Tretinoin, all trans -retinoic acid, is a retinoid.
Tretinoin is used topically for the treatment of acne vulgaris, principally grades I-III, in which comedones, papules, and pustules predominate. Tretinoin therapy is not curative and relapses generally occur within 3-6 weeks after the drug is discontinued. Best results are usually obtained in the treatment of early stages of acne vulgaris in which numerous comedones are present. The drug is not effective for the treatment of most cases of severe pustular and deep nodulocystic acne; however, it has been suggested that it may be used adjunctively in the management of associated comedones.
Tretinoin is used topically as a 0.05 or 0.1%† cream for palliative therapy to improve dermatologic changes (e.g., fine wrinkling, mottled hyperpigmentation, roughness) associated with photodamage.104, 105, 112, 113, 114, 115, 116, 117, 120, 122, 126, 128, 129 Clinical studies to date indicate that therapy with the drug may at least partially reverse photodamaged skin clinically and histologically.104, 105, 112, 113, 114, 115, 116, 117, 120, 122, 126, 128, 129 However, many patients can achieve desired palliative effects on certain photoaging-associated dermatologic changes without tretinoin by employing a comprehensive skin care plan, emollient creams, and a sun avoidance program that includes the use of effective sunscreens (minimum strength of SPF 15) and protective clothing.128 Therefore, topical tretinoin therapy should be used under medical supervision as an adjunct to a comprehensive skin care plan and sun avoidance program and should be reserved for patients who do not achieve the desired effects with such programs alone (i.e., without tretinoin).128 Patients should be advised that topical therapy with tretinoin does not eliminate wrinkles, repair photodamaged skin, reverse photoaging, or restore a more youthful or younger dermal histologic pattern, and that most of the mitigating effects of tretinoin on fine wrinkles, mottled hyperpigmentation, and tactile roughness of skin will be lost in the majority of patients once such combined, comprehensive therapy is discontinued.128 The manufacturer states that safety and efficacy of topical tretinoin therapy for photoaging beyond 48 weeks have not been established.128
Short-term (16-24 weeks) controlled studies in patients with mild to moderate photodamaged skin have shown that topical tretinoin 0.05 or 0.1% cream may reduce fine wrinkling and increase skin pinkness and, to a lesser degree, reduce coarse wrinkling and tactile roughness of the skin on the forearm and face of patients with photodamaged skin.104, 105, 112, 113, 114, 115, 121, 122, 126, 128, 129 However, after such improvement, deep coarse wrinkles and telangiectasis still will be evident, at least with short-term (4-6 months) therapy.105, 113, 122, 123, 126, 128 Similar findings of improved skin appearance, including improvements in fine wrinkles, mottled hyperpigmentation, and roughness, have been noted in several other placebo-controlled studies in patients with mild to moderately severe photodamaged skin receiving topical tretinoin (0.05 or 0.1%) cream therapy for up to 12 months.113, 114, 115, 116, 117, 120, 121, 122, 126, 128 In 2 studies employing a 0.05% tretinoin cream to the face, moderate improvements in these respective findings (manifested as a 2-point reduction in a 10-point scale of photodamage severity) were observed in 24, 38, and 16% of patients at 24 weeks;128 minimal improvements (manifested as a 1-point reduction in severity) were observed in 27-40% of patients and no improvement was observed in 35-49% of patients.128 Most patients also were instructed to avoid sun exposure and to use an effective sunscreen.113, 114, 115, 116, 117, 120, 121, 122, 128 Lentigines (hyperpigmented macules, liver spots) and solar-induced freckling also may show improvement (e.g., lightening or disappearance);105, 117 in one study employing tretinoin 0.1% cream for 10 months, hyperpigmented areas did not return during a 6-month follow-up after discontinuance of the drug, and further improvement was observed in most other patients who continued tretinoin beyond 10 months.117 Some clinical improvement occasionally may be evident within 2 weeks of initiating therapy, consisting mainly of an increase in tightness and pinkness of the skin; clinically important changes in wrinkles usually are evident within 8 weeks.105, 121, 123, 129
Although the manufacturer states that safety and efficacy of topical tretinoin have not been established in patients with actinic keratoses†, 128 there is limited evidence that the drug also can reduce or eradicate microscopic actinic keratoses and improve clinically recognizable lesions in some patients with this condition.104, 105 However, macular, erythematous flare-ups of actinic keratoses may occur for several months prior to resolution or reduction in size.104, 105, 115, 121, 123, 125, 126 The manufacturer also states that safety and efficacy of topical tretinoin therapy have not been established for dermatologic neoplasms,128 nor have they been established for patients with moderately or heavily pigmented skin.128
The most frequent adverse effect associated with tretinoin therapy for photoaging is dermatitis, which occurs in almost all patients, is characterized by erythema, localized swelling, xerosis, and mild scaling, and often requires withholding one or more applications of the drug.104, 105, 125 Changes in the skin induced by the drug (e.g., thinned horny layer, amplified vasculature) also may result in increased reactivity to environmental (e.g., photosensitivity, wind and cold exposure) and other stimuli (e.g., excessive heat, diaphoresis, increased skin contact with jewelry, concomitant use of irritating cosmetics or facial saunas); in addition, patients may be more susceptible to the development of a sunburn within the first few months of topical tretinoin therapy.104, 105, 115, 123, 124, 125, 126, 128, 129
Tretinoin has been used topically for the treatment of flat warts†. The drug also has been used with topical fluorouracil for the temporary, initial combination therapy of multiple actinic (solar) keratoses† on areas other than the head and neck (e.g., hands, arms). In concentrations of 0.1-0.3%, tretinoin has been used topically for the treatment of other skin conditions† such as psoriasis, ichthyosis congenita, icthyosis vulgaris, lamellar icthyosis, keratosis palmaris et plantaris, epidermolytic hyperkeratosis, senile comedones, senile keratosis, keratosis follicularis (Darier's disease), and basal cell carcinomas. However, use of topical tretinoin in these conditions remains investigational.
For systemic uses of tretinoin (e.g., cancer), see Tretinoin 10:00.
Tretinoin is applied topically to the skin as a cream, gel, or solution. Patients should be instructed carefully in proper use of the drug, including associated precautions. (See Cautions: Precautions and Contraindications and also Drug Interactions.)
For the treatment of acne, tretinoin is applied topically to the cleansed, affected area, usually at bedtime. Tretinoin topical solution may be applied using clean fingertips, a gauze pad, or cotton swab. If gauze or cotton is used, oversaturation should be avoided so that the solution will not run onto areas not being treated. Excessive application of tretinoin gel results in “pilling” of the gel or “caking” of the gel containing microspheres, which minimizes the likelihood of overapplication by the patient.
For the treatment of photoaging or heliodermatitis, patients should gently wash their face with a mild soap, pat the skin dry, and wait 20-30 minutes before applying tretinoin cream to affected areas of the face with a clean fingertip, taking care to avoid the eyes, ears, nostrils, and mucous membranes and mouth.115, 117, 121, 123, 124, 126, 128, 129, 136 The topical cream is applied at bedtime using the minimum amount necessary to cover the affected area lightly.128, 136 Gentle washing of treated skin with the fingertips peels away loose outer layers of the skin that may form during tretinoin therapy, and some clinicians state that gentle use of a washcloth may help to remove these areas of skin; however, erosion may occur if patients are not careful with scale removal.129
Excessive application of tretinoin does not increase the therapeutic effects of the drug and may produce marked inflammatory reactions, including peeling and discomfort.
For the treatment of acne, tretinoin is applied once daily before retiring, using enough to cover the entire affected area lightly. Because of the drug's potential to cause severe irritation and peeling, tretinoin may initially be applied once every 2 or 3 days, preferably with the lower concentration cream or gel; if tolerated, the solution or higher concentration cream or gel may then be used.
A typical response following topical application of tretinoin is manifested by redness and scaling within 7-10 days. Excessive use may cause the skin to become flaming red, chapped, and swollen. During initial therapy, comedones that had not been especially noticeable may become more pronounced. With continued therapy the lesions disappear, leaving an inflammatory background. Therapeutic effects of tretinoin are usually apparent after 2-3 weeks; however, optimal effects may require more than 6 weeks of therapy. Some clinicians have reported decreased scaling and redness after 8-10 weeks of therapy.
In patients in whom it has been necessary to temporarily discontinue or reduce the frequency of tretinoin applications, therapy may be reinstated when the patient is able to tolerate the drug. Some patients require less frequent applications of the drug or other dosage forms, while others respond better to more frequent applications. Changes in dosage form, drug concentration, or frequency of application should be closely monitored by careful observation of the patient's response and tolerance. After a satisfactory response is achieved, it may be possible to maintain the effects of tretinoin with less frequent application, or other dosage forms.
Dosage of tretinoin should be individualized according to the patient's response and tolerance, depending on skin type, degree of photoaging present, race, and/or age of the patient.115, 121, 124, 125 For the treatment of photoaging, tretinoin is applied once daily before retiring, using a pea-sized amount of the 0.02 or 0.05% cream104, 113, 114, 122, 126, 128, 136 to cover the entire face lightly;120, 123, 136 use of the drug at night reduces the probability of photoinactivation.123, 129 Patients should be advised that use of larger than recommended amounts will not speed results but can cause overdosage.128, 136 Tretinoin also has been applied topically as a 0.1% cream for the treatment of photoaging†, 105, 112, 114, 115, 116, 126, 129 but this preparation currently is not commercially available in the US.136 Because of the drug's potential to cause severe irritation, erythema, and peeling, some clinicians suggest that the frequency of tretinoin administration may be reduced to once every other night or every third night in patients who do not tolerate daily therapy well.105, 113, 122, 123, 124, 125, 126
Patients in whom it has been necessary to temporarily discontinue or reduce the frequency of tretinoin applications may reinstate therapy at reduced dosage once they are able to tolerate the drug again.115, 122, 123, 124, 125, 136 Mild scaling can be used as a guide to determine the level of tolerance.115, 124 Use of moisturizers concomitantly at night to counteract the drying effects of tretinoin may dilute the therapeutic effect of the drug; therefore, some clinicians suggest that moisturizers be used during the day in an attempt to minimize such potential interference.104, 124, 125, 126
Within 3-4 weeks, some clinicians have noted that patients may be able to tolerate greater amounts of cream, although the manufacturer does not recommend any increase in the amount applied.115, 117, 123, 124, 125, 126, 129 Changes in frequency or amount of application should be closely monitored by careful observation of the patient's response and tolerance, and the patient should be advised not to exceed the recommended dosage.125 Therapeutic response occurs gradually over the next 6 months of therapy, and clinically important decreases in fine wrinkles may not be apparent for 8 weeks.121, 123, 136 The manufacturer reports that a maximum response occurs within 6 months and that deterioration of histologic improvement (e.g., atypical melanocyte or keratinocytes, increase in dermal elastosis) has occurred in patients receiving the drug for longer than 48 weeks;136 other clinicians have reported continued clinical or histologic improvement for longer periods.104, 115, 123, 124, 125, 126, 129 Although most of the palliative effects of tretinoin on fine wrinkles, mottled hyperpigmentation, and tactile roughness of skin will be lost in the majority of patients once the drug and accompanying comprehensive skin care and sun avoidance are discontinued,136 the manufacturer states that safety and efficacy of topical tretinoin therapy beyond 48 weeks have not been established.136 After the maximum response has been achieved, maintenance therapy of 2-4 applications weekly has been suggested for some patients.115, 123, 124, 125, 126
The major adverse effects of tretinoin topical therapy are local inflammatory reactions which are reversible when therapy is discontinued. A transitory feeling of warmth or slight stinging may occur following each application of the drug. Redness and scaling of the skin appear to be necessary for the therapeutic response. If severe erythema, edema, blistering, or crusting of the skin occurs, the patient should be instructed to use the drug less frequently, or the drug should be discontinued permanently or until the integrity of the skin is restored, depending on the severity of the reaction. The skin usually recovers within a few days after tretinoin therapy is discontinued. Temporary hyperpigmentation or hypopigmentation has occurred in some patients following repeated topical application of the drug. True contact allergy to topical tretinoin is rare.
Precautions and Contraindications
Tretinoin should be used with extreme caution in patients with eczema, since the drug may produce severe irritation of eczematous skin. Exposure to ultraviolet (UV) light increases the intensity of the inflammatory reaction; in addition, although the clinical importance to humans is not known, studies in hairless albino and pigmented mice suggest that tretinoin may accelerate the tumorigenic potential of carcinogenic dosages of UVB and UVA light from a solar simulator.135 Patients receiving tretinoin topical therapy should minimize exposure to sunlight or other UV rays including sunlamps, and patients with sunburn should not use tretinoin until full recovery occurs. Complete avoidance of sunlamps is recommended for patients receiving topical tretinoin therapy for photoaging.128 Patients who may be subjected to considerable sun exposure because of their occupation and those with inherent sensitivity to the sun should be especially cautious; when exposure cannot be avoided, use of sunscreen products and protective clothing over treated areas may be prudent. Weather extremes (e.g., wind, cold) may be irritating to patients receiving tretinoin topical therapy.
Patients receiving topical tretinoin therapy for photodamaged skin should be advised that such therapy is palliative and not curative, and that the drug should be used only as directed as part of a comprehensive skin care and sun avoidance program.128 Such patients also should be given a copy of the patient information provided by the manufacturer and advised that topical tretinoin is not a cosmetic preparation.128 They also should be cautioned to inform their clinician if they are using other drugs that potentially could increase the sensitivity of their skin to sunlight (e.g., fluoroquinolone anti-infectives, thiazide diuretics, sulfonamides, phenothiazines),128 and to consult with them before using any prescription drug or facial cream during topical tretinoin therapy.128 (See Drug Interactions.)
Tretinoin should not come in contact with the eyes, mouth, angles of the nose, mucous membranes, or open wounds. The drug should be discontinued if hypersensitivity to any of the ingredients in the formulation occurs.
Safety and efficacy of tretinoin gel (microsphere formulation) in children younger than 12 years of age have not been established.135 In addition, safety and efficacy of tretinoin emollient cream (Renova®) in pediatric patients younger than 18 years of age have not been established.136
Safety and efficacy of tretinoin emollient cream (Renova®) in adults older than 50 years of age have not been established.136 In addition, clinical studies of tretinoin gel (microsphere formulation) did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.135
Mutagenicity and Carcinogenicity
In vivo and in vitro (Ames) tests have not demonstrated that tretinoin is mutagenic.135 However, ingredients in the microsphere formulation of the drug have shown potential for genetic toxicity and teratogenesis.135 Ethylene glycol dimethacrylate (EGDMA), a component of the acrylate copolymer excipient, has shown mutagenic potential in vitro in chromosomal aberration studies in mammalian cells in the absence of metabolic activation, but was negative for genetic toxicity in the Ames assay, the HGPRT forward mutation assay, and the mouse micronucleus assay.135
Carcinogenicity of tretinoin was evaluated in a 91-week dermal study in CD-1 mice.135 For purposes of comparisons of the animal exposure with systemic human exposure, the maximum human systemic dose applied topically is defined by the manufacturer as 1 g of 0.1% tretinoin gel (microsphere formulation) applied daily to a 50-kg individual (tretinoin 0.02 mg/kg).135 When mice received 0.017 and 0.035% formulations of tretinoin at dosages 2 and 4 times, respectively, the maximum human systemic dose applied topically (when normalized for total body surface area), cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice and dose-related hepatic tumors were observed in male mice.135 The clinical importance of these findings is not clear because they occurred at dosages that exceeded the dermal maximally tolerated dose of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice.135 There was no evidence of carcinogenic potential when tretinoin dosages of 0.025 mg/kg daily (0.1 times the maximum human systemic dose, normalized for total body surface area) were administered topically to mice.135
Pregnancy, Fertility, and Lactation
Retinoids (e.g., isotretinoin) have been reported to cause serious fetal harm when administered to pregnant women.130, 131, 132, 133 (See Cautions: Pregnancy, Fertility, and Lactation, in Isotretinoin 84:36.) Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuman primates.134, 135, 136, 137 Tretinoin was teratogenic in Wistar rats when given orally or topically in dosages exceeding 1 mg/kg daily (8 times the maximum human systemic dosage normalized for total body surface area).135 In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than other species examined, fetal malformations were reported at oral dosages of 10 mg/kg daily or greater, but none were observed at 5 mg/kg daily (83 times the maximum human systemic dosage normalized for total body surface area), although increased skeletal variations were observed at all dosages.134, 135, 136 Dose-related increased embryolethality and abortion also were reported.134, 135, 136 Similar results also have been reported in pigtail macaques.134, 135, 136
Topical tretinoin in animal teratogenicity tests has generated equivocal results.134, 135, 136 There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at dosages exceeding 1 mg/kg daily (8 times the maximum human systemic dosage normalized for total body surface area).134, 135, 136 Bone anomalies (short [13%] or bent [6%] humerus, incompletely ossified os parietal [14%]) also have been reported in rats when tretinoin 10 mg/kg daily was applied dermally.134, 135, 136 Topical tretinoin cream was associated with an increased incidence of cleft palate and hydrocephaly in rabbits when administered in a dosage 91 times the topical human dosage (based on topical application of 1 g of 0.1% tretinoin cream in a 50-kg adult).134 In New Zealand white rabbits treated with topical tretinoin at dosages 80 times the recommended human topical clinical dosage, an increased incidence of domed head and hydrocephaly was noted in some of the fetuses, typical of retinoid-induced fetal malformations in this species;134 no abnormalities were observed at dosages 3 times the maximum human systemic dosage of tretinoin after topical administration of 0.1% tretinoin gel (microsphere formulation), normalized for total body surface area.135 In addition, topical tretinoin in formulations other than the gel (microsphere formulation) was not teratogenic when given in dosages of 42 or 27 times the maximum human systemic topical dosage in rats or rabbits, respectively.135 However, delayed ossification of several bones, occurred in rabbits and a dose-dependent incease in supernumerary ribs was observed in rats at these topical dosages.135
Oral tretinoin was fetotoxic in rats at dosages 21 times the maximum human systemic dosage normalized for total body surface area, resulting in skeletal variations and increased intrauterine death in rats.135Topical tretinoin has been shown to be fetotoxic in rabbits when administered in dosages 8 times the maximum human systemic dosage applied topically and normalized for total body surface area), resulting in fetal resorption and variations in ossification.135
When given subcutaneously to rabbits, tretinoin was teratogenic at a dosage of 2 mg/kg daily but not at 1 mg/kg daily.134 These dosages are approximately 400 and 200 times, respectively, the human topical dosage of tretinoin cream (based on topical application of 1 g of 0.025% tretinoin cream in a 50-kg adult).134
With widespread use of any drug, a small number of birth defect reports associated with the administration of the drug would be expected by chance alone.134, 135, 136 During 2 decades of clinical use of one formulation of topical tretinoin (Retin-A®), 30 cases of temporally associated congenital malformations have been reported.134, 135, 136 Although no definite pattern of teratogenicity and no causal associations have been established from these cases, 5 of the reports described the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain).134, 135, 136 The relevance of these spontaneous reports in terms of risk to the fetus is unknown.134, 135, 136
To date, there have been no adequate and well-controlled studies performed in pregnant women, and the teratogenic blood level of tretinoin is not known.134, 135 The manufacturer of some topical tretinoin preparations (e.g., Retin-A®) state that topical tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus,135, 137 while manufacturers of other tretinoin formulations (e.g., Avita® cream, Renova® emollient cream) state that these products should not be used during pregnancy.134, 136
Dermal fertility and perinatal development studies with tretinoin gel (microsphere formulation) or cream have not been performed in any species.134, 135 In dermal segment I fertility studies of topical tretinoin formulations other than the gel (microsphere formulation), however, slight (not statistically significant) decreases in sperm count and motility in male rats have been observed at dosages of 0.5 mg/kg daily (4 times the maximum human systemic dose applied topically, and normalized for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos have been observed in female rats treated at dosages of 0.25 mg/kg daily (2 times the maximum human systemic dose applied topically and normalized for total body surface area) or greater.135 In oral fertility and perinatal development studies in rats, decreased survival of neonates and growth retardation were observed at tretinoin dosages exceeding 2 mg/kg daily (greater than 100 times the recommended human clinical dosage of 1 g in a 50-kg adult).134, 135 In male mice treated topically with tretinoin gel (microsphere formulation) at 0.5, 2, or 5 mg/kg daily (2, 8, or 21 times the maximum human systemic dosage after topical administration of tretinoin gel [microsphere formulation], normalized for total body surface area) for 90 days, a reduction in testicular weight, but with no pathologic change, was observed at the 2 or 5 mg/kg daily dosages.135 Similarly, in female mice, there was a reduction in ovarian weights, but without any underlying pathologic change, at 5 mg/kg daily (21 times the recommended human dosage).135 In this study, there was a dose-related increase in the plasma concentration of tretinoin 4 hours after the first dose.135 A separate toxicokinetic study in mice indicates that systemic exposure is greater after topical application to unrestrained animals than to restrained animals, suggesting that the systemic toxicity observed is probably related to oral ingestion.135 Male and female dogs treated with topical tretinoin gel (microsphere formulation) at dosages of 0.2, 0.5, or 1 mg/kg daily (5, 12, or 25 times the maximum human systemic dosage after topical administration of tretinoin gel [microsphere formulation], normalized for total body surface area, respectively) for 90 days showed no evidence of reduced testicular or ovarian weights or pathologic change.135
It is not known whether topically applied tretinoin is excreted in human milk.134, 135, 136, 137 Caution should be exercised when topical tretinoin is administered to a nursing woman.134, 135, 136, 137
Concomitant use of tretinoin with other topical medications (especially those containing keratolytic agents such as sulfur, resorcinol, benzoyl peroxide, or salicylic acid) should be undertaken with caution because of the possibility of interactions. In patients who have used keratolytic agents, sufficient time should elapse for the effects of these drugs to subside before initiating tretinoin therapy. Patients receiving tretinoin therapy should not wash their faces more frequently than 2 or 3 times daily, using a mild, bland soap. Medicated or drying soaps and abrasive soaps and cleansers generally should not be used. Use of topical preparations with high concentrations of alcohol, menthol, spices, or lime such as shaving lotions, astringents, and perfume should be avoided, since they may cause stinging of treated skin, especially during initial therapy. Patients also should avoid the use of irritating cosmetics (e.g., toners, peeling [desquamating] agents), permanent wave solutions, electrolysis, or hair depilatories during topical tretinoin therapy.115, 124, 125, 126, 127, 136 Non-medicated cosmetics may be used by patients receiving tretinoin therapy, but the areas to be treated should be cleansed thoroughly before tretinoin is applied; medicated cosmetics should not be used.
The precise mechanism of action of topically applied tretinoin in the treatment of acne has not been determined. Although it has been stated that tretinoin inhibits keratinization, this hypothesis has not been confirmed in all studies. The drug appears to act as an irritant on the follicular epithelium, preventing horny cells from sticking together. It has been suggested that the mode of action may be related to the ability of the drug to labilize lysosomes, thereby releasing proteolytic and hydrolytic enzymes capable of inciting inflammatory reactions. In existing comedones, increased horny cell production weakens the attachment of the comedo resulting in its extrusion. Injury to the follicular epithelium also may cause formation of an intrafollicular abscess resulting in suppurative discharge of the comedo. These effects cause horny cells to be readily sloughed and expelled from the follicular orifice, thereby inhibiting formation of additional comedones. In addition, tretinoin may act by modulating the proliferation and differentiation of epidermal cells.135 These effects are mediated by tretinoin's interaction with a family of nuclear retinoic acid receptors (RAR).135 Activation of these nuclear receptors causes changes in gene expression.135 The exact mechanisms whereby tretinoin-induced changes in gene expression regulate skin function are not understood.135 Although tretinoin activates 3 retinoid acid nuclear receptors (RARα, RARβ, and RARγ), which may act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation, it has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors, other mechanisms, or both.135
Tretinoin does not appear to affect bacterial colonization (principally by Propionibacterium acnes ) or lipid composition on the surface of the skin.
In normal skin, tretinoin produces a mild inflammatory reaction resulting in acanthosis and parakeratosis. High concentrations of the drug may cause severe epidermal damage and vesiculation. In rats, topical application of 1% tretinoin has been reported to promote wound healing and to reverse the wound healing retardation action of systemic anti-inflammatory agents.
In animals, topical tretinoin has been shown to enhance repair of skin damaged by ultraviolet radiation (UVB); this effect appears to result from increased number and activity of fibroblasts and collagen formation induced by the drug.100, 101, 102, 116 The drug also may reduce collagen degradation by inducing tissue inhibitors of collagenase.112, 116, 118, 119 In humans, studies to date indicate that topical tretinoin can at least partially reverse photodamaged skin histologically and clinically.104, 105, 112, 113, 115, 116, 121, 122, 123, 124, 125, 126, 129 Histologic changes in photodamaged skin associated with topical tretinoin therapy include restoration of the epidermis to a normal morphologic appearance and increased epidermal thickness,104, 105, 113, 114, 117, 123, 124, 125, 126, 129 a reduction or eradication of microscopic actinic keratoses,104, 105, 124 dispersion of melanin granules and decreased melanin content,104, 113, 114, 123, 124, 125, 126, 129 stratum corneum compaction,104, 105, 113, 117, 126 new collagen formation in the papillary dermis,104, 116, 123, 124, 125, 129 increases in epidermal-dermal anchoring fibrils,112, 114, 116, 126, 129 angiogenesis,104, 123, 124, 125 and exfoliation of retained follicular horn.104, 126 Elastotic deposits are apparently not affected.104, 105 Clinical changes may include a reduction in fine wrinkling and increased skin pinkness and, to a lesser degree, reduction in coarse wrinkling and tactile roughness of the skin.105 Studies are currently under way to further evaluate the effects of tretinoin on photoaging induced by UVB in humans.103, 104, 105
For information on the antineoplastic activity of the drug, see Pharmacology in Tretinoin 10:00.
Tretinoin appears to be only minimally absorbed following topical application. In in vitro studies on human skin using tretinoin 0.1% in isopropyl alcohol (no longer commercially available in the US), about 80% of the applied dose remained on the surface; about 9% and 18% penetrated into the horny layer within 10 minutes and 16 hours, respectively; and lesser amounts penetrated into the epidermis and dermis. In one study in which radiolabeled tretinoin 0.05% gel (no longer commercially available in the US) was applied to the skin and left for 12 hours, about 0.1% was of the applied dose was excreted in urine within 24 hours; no measurable radioactivity occurred in plasma. In another study, following topical application to the back of a 0.1% ointment (no longer commercially available in the US) and a 16-hour occlusive dressing, 50% of the applied drug remained on the skin surface and 6% was excreted in urine within 56 hours.
For information on the systemic pharmacokinetics of the drug, see Pharmacokinetics in Tretinoin 10.00.
Tretinoin, all trans -retinoic acid, is a derivative of vitamin A. The drug occurs as a yellow to light orange, crystalline powder and is insoluble in water and slightly soluble in alcohol.
Tretinoin preparations should be stored in tight, light-resistant containers at 15-30°C.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Topical | Cream | 0.02% | Renova® Emollient | |
0.025%* | ||||
OrthoNeutrogena | ||||
0.05% | Renova® Emollient | OrthoNeutrogena | ||
Retin-A® | OrthoNeutrogena | |||
0.1%* | Retin-A® | OrthoNeturogena | ||
Gel | 0.01% | Retin-A® | OrthoNeutrogena | |
0.025% | Avita® | Mylan | ||
Retin-A® | OrthoNeutrogena | |||
Gel (containing microspheres) | 0.04% | Retin-A® Micro® | OrthoNeutrogena | |
0.1% | Retin-A® Micro® | OrthoNeutrogena | ||
Solution | 0.05%* | Retin-A® | OrthoNeutrogena |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
100. Kligman LH, Duo CH, Kligman AM. Topical retinoic acid enhances repair of ultraviolet damaged dermal connective tissue. Connect Tissue Res . 1984; 12:139-50. [PubMed 6723309]
101. Kligman LH. Photoaging: manifestations, prevention, and treatment. Dermatol Clin . 1986; 4:517-28. [PubMed 3521997]
102. Kligman LH. Effects of all-trans-retinoic acid on the dermis of hairless mice. J Am Acad Dermatol . 1986; 15(4 Part 2):779-85,884-7. [PubMed 3771852]
103. Anon. Ortho testing antiaging use of acne remedy. Med Advert News . 1986; 5(Oct 1):1.
104. Kligman AM, Grove GL, Hirose R et al. Topical tretinoin for photoaged skin. J Am Acad Dermatol . 1986; 15(4 Part 2):836-59. [PubMed 3771853]
105. Weiss JS, Ellis CN, Headington JT et al. Topical tretinoin improves photoaged skin: a double-blind vehicle-controlled study. JAMA . 1988; 259:527-32. [PubMed 3336176]
106. Gilchrest BA. At last! A medical treatment for skin aging. JAMA . 1988; 259:569-70. [PubMed 3336180]
107. Anon. Tretinoin for aging skin. Med Lett Drugs Ther . 1988; 30:69-70. [PubMed 3290638]
108. Anon. Does topical tretinoin prevent cutaneous ageing? Lancet . 1988; 1:977-8. Editorial.
109. Okun MR. Topical tretinoin for photoaged skin. JAMA . 1988; 259:3271-2.
110. Kanigsberg ND. Topical tretinoin for photoaged skin. JAMA . 1988; 259:3272.
111. Anon. Retin-A risky, unproven for wrinkles. FDA Consum . 1988; 22:4.
112. Woodley DT, Zelickson AS, Briggaman RA et al. Treatment of photoaged skin with topical tretinoin increases epidermal-dermal anchoring fibrils. JAMA . 1990; 263:3057-9. [PubMed 2342217]
113. Olsen EA, Katz HI, Levine N et al. Tretinoin emollient cream: a new therapy for photodamaged skin. J Am Acad Dermatol . 1992; 26:215-24. [PubMed 1552056]
114. Anon. Tretinoin for photodamaged skin. Med Lett Drugs Ther . 1992; 34:28-9. [PubMed 1542280]
115. Kligman AM. Current status of topical tretinoin in the treatment of photoaged skin. Drugs Aging . 1992; 2:7-13. [PubMed 1554975]
116. Griffiths CEM, Russman AN, Majmudar G et al. Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). N Engl J Med . 1993; 329:530-5. [PubMed 8336752]
117. Rafal ES, Griffiths CEM, Ditre CM et al. Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage. N Engl J Med . 1992; 326:368-74. [PubMed 1729619]
118. Bauer EA, Seltzer JL, Eisen AZ. Inhibition of collagen degradative enzymes by retinoic acid in vitro. J Am Acad Dermatol . 1982; 6:603-7. [PubMed 6279711]
119. Clark SD, Kobayashi DK, Welgus HG. Regulation of the expression of tissue inhibitor of metalloproteinases and collagenase by retinoids and glucocorticoids in human fibroblasts. J Clin Invest . 1987; 80:1280-8. [PubMed 2824558]
120. Anon. Ortho's Renova effective for cosmetic treatment of photodamaged skin, advisory panel finds; reduction seen in appearance of fine wrinkles, hyperpigmentation. F-D-C Rep . 1992; 54:3-4.
121. Lever L, Kumar P, Marks R. Topical retinoic acid for treatment of solar damage. Br J Dermatol . 1990; 122:91-8. [PubMed 2404514]
122. Weinstein GD, Nigra TP, Pochi PE et al. Topical tretinoin for treatment of photodamaged skin: a multicenter study. Arch Dermatol . 1991; 127:659-65. [PubMed 2024983]
123. Goldfarb MT, Ellis CN, Weiss JS et al. Topical tretinoin and photoaged skin. Cutis . 1989; 43:476-82. [PubMed 2721243]
124. Kligman AM. Guidelines for the use of topical tretinoin (Retin-A) for photoaged skin. J Am Acad Dermatol . 1989; 21:650-4. [PubMed 2778128]
125. Kligman AM. The treatment of photoaged human skin by topical tretinoin. Drugs . 1989; 38:1-8. [PubMed 2766960]
126. Noble S, Wagstaff AJ. Tretinoin: a review of its pharmacological properties and clinical efficacy in the topical treatment of photodamaged skin. Drugs Aging . 1995; 6:479- 96. [PubMed 7663068]
127. Ortho Pharmaceutical Corporation, Raritan, NJ: Personal communication.
128. Ortho Pharmaceutical Corporation. Renova® (tretinoin) 0.02% emollient cream prescribing information. Raritan, NJ; 2000 Aug.
129. Goldfarb MT, Ellis CN, Weiss JS et al. Topical tretinoin therapy: its use in photoaged skin. J Am Acad Dermatol . 1989; 21:645-50. [PubMed 2674226]
130. Anon. Update on birth defects with isotretinoin. FDA Drug Bull . 1984; 14:15-6. [PubMed 6592122]
131. Roche Laboratories. Accutane® (isotretinoin) capsule prescribing information. Nutley, NJ; 1990 May.
132. Benke PJ. The isotretinoin teratogen syndrome. JAMA . 1984; 251:3267-9 (IDIS 186330) [PubMed 6587131]
133. de la Cruz E, Sun S, Vangvanichyakorn K et al. Multiple congenital malformations associated with maternal isotretinoin therapy. Pediatrics . 1984; 74:428-30 (IDIS 189774) [PubMed 6591112]
134. Bertek Pharmaceuticals Inc. Avita® (tretinoin cream) 0.025% prescribing information (dated 2002 Jan). In: Physicians' desk reference. 57th ed. Montvale, NJ: Medical Economics Company Inc; 2003:986-8.
135. Ortho Pharmaceutical Corporation. Retin-A® Micro® (tretinoin gel) microsphere, 0.1% prescribing information. Skillman, NJ; 2002 May.
136. Ortho Pharmaceutical Corporation. Renova® (tretinoin emollient cream) 0.05% prescribing information. Raritan, NJ; 1998 Feb.
137. Ortho Pharmaceutical Corporation. Retin-A® (tretinoin) liquid/cream/gel prescribing information. Raritan, NJ; 1996 Dec.