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Manufacturer
ACTAVIS PHARMA/
SKU
00472011745

tretinoin 0.025% cream

Generic
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Uses

Acne

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.

Photoaging

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. Clinical studies to date indicate that therapy with the drug may at least partially reverse photodamaged skin clinically and histologically. 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. 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). 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. The manufacturer states that safety and efficacy of topical tretinoin therapy for photoaging beyond 48 weeks have not been established.

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. However, after such improvement, deep coarse wrinkles and telangiectasis still will be evident, at least with short-term (4-6 months) therapy. 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. 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; 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. Most patients also were instructed to avoid sun exposure and to use an effective sunscreen. Lentigines (hyperpigmented macules, liver spots) and solar-induced freckling also may show improvement (e.g., lightening or disappearance); 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. 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.

Although the manufacturer states that safety and efficacy of topical tretinoin have not been established in patients with actinic keratoses, 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. However, macular, erythematous flare-ups of actinic keratoses may occur for several months prior to resolution or reduction in size. The manufacturer also states that safety and efficacy of topical tretinoin therapy have not been established for dermatologic neoplasms, nor have they been established for patients with moderately or heavily pigmented skin.

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. 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.

Other Topical Uses

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.

Systemic Uses

For systemic uses of tretinoin (e.g., cancer), see Tretinoin 10:00.

Dosage and Administration

Administration

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.)

Acne

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.

Photoaging

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. The topical cream is applied at bedtime using the minimum amount necessary to cover the affected area lightly. 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.

Dosage

Excessive application of tretinoin does not increase the therapeutic effects of the drug and may produce marked inflammatory reactions, including peeling and discomfort.

Acne

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.

Photoaging

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. For the treatment of photoaging, tretinoin is applied once daily before retiring, using a pea-sized amount of the 0.02 or 0.05% cream to cover the entire face lightly; use of the drug at night reduces the probability of photoinactivation. Patients should be advised that use of larger than recommended amounts will not speed results but can cause overdosage. Tretinoin also has been applied topically as a 0.1% cream for the treatment of photoaging, but this preparation currently is not commercially available in the US. 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.

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. Mild scaling can be used as a guide to determine the level of tolerance. 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.

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. 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. 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. 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; other clinicians have reported continued clinical or histologic improvement for longer periods. 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, the manufacturer states that safety and efficacy of topical tretinoin therapy beyond 48 weeks have not been established. After the maximum response has been achieved, maintenance therapy of 2-4 applications weekly has been suggested for some patients.

Cautions

Adverse Effects

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. 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. 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. 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. 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), and to consult with them before using any prescription drug or facial cream during topical tretinoin therapy.(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.

Pediatric Precautions

Safety and efficacy of tretinoin gel (microsphere formulation) in children younger than 12 years of age have not been established. In addition, safety and efficacy of tretinoin emollient cream (Renova) in pediatric patients younger than 18 years of age have not been established.

Geriatric Precautions

Safety and efficacy of tretinoin emollient cream (Renova) in adults older than 50 years of age have not been established. 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.

Mutagenicity and Carcinogenicity

In vivo and in vitro (Ames) tests have not demonstrated that tretinoin is mutagenic. However, ingredients in the microsphere formulation of the drug have shown potential for genetic toxicity and teratogenesis. 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.

Carcinogenicity of tretinoin was evaluated in a 91-week dermal study in CD-1 mice. 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). 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. 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. 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.

Pregnancy, Fertility, and Lactation

Pregnancy

Retinoids (e.g., isotretinoin) have been reported to cause serious fetal harm when administered to pregnant women. (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. 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). 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. Dose-related increased embryolethality and abortion also were reported. Similar results also have been reported in pigtail macaques.

Topical tretinoin in animal teratogenicity tests has generated equivocal results. 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). 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. 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). 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; 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. 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. 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.

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.Topical 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.

When given subcutaneously to rabbits, tretinoin was teratogenic at a dosage of 2 mg/kg daily but not at 1 mg/kg daily. 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).

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. During 2 decades of clinical use of one formulation of topical tretinoin (Retin-A), 30 cases of temporally associated congenital malformations have been reported. 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). The relevance of these spontaneous reports in terms of risk to the fetus is unknown.

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. 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, while manufacturers of other tretinoin formulations (e.g., Avita cream, Renova emollient cream) state that these products should not be used during pregnancy.

Fertility

Dermal fertility and perinatal development studies with tretinoin gel (microsphere formulation) or cream have not been performed in any species. 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. 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). 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. 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). In this study, there was a dose-related increase in the plasma concentration of tretinoin 4 hours after the first dose. 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. 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.

Lactation

It is not known whether topically applied tretinoin is excreted in human milk. Caution should be exercised when topical tretinoin is administered to a nursing woman.

Drug Interactions

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. 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.

Pharmacokinetics

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.

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