skin care and sun avoidance program including avoidance of the sun and protective clothing should accompany the use of this cream. The concurrent use of daily sunscreen with SPF 30 is recommended both during and after discontinuation of treatment.
- Wash hands before and after application.
- Apply cream at least 30 minutes before bedtime.
- After washing the face with a mild, soapless cleanser, apply a thin layer of the cream topically with the fingers to the areas of discoloration and also to roughly one-half inch of the surrounding, normally colored skin on the face; the cream should be massaged gently into the affected areas until no longer visible.
- Do not cover the treated area with an occlusive dressing.
- Do not apply the cream to the eye area; avoid contact with the mouth, eyes, and other mucous membranes. If contact with the eye(s) occur, the eye(s) should be washed with large amounts of water; contact prescriber if ocular irritation persists. Do not use on irritated, denuded, or damaged skin.
hydroquinone-tretinoin-kojic acid-hydrocortisone topical cream is contraindicated for use if hypersensitivity to the cream components is present, including sulfite hypersensitivity and corticosteroid hypersensitivity. Cutaneous hypersensitivity reactions have been reported with the use of hydroquinone-tretinoin-kojic acid-hydrocortisone. Hydroquinone-tretinoin-kojic acid-hydrocortisone topical cream is a dermal irritant and the safety and efficacy of long-term use (> 8 weeks) has not been evaluated. Hydroquinone-tretinoin-kojic acid-hydrocortisone is for external use only; avoid accidental exposure to the mouth, paranasal creases, and mucous membranes. Care should also be taken to avoid ocular exposure.
Tretinoin has been reported to cause severe irritation on eczematous skin, therefore hydroquinone-tretinoin-kojic acid-hydrocortisone should be used with the utmost caution in patients with eczema.
Because of heightened burning susceptibility, sunlight (UV) exposure to treated areas should be avoided or minimized during the use of hydroquinone-tretinoin-kojic acid-hydrocortisone cream. Patients should use protective clothing and comply with a comprehensive sun avoidance program. It is not known whether hydroquinone-tretinoin-kojic acid-hydrocortisone is degraded (either by sunlight or interior lighting) following application to the skin. Patients with sunburn should be advised not to use hydroquinone-tretinoin-kojic acid-hydrocortisone until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise caution when using this product. Hydroquinone-tretinoin-kojic acid-hydrocortisone should not be administered if the patient is taking concurrent photosensitizing drugs due potential for additive photosensitivity.
Systemic absorption of topical corticosteroids such as hydrocortisone can produce reversible hypothalamic-pituitary-adrenal (HPA) suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. Conditions that increase systemic absorption of fluocinolone include use over large surface areas, prolonged use, use in areas where the epidermal barrier is disrupted (i.e., skin abrasion), and the use of an occlusive dressing (which should be avoided with the use of this product). If HPA axis suppression is noted, an attempt should be made to withdraw the use of hydroquinone-tretinoin-kojic acid-hydrocortisone or to reduce the frequency of application.
The safety and effectiveness of hydroquinone-tretinoin-kojic acid-hydrocortisone has not been established in pediatric patients. Children and infants may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. Hydroquinone-tretinoin-kojic acid-hydrocortisone cream should not be used in children.
Topical corticosteroids, like hydrocortisone should be used with caution in individuals with dermatological infections; the normal inflammatory response to local infections can be masked by hydrocortisone. Application of any product containing topical corticosteroids to areas of infection, including tuberculosis of the skin, dermatologic fungal infection, and cutaneous or systemic viral infection (e.g., herpes infection, measles, varicella), should be initiated or continued only if the appropriate anti-infective treatment is instituted.
Pregnancy: The components of hydroquinone-tretinoin-kojic acid-hydrocortisone cream are defined by the FDA as pregnancy risk category C; it is important to consider that the potential fetal risk of this drug will more than likely outweigh any benefits in the treatment of melasma. No adequate or well-controlled trials have been conducted with hydroquinone-tretinoin-kojic acid-hydrocortisone cream in pregnant women. This cream is recommended to be avoided in pregnancy or in females who are trying to become pregnant. There have been observations of teratogenic/embryotoxic effects of tretinoin and other retinoids at topically applied doses in rats and rabbits. Corticosteroids have also been shown to be teratogenic in animals when administered systemically at relatively low dosages. Some corticosteroids have been shown to be teratogenic after dermal application in animals. Females of childbearing potential should practice adequate contraception.3
Breast-feeding: It is not known whether hydroquinone-tretinoin-kojic acid-hydrocortisone is distributed into breast milk, and caution should be exercised when administering hydroquinone-tretinoin-kojic acid-hydrocortisone during breast-feeding.3 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Corticosteroids distribute into breast milk, and the manufacturer of systemic hydrocortisone products states that a decision to nurse requires weighing the possible benefits of the drug against the potential hazards to the mother and infant.4 Hydrocortisone has not been studied during breast feeding, however (hydrocortisone) cortisol is a normal component of breast milk. While the American Academy of Pediatrics does not comment on the use of hydrocortisone during breast-feeding, it does consider other corticosteroids (prednisone and prednisolone) to be usually compatible with breast-feeding.5 It is not known whether topical administration of hydrocortisone could result in sufficient systemic absorption to produce detectable quantities in breast milk; however, increased blood pressure has been reported in an infant whose mother applied a topical corticosteroid ointment directly to the nipples. If applied topically, care should be used to ensure the infant will not come into direct contact with the area of application. Most authorities recommend caution when prescribing topical corticosteroids to breast-feeding women. Otic products containing hydrocortisone as a component appear to pose minimal corticosteroid risk, given the low dosage and limited area and limited duration of usual use. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Adverse Reactions: Application of high concentrations or prolonged use of hydroquinone, a component of hydroquinone-tretinoin-kojic acid-hydrocortisone, can produce skin hyperpigmentation, especially on areas exposed to sunlight. Exogenous ochronosis (blue-black skin hyperpigmentation or skin discoloration) has been reported and is considered to be an adverse reaction to hydroquinone rather than an idiosyncratic reaction. Ochronosis may develop at any time during use and may be irreversible once established. Treatment should be discontinued if this occurs. The majority of patients who develop ochronosis are African-American, but it may also occur in Caucasians and Hispanics. Reversible brown nail discoloration of the hand may also occur when applying hydroquinone.3
Application of hydroquinone-tretinoin-kojic acid-hydrocortisone to the paranasal and infraorbital areas increases the risk of skin irritation; xerosis and fissuring has occurred in these areas. Hydroquinone has been associated with corneal staining and corneal opacification if applied to the eye; hydroquinone-tretinoin-kojic acid-hydrocortisone should not be applied to the eye.3
During topical hydroquinone-tretinoin-kojic acid-hydrocortisone therapy increased photosensitivity may be seen. During treatment patients should use sunscreen (minimum SPF 30) and protective clothing. Patients with a sunburn should not use hydroquinone-tretinoin-kojic acid-hydrocortisone until fully recovered.3
Systemic absorption of topical corticosteroids such as hydrocortisone can produce reversible hypothalamic-pituitary-adrenal (HPA) suppression with possible adrenocortical insufficiency after stopping treatment. In some patients, systemic absorption can produce manifestations of Cushing's syndrome, hyperglycemia, and glycosuria. If HPA axis suppression is noted during treatment with fluocinolone; hydroquinone; tretinoin, an attempt should be made to withdraw the drug or reduce the frequency of application.3
In general, excessive use of corticosteroids can lead to impaired wound healing. Since hydrocortisone is a topical corticosteroid, hydroquinone-tretinoin-kojic acid-hydrocortisone should not be applied directly or near healing wounds. A propensity for skin ulcer may develop in patients with markedly impaired circulation who use topical corticosteroids. Additionally, adverse reactions that have been reported with topical corticosteroids may occur with the use of hydroquinone-tretinoin-kojic acid-hydrocortisone, and include: burning, itching, irritation, dryness, folliculitis, acneiform eruptions, skin hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, and miliaria. Of note, these reactions may occur more frequently with the use of occlusive dressings, especially with higher potency corticosteroids.3
Hydroquinone has also been associated with a bitter taste (dysgeusia) and anesthetic effect if applied to the lips; avoid application of this product to the lips. Additionally reported adverse events include paresthesias (3%), hyperesthesia (2%), and xerostomia (1%).3
Storage: Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.
- 1. Kang S. Photoaging and tretinoin. Dermatol Clin 1998;16:357-364.
- 2. Morley KW, Dinulos JG. Update on topical glucocorticoid use in children. Curr Opin Pediatr 2012;24(1):121-128
- 3. Tri-Luma (fluocinolone; hydroquinone; tretinoin) cream package insert. Fort Worth, TX: Galderma Laboratories, L.P.; 2014 Apr.
- 4. Cortef (hydrocortisone tablets, USP) package insert. New York, NY: Pharmacia & Upjohn Co., Inc.; 2016 Jul.
- 5. American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776-89.