This monograph discusses the topical use of fluocinolone; hydroquinone; tretinoin combination product for the management of melasma. Clinicians may wish to consult the individual monographs for more information about each agent.
Fluocinolone, hydroquinone, and tretinoin (all-trans retinoic acid) are 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. Two studies of the efficacy and safety of fluocinolone-hydroquinone-tretinoin for the treatment of melasma demonstrated that the combination of the three drugs was superior to any combination containing two of the three active ingredients. With proper avoidance of sun exposure, the use of fluocinolone-hydroquinone-tretinoin topical cream will resolve the treated melasma spots in 13-38% of patients, although few patients maintain complete clearing of melasma (1-2%). 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. Tri-Luma(TM) cream was granted FDA approval for the treatment of melasma in May 2002.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-Tretinoin is classified as a hazardous drug.
-NIOSH 2016 List: Group 3
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Topical Administration
-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.
The most common adverse reactions to topical fluocinolone; hydroquinone; tretinoin therapy is irritation of mild to moderate severity, including burning (18%), desquamation (38%), dryness (14%), erythema (41%), and pruritus (11%). Other adverse skin events include acne vulgaris (5%), telangiectasia (3%), pigmentary changes (2%), skin irritation (2%), papules (1%), acneiform rash (1%), rosacea (1%), rash (unspecified) (1%), and vesicles (1%). Skin sensitization and contact dermatitis may occur. If severe erythema, edema, vesicle formation, or crusting develops, fluocinolone; hydroquinone; tretinoin should be discontinued until skin integrity is restored. Therapy may be reinitiated with consideration of less frequent application.
Application of high concentrations or prolonged use of hydroquinone, a component of fluocinolone; hydroquinone; tretinoin, 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.
Application of fluocinolone; hydroquinone; tretinoin 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; fluocinolone; hydroquinone; tretinoin should not be applied to the eye.
During topical fluocinolone; hydroquinone; tretinoin 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 fluocinolone; hydroquinone; tretinoin until fully recovered.
Systemic absorption of topical corticosteroids such as fluocinolone 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.
In general, excessive use of corticosteroids can lead to impaired wound healing. Since fluocinolone is a topical corticosteroid, fluocinolone; hydroquinone; tretinoin 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 fluocinolone; hydroquinone; tretinoin, 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.
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%).
This monograph discusses the topical use of fluocinolone, hydroquinone and tretinoin combination product. Clinicians may wish to consult the individual drug monographs for more information about the contraindications and precautions of each agent.
Fluocinolone; hydroquinone; tretinoin 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 fluocinolone; hydroquinone; tretinoin. Fluocinolone; hydroquinone; tretinoin topical cream is a dermal irritant and the safety and efficacy of long-term use (> 8 weeks) has not been evaluated. Fluocinolone; hydroquinone; tretinoin 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 fluocinolone; hydroquinone; tretinoin 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 fluocinolone; hydroquinone; tretinoin cream. Patients should use protective clothing and comply with a comprehensive sun avoidance program. It is not known whether fluocinolone; hydroquinone; tretinoin is degraded (either by sunlight or interior lighting) following application to the skin. Patients with sunburn should be advised not to use fluocinolone; hydroquinone; tretinoin 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. Fluocinolone; hydroquinone; tretinoin should not be administered if the patient is taking concurrent photosensitizing drugs (see Drug Interactions) due potential for additive photosensitivity.
Fluocinolone; hydroquinone; tretinoin is 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 fluocinolone; hydroquinone; tretinoin 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.
According to the manufacturer, it is not known whether fluocinolone, hydroquinone, or tretinoin is distributed into breast milk, and caution should be exercised when administering fluocinolone; hydroquinone; tretinoin during breast-feeding. 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.
Systemic absorption of topical corticosteroids such as fluocinolone 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 fluocinolone; hydroquinone; tretinoin or to reduce the frequency of application.
The safety and effectiveness of fluocinolone; hydroquinone; tretinoin 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. Fluocinolone; hydroquinone; tretinoin cream should not be used in children.
Topical corticosteroids, like fluocinolone; hydroquinone; tretinoin, should be used with caution in individuals with dermatological infections; the normal inflammatory response to local infections can be masked by fluocinolone. 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.
For the short-term (up to 8 weeks) treatment of moderate to severe melasma of the face resulting from pregnancy, hormone replacement therapy, or the use of oral contraceptives:
Topical dosage (Tri-Luma cream):
Adults: Apply cream topically to the affected area(s) once daily at night, at least 30 minutes before bedtime. Up to 4 weeks of therapy may be required before improvement is evident.
Adolescents and Children <= 18 years: Use not recommended.
Maximum Dosage Limits:
-Adults
No maximum dosage information is available.
-Elderly
No maximum dosage information is available.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Adapalene; Benzoyl Peroxide: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. (Minor) Keratolytic agents or products that contain keratolytic agents, such as benzoyl peroxide, can potentiate the skin irritation caused by hydroquinone and hydroquinone-containing products. Also, concurrent use of topical hydroquinone and topical peroxide (e.g., benzoyl peroxide) on the same area of skin can result in transient dark staining of the skin due to oxidation of hydroquinone. Removal of staining can be accomplished by discontinuing concurrent use and by normal soap cleansing. Concurrent application of such agents should generally be avoided.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Atenolol; Chlorthalidone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Azilsartan; Chlorthalidone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Benzoyl Peroxide: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. (Minor) Keratolytic agents or products that contain keratolytic agents, such as benzoyl peroxide, can potentiate the skin irritation caused by hydroquinone and hydroquinone-containing products. Also, concurrent use of topical hydroquinone and topical peroxide (e.g., benzoyl peroxide) on the same area of skin can result in transient dark staining of the skin due to oxidation of hydroquinone. Removal of staining can be accomplished by discontinuing concurrent use and by normal soap cleansing. Concurrent application of such agents should generally be avoided.
Benzoyl Peroxide; Clindamycin: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. (Minor) Keratolytic agents or products that contain keratolytic agents, such as benzoyl peroxide, can potentiate the skin irritation caused by hydroquinone and hydroquinone-containing products. Also, concurrent use of topical hydroquinone and topical peroxide (e.g., benzoyl peroxide) on the same area of skin can result in transient dark staining of the skin due to oxidation of hydroquinone. Removal of staining can be accomplished by discontinuing concurrent use and by normal soap cleansing. Concurrent application of such agents should generally be avoided.
Benzoyl Peroxide; Erythromycin: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. (Minor) Keratolytic agents or products that contain keratolytic agents, such as benzoyl peroxide, can potentiate the skin irritation caused by hydroquinone and hydroquinone-containing products. Also, concurrent use of topical hydroquinone and topical peroxide (e.g., benzoyl peroxide) on the same area of skin can result in transient dark staining of the skin due to oxidation of hydroquinone. Removal of staining can be accomplished by discontinuing concurrent use and by normal soap cleansing. Concurrent application of such agents should generally be avoided.
Benzoyl Peroxide; Sulfur: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. (Minor) Keratolytic agents or products that contain keratolytic agents, such as benzoyl peroxide, can potentiate the skin irritation caused by hydroquinone and hydroquinone-containing products. Also, concurrent use of topical hydroquinone and topical peroxide (e.g., benzoyl peroxide) on the same area of skin can result in transient dark staining of the skin due to oxidation of hydroquinone. Removal of staining can be accomplished by discontinuing concurrent use and by normal soap cleansing. Concurrent application of such agents should generally be avoided.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Chlorothiazide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Chlorpromazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Chlorthalidone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Ciprofloxacin: (Major) Avoid the concomitant use of tretinoin with other drugs known to cause photosensitivity, such as ciprofloxacin. Concomitant use with other photosensitizing agents may increase the risk of a photosensitivity reaction.
Clindamycin; Adapalene; Benzoyl Peroxide: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. (Minor) Keratolytic agents or products that contain keratolytic agents, such as benzoyl peroxide, can potentiate the skin irritation caused by hydroquinone and hydroquinone-containing products. Also, concurrent use of topical hydroquinone and topical peroxide (e.g., benzoyl peroxide) on the same area of skin can result in transient dark staining of the skin due to oxidation of hydroquinone. Removal of staining can be accomplished by discontinuing concurrent use and by normal soap cleansing. Concurrent application of such agents should generally be avoided.
Codeine; Phenylephrine; Promethazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Codeine; Promethazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Fluphenazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Gemifloxacin: (Major) Avoid the concomitant use of tretinoin with other drugs known to cause photosensitivity, such as gemifloxacin. Concomitant use with other photosensitizing agents may increase the risk of a photosensitivity reaction.
Glimepiride: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Glipizide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Glipizide; Metformin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Glyburide: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Glyburide; Metformin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Levofloxacin: (Major) Avoid the concomitant use of tretinoin with other drugs known to cause photosensitivity, such as levofloxacin. Concomitant use with other photosensitizing agents may increase the risk of a photosensitivity reaction.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Metolazone: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Metyrapone: (Major) Medications which affect pituitary or adrenocortical function, including all corticosteroid therapy, should be discontinued prior to and during testing with metyrapone. Patients taking inadvertent doses of corticosteroids on the test day may exhibit abnormally high basal plasma cortisol levels and a decreased response to the test. Although systemic absorption of topical corticosteroids is minimal, temporary discontinuation of these products should be considered if possible to reduce the potential for interference with the test results.
Moxifloxacin: (Major) Avoid the concomitant use of tretinoin with other drugs known to cause photosensitivity, such as moxifloxacin. Concomitant use with other photosensitizing agents may increase the risk of a photosensitivity reaction.
Ofloxacin: (Major) Avoid the concomitant use of tretinoin with other drugs known to cause photosensitivity, such as ofloxacin. Concomitant use with other photosensitizing agents may increase the risk of a photosensitivity reaction.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Perphenazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Perphenazine; Amitriptyline: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Phenothiazines: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Pioglitazone; Glimepiride: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Prochlorperazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Promethazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Promethazine; Dextromethorphan: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Promethazine; Phenylephrine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Sulfonylureas: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as sulfonylureas, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Thiazide diuretics: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Thioridazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Tretinoin; Benzoyl Peroxide: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. (Minor) Keratolytic agents or products that contain keratolytic agents, such as benzoyl peroxide, can potentiate the skin irritation caused by hydroquinone and hydroquinone-containing products. Also, concurrent use of topical hydroquinone and topical peroxide (e.g., benzoyl peroxide) on the same area of skin can result in transient dark staining of the skin due to oxidation of hydroquinone. Removal of staining can be accomplished by discontinuing concurrent use and by normal soap cleansing. Concurrent application of such agents should generally be avoided.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Trifluoperazine: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as phenothiazines, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Voriconazole: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and fluocinolone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and fluocinolone is a CYP3A4 substrate.
Topical fluocinolone-hydroquinone-tretinoin cream is 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.
-Fluocinolone: 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.
-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. 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.
Fluocinolone; hydroquinone; tretinoin is applied topically as a cream. Anti-inflammatory effects are usually not seen for hours after fluocinolone application, since the mechanism of action requires alterations in synthesis of proteins. Because fluocinolone is fluorinated and also contains a substituted 17-hydroxyl group, it is not metabolized in the skin. Fluocinolone is metabolized primarily in the liver and excreted by the kidneys.
-Route-Specific Pharmacokinetics
Topical Route
-Fluocinolone: The extent of percutaneous absorption of the topical corticosteroids is dependent on many factors, including the pharmaceutical vehicle and the integrity of the epidermis. Absorption after topical application of fluocinolone is increased in areas that have skin damage, inflammation, or occlusion, or in areas where the stratum corneum is thin such as the face. Repeated application results in a cumulative depot effect in the skin, which may lead to a prolonged duration of action and increased systemic absorption. Although, after once daily topical application of fluocinolone; hydroquinone; tretinoin cream to intact skin for eight weeks, plasma concentrations were below quantitation limit in study patients.
-Hydroquinone: After once daily topical application of fluocinolone; hydroquinone; tretinoin cream to intact skin for eight weeks, 18% of patients in clinical trials showed evidence of hydroquinone systemic absorption. The exposure to hydroquinone is reflected in Cmax values considered to be negligible, ranging from 25.55-86.52 ng/mL.
-Tretinoin: Following topical application, a minimal amount of drug is absorbed systemically. After once daily topical application of fluocinolone; hydroquinone; tretinoin cream to intact skin for eight weeks, tretinoin appeared to have minimal systemic absorption. The Cmax values for tretinoin ranged from 2-5.34 ng/mL, which reflects a minimal increase in normal endogenous levels of tretinoin.