40 years of topical tretinoin use in review.

Topical tretinoin has been approved for use in dermatology for 40 years and is currently approved for the treatment of acne vulgaris and photodamage. During this time, topical tretinoin has accumulated significant efficacy and safety data in the treatment of acne and photodamaged skin and demonstrated clinical potential for treating a range of other dermatologic conditions. The diverse effects may be due to complex underlying mechanisms of action associated with tretinoin, including keratolytic activity, collagenesis, and other mechanisms associated with the activation of nuclear retinoic acid receptors (RARα, RARß, and RARγ). In this article, we review the history of topical tretinoin use to date and outline emerging research suggesting that topical tretinoin may have potential clinical use for treating a multitude of other dermatological conditions when used either as monotherapy or in combination with other agents. We also describe newer formulations of topical tretinoin that have been designed to reduce irritation potential. In light of the substantial history of safety and efficacy of topical tretinoin in acne and photodamage, we speculate that it holds promise in treating many additional dermatological conditions, which may be explored in future research.

Tretinoin gel microsphere pump 0.04% plus 5% benzoyl peroxide wash for treatment of acne vulgaris: morning/morning regimen is as effective and safe as morning/evening regimen.

Topical tretinoin and benzoyl peroxide (BPO) are often prescribed in combination for the treatment of acne vulgaris; however, these products have not traditionally been administered simultaneously because of the potential for tretinoin degradation by BPO as well as the instability of tretinoin in daylight. The primary objective of this randomized, investigator-blinded, 12-week, phase 4 trial was to determine non-inferiority of a once-daily morning combination regimen of 5% BPO wash + tretinoin gel microsphere (TGM) 0.04% pump versus a sequential regimen (BPO in the morning/TGM in the evening) in patients > or = 12 years old with moderate facial acne vulgaris. The primary efficacy endpoint was the change from baseline in total acne lesions; the primary safety endpoint was the change in cutaneous irritation scores. The 247 participants (mean age: 18.5 years) were randomized to either the morning/morning regimen (n = 123) or the morning/evening regimen (n = 124). The morning/morning regimen was determined to be non-inferior to the morning/evening regimen in reduction of total acne lesions. The tolerability of both regimens was comparable. The morning/morning regimen is a safe and effective treatment option for patients with moderate acne vulgaris.

Irritation potential of tretinoin gel microsphere pump versus adapalene plus benzoyl peroxide gel.

This single-center, investigator-blinded, randomized, split-face, phase 4 study compared the irritation potential of tretinoin gel microsphere (TGM) 0.04% in a pump dispenser with adapalene 0.1% plus benzoyl peroxide 2.5% gel (ADA-BPO 0.1%/2.5%) in a panel of 170 subjects. Participants were treated with TGM 0.04% pump on a randomly assigned side of the face and ADA-BPO 0.1%/2.5% gel on the other side of the face daily for three consecutive weeks. Expert grader assessments of erythema and dryness and subject self-assessments of burning/stinging and itching were conducted daily, except on weekends. TGM 0.04% pump was associated with better facial tolerance as demonstrated by significantly less cumulative erythema (P < 0.0001), dryness (P < 0.0001), burning/stinging (P < 0.0001) and itching (P < 0.0001) compared with ADA-BPO 0.1%/2.5% gel. While both agents were well tolerated by most patients, TGM 0.04% pump demonstrated significantly better tolerance than ADA-BPO 0.1%/2.5% gel in both neurosensory parameters and signs of contact irritation.

Acne quality of life and patient satisfaction following treatment with tretinoin pump.

Patient satisfaction and quality of life are important considerations when assessing products used to treat acne vulgaris, as these factors may affect treatment adherence and subsequent treatment outcomes. The objective of this analysis was to determine patient satisfaction and improvement in quality of life after treatment with tretinoin gel microsphere (TGM) in a pump dispenser. Assessments were made during a phase IV, prospective, 12-week, open-label, community-based trial in which 544 patients who were dissatisfied with their current acne treatments received TGM 0.04% or 0.1% in addition to < or = 2 concurrent non-retinoid acne therapies. At week 12, significant improvement was reported in both patient acne therapy satisfaction and in the overall mean Acne Quality of Life Index scale (P < 0.0001 versus baseline for both measures). The majority of patients (82.3%) rated the pump dispenser as an "excellent" or "very good" means of dispensing medication, and 86.0% rated their overall satisfaction with the pump treatment application as "very satisfied" or "extremely satisfied." The results of this study indicate that the use of TGM in a pump dispenser in patients with acne vulgaris is associated with significant increases in both quality of life and patient satisfaction.

Tretinoin microsphere gel in facial acne vulgaris: a meta-analysis.

BACKGROUND: Acne vulgaris can persist beyond adolescence into the fourth decade of life or later; most patients have a combination of inflammatory and noninflammatory lesions. OBJECTIVE: To determine whether tretinoin microsphere gel (TMG) 0.04% applied once nightly is well tolerated and effective in reducing inflammatory and noninflammatory lesions in adolescents and adults with mild to moderate facial acne. METHODS: The results of 3 randomized, double-blind, vehicle-controlled studies of TMG 0.04% applied once nightly for 12 consecutive weeks in a total of 629 patients, ages 11 to 49 years, were combined. Reductions in acne lesion counts were assessed twice monthly, and an investigator's global evaluation (IGE) was performed at the study endpoint (week 12). RESULTS: Tretinoin microsphere gel 0.04% was significantly superior to the vehicle gel in reducing both inflammatory and noninflammatory lesions over the 12-week treatment period, and produced a higher successful treatment rate than the vehicle gel, as judged by IGE ratings at week 12. The most frequent adverse events were erythema, peeling, and dryness, which were mostly mild and occurred in 59.7% to 63.3% of patients with TMG 0.04%, as compared with 26.9% to 51.0% of patients with the vehicle gel (placebo). CONCLUSION: The TMG 0.04% formulation is significantly superior when compared to its vehicle gel in reducing inflammatory and noninflammatory acne lesions over a period of 12 weeks and is well tolerated.

Cumulative irritation potential of topical retinoid formulations.

BACKGROUND: Localized irritation can limit treatment success with topical retinoids such as tretinoin and adapalene. The factors that influence irritant reactions have been shown to include individual skin sensitivity, the particular retinoid and concentration used, and the vehicle formulation. OBJECTIVE: To compare the cutaneous tolerability of tretinoin 0.04% microsphere gel (TMG) with that of adapalene 0.3% gel and a standard tretinoin 0.025% cream. METHODS: The results of 2 randomized, investigator-blinded studies of 2 to 3 weeks' duration, which utilized a split-face method to compare cumulative irritation scores induced by topical retinoids in subjects with healthy skin, were combined. Study 1 compared TMG 0.04% with adapalene 0.3% gel over 2 weeks, while study 2 compared TMG 0.04% with tretinoin 0.025% cream over 3 weeks. RESULTS: In study 1, TMG 0.04% was associated with significantly lower cumulative scores for erythema, dryness, and burning/stinging than adapalene 0.3% gel. However, in study 2, there were no significant differences in cumulative irritation scores between TMG 0.04% and tretinoin 0.025% cream. Measurements of erythema by a chromameter showed no significant differences between the test formulations in either study. CONCLUSION: Cutaneous tolerance of TMG 0.04% on the face was superior to that of adapalene 0.3% gel and similar to that of a standard tretinoin cream containing a lower concentration of the drug (0.025%).

Tretinoin microsphere gel in younger acne patients.

BACKGROUND: Facial acne is common in adolescents and can have a significant psychosocial impact. Treatments prescribed should not add stress by causing excessive localized irritation. OBJECTIVE: To determine whether the lowest concentration of tretinoin microsphere gel (TMG) currently available (0.04%) provides an acceptable balance of efficacy and tolerability for adolescents with moderate facial acne. METHODS: The findings of 2 multicenter, randomized, double-blind, vehicle-controlled trials of TMG 0.04% applied once nightly for 12 weeks in 245 adolescents ages 11 to 16 years with moderate facial acne were combined. Patients were evaluated via changes in acne lesion counts and the occurrence of cutaneous and other adverse effects. RESULTS: Tretinoin microsphere gel 0.04% reduced total, noninflammatory, and inflammatory lesion counts to a significantly greater extent than the vehicle gel at 12 weeks (P<.000005). The mean percentage reductions in noninflammatory and inflammatory lesion counts at 12 weeks in females were 45.0% and 51.4%, respectively; and in males, 20.5% and 36.7%, respectively. Tretinoin microsphere gel 0.04% was tolerated well, with over 70% of patients experiencing no cutaneous adverse events (AEs). CONCLUSION: Tretinoin microsphere gel 0.04% is effective in significantly reducing all types of acne lesions in adolescents with moderate facial acne ages 11 to 16 years, and has a low incidence of cutaneous AEs.

Photographic assessment of tretinoin microsphere gel in moderate acne.

BACKGROUND: True objective measures for assessing responsiveness to acne treatments are lacking. Photographic documentation can therefore be a valuable adjunct to treatment assessment. OBJECTIVES: To photographically document the ability of tretinoin microsphere gel (TMG) 0.1% in improving facial acne. METHODS: A standardized photographic technique was used to assess the efficacy and tolerability of TMG 0.1% applied once nightly for 12 weeks in an open-label trial involving 30 patients (Caucasian and Hispanic) ages 11 to 40 years with moderately severe facial acne. RESULTS: An assessment of frontal, left-sided, and right-sided color photographs at week 12 indicated that TMG 0.1% reduced total, noninflammatory, and inflammatory acne lesion counts by 47.8%, 53.5%, and 33.2%, respectively; and produced an "excellent/ good" investigator's global evaluation (4-point scale) treatment response in 63.6% of patients. Tretinoin microsphere gel 0.1% was well tolerated, and more than 63% of subjects did not exhibit cutaneous adverse effects at week 12. CONCLUSIONS: The standardized photographic technique proved to be a useful tool for documenting the efficacy of TMG 0.1% in consistently and significantly improving moderately severe facial acne over a 12-week treatment period.

Phase 4 study to assess tretinoin pump for the treatment of facial acne.

It is well known that the setting of clinical trials for registration studies do not necessarily represent efficacy seen in clinical practice, where physicians have the flexibility to select, combine, and change the acne treatment prescription. In this phase 4, open-label, multicenter, community-based study, 544 patients who were dissatisfied with their current acne treatment received tretinoin gel microsphere (TGM) 0.04% or 0.1% in a pump dispenser for 12 weeks. Patients were allowed the use of up to 2 other concurrent acne therapies, not including other retinoids. A total of 361 patients received TGM 0.04% and 183 received TGM 0.1%. Compliance was high (defined as 75% to 100% of prescribed doses taken) for approximately 95% of patients in both groups at every evaluation. At week 12, the mean modified Global Acne Grade score (mGAGs) and the investigator global evaluation (IGE) demonstrated significant (P<.0001) improvement from baseline for both concentrations, with 72% having at least moderate improvement. In approximately 25% of patients, acne was assessed as cleared or almost cleared. Most side effects were characteristic of topical retinoids. These results indicate TGM in a pump dispenser as an effective, well-tolerated acne treatment that is associated with a high rate of compliance.

A double-blinded, randomized, vehicle-controlled, multicenter, parallel-group study to assess the safety and efficacy of tretinoin gel microsphere 0.04% in the treatment of acne vulgaris in adults.

This double-blinded, randomized, vehicle-controlled, multicenter, parallel-group, 12-week, phase 4 study was conducted in adults with mild to moderate acne vulgaris. Of 178 subjects randomized to be treated, 88 subjects (49%) were treated with tretinoin gel microsphere 0.04% and 90 subjects (51%) were treated with vehicle. Inflammatory lesion counts were statistically significantly reduced at 2 weeks in tretinoin-treated subjects (P = .0110), and reductions in total lesion counts also were noted. The reduction in total lesion counts reached statistical significance at week 4 (P = .0305); at week 12, mean total, inflammatory, and noninflammatory lesion counts were statistically significantly lower in the tretinoin treatment group versus vehicle group (P < .05), and mean percentage reductions in lesion counts were significantly greater in the subjects with noninflammatory lesions treated with tretinoin compared with vehicle (P < .05). Mean percentage reductions in total, inflammatory, and noninflammatory lesion counts were 35.5%, 38.2%, and 33.6%, respectively, at week 12 for the tretinoin treatment group compared with 20.9%, 19.2%, and 20.4%, respectively, for the vehicle group (all P < .05). All adverse events were of mild or moderate intensity with the exception of severe skin irritation in one tretinoin-treated subject. At week 12, there were no statistically significant differences between treatment groups for any measured tolerability parameter.

Tretinoin gel microspheres 0.04% versus 0.1% in adolescents and adults with mild to moderate acne vulgaris: a 12-week, multicenter, randomized, double-blind, parallel-group, phase IV trial.

BACKGROUND: Topical retinoids are considered first-line therapy in the treatment of acne vulgaris, yet can be associated with cutaneous irritation, including erythema, peeling, dryness, burning, and itching. Tretinoin gel microsphere (TGM) formulations were developed to minimize these effects. A lower-strength TGM formulation may be desirable to further reduce exposure to tretinoin. OBJECTIVE: This study was conducted to assess the efficacy and safety profile of a lower-dose TGM (0.04%) formulation compared with TGM 0.1% for the treatment of mild to moderate acne vulgaris. METHODS: In this multicenter, double-blind, parallel-group, Phase IV dose-ranging study, patients with facial acne were randomized to apply either TGM 0.04% or TGM 0.1% to the face each night for 12 weeks. Patients must have discontinued systemic retinoid treatment for at least 1 year before the study and were not to have used any topical retinoids, systemic antibiotics, nicotinamide, or systemic steroids for at least 1 month. All other topical medications applied to the face (including corticosteroids, antimicrobials, salicylic acid, and benzoyl peroxide) were to be discontinued at least 2 weeks before the study. End points were the acne lesion count (total, inflammatory, and noninflammatory lesions) and the investigators' and patients' assessments of improvement. Adverse events (including severity and relationship to treatment) and signs and symptoms of cutaneous irritation at the treatment site were monitored at each study visit. RESULTS: One hundred fifty-six patients (78 TGM 0.04%, 78 TGM 0.1%) were randomized and received treatment. Patients ranged in age from 12 to 41 years (mean, 18.4 years) and were predominantly white (n = 89 [57.1%]) and male (n = 80 [51.3%]). Both TGM 0.04% and TGM 0.1% were associated with a reduction from baseline in total, inflammatory, and noninflammatory lesions. The differences between groups in the change in lesion counts from baseline to weeks 2, 4, 8, and 12 were not statistically significant. However, there was a greater reduction in inflammatory lesions at week 2 for TGM 0.1% compared with TGM 0.04% (14.8% vs 6.0%, respectively; P < 0.047). Both treatment groups had similar improvements in the investigators' global evaluation and the patients' assessment of the response to treatment. Both TGM 0.04% and TGM 0.1% were well tolerated. The most common adverse events were skin-associated burning sensation (2.6% in the TGM 0.04% group and 7.7% in the TGM 0.1% group) and irritation (6.4% and 3.8%, respectively). In the TGM 0.04% group, significantly fewer patients experienced dryness of the treatment area during the early phase of treatment (P < 0.027). However, for other measures of cutaneous irritation (peeling, burning/stinging, and itching), either there were no statistically significant differences between treatment groups or, in the case of erythema, there was a significant difference in favor of TGM 0.1% (P = 0.035). CONCLUSIONS: Both TGM 0.04% and TGM 0.1% were associated with reductions in lesion counts in these patients with mild to moderate facial acne. Both concentrations were generally well tolerated. The results suggested an early (week 2) incremental benefit for the use of TGM 0.1% in the treatment of inflammatory lesions.

The effect of simulated solar UV irradiation on tretinoin in tretinoin gel microsphere 0.1% and tretinoin gel 0.025%.

Topical tretinoin is highly effective and widely used in the treatment of acne vulgaris. Tretinoin gel microsphere 0.1% (TGM)--alone or in combination with erythromycin-benzoyl peroxide (EBP) or clindamycin-benzoyl peroxide (CBP) topical gels-and tretinoin gel 0.025% (TG)--alone or, combined with EBP-were exposed to simulated solar UV irradiation to determine the degree of tretinoin photodegradation/isomerization. The investigation revealed that 94% and 84% of the initial tretinoin in the TGM formulation remained stable after 2 and 6 hours, respectively, of simulated solar UV irradiation. When combined with EBP topical gel, 89% and 81% of the initial tretinoin remained stable after 2 and 6 hours, respectively, of exposure to simulated solar UV irradiation; 86% and 80% of the tretinoin remained stable after 2 and 6 hours, respectively, when combined with CBP topical gel. In contrast, only 19% and 10% of the tretinoin remained unchanged after 2 and 6 hours, respectively, of simulated solar UV irradiation of TG. Combined with the EBP topical gel, undegraded tretinoin quantities were further reduced to 7% and 0% at 2 and 6 hours, respectively, with TG. These data suggest that the TGM formulation offers marked protection against tretinoin photodegradation compared with TG, even in the presence of a topical gel containing a potent antibiotic or a strong oxidizing agent. Although simulated solar UV irradiation is not entirely reflective of actual conditions, the results appear to be substantial.

Tretinoin microsphere gel 0.1% for photodamaged facial skin: a placebo-controlled trial.

Tretinoin microsphere gel (TMG) 0. 1% was evaluated as a treatment of photodamaged skin. The study included a 6-month, randomized, double-blinded, placebo-controlled phase and an additional 6-month open-label phase during which all subjects received TMG 0. 1%. Forty-five subjects with moderate to severe photodamaged facial skin applied study gel topically to the face once nightly (22 subjects received TMG 0.1% and 23 subjects received placebo). At 6 months, TMG 0. 1% was found to be superior to placebo in improving overall severity of photodamage (P=.0003) and in the investigator's global assessment of clinical response (P<.0001). Statistically significant improvement relative to placebo was observed in fine wrinkling (P<.0001), mottled hyperpigmentation (P=.0002), yellowing/ sallowness (P<.0001), and lentigines (P=.0054). The improvements observed after 6 months of open-label therapy were consistent with the results observed in TMG 0. 1%-treated subjects during double-blinded treatment. Most signs and symptoms of cutaneous irritation were mild throughout the treatment period. At one month, a higher proportion of subjects in the TMG 0. 1% group relative to the placebo group experienced an increase in severity of cutaneous irritation. After 6 months, the difference between treatment groups was statistically significant only for peeling (P=.001) and dryness (P=.007).

Long-term efficacy and safety of tretinoin emollient cream 0.05% in the treatment of photodamaged facial skin: a two-year, randomized, placebo-controlled trial.

BACKGROUND: Long-term (>1 year) placebo-controlled studies of tretinoin in the treatment of photodamaged skin have not been conducted. Recently, we conducted a 2-year placebo-controlled study of tretinoin emollient cream 0.05%, including histopathologic assessment of safety and analysis of markers of collagen deposition. OBJECTIVE: The objective of the study was to determine the long-term safety and efficacy of tretinoin emollient cream 0.05% in the treatment of moderate to severe facial photodamage. METHODS: A total of 204 subjects were treated with tretinoin or placebo (vehicle emollient cream) applied to the entire face once a day for up to 2 years. Clinical and histologic effects were assessed at regularly scheduled clinic visits. RESULTS: Treatment with tretinoin resulted in significantly greater improvement relative to placebo in clinical signs of photodamage (fine and coarse wrinkling, mottled hyperpigmentation, lentigines, and sallowness), overall photodamage severity, and investigator's global assessment of clinical response (p<0.05). Histologic evaluation showed no increase in keratinocytic or melanocytic atypia, dermal elastosis, or untoward effects on stratum corneum following treatment with tretinoin compared with placebo. Immunohistochemistry studies, conducted at three study centers, showed a significant increase relative to placebo in facial procollagen 1C terminal, a marker for procollagen synthesis, at month 12 (p=0.0074). CONCLUSION: Long-term treatment with tretinoin emollient cream 0.05% is safe and effective in subjects with moderate to severe facial photodamage.