REVIEW ARTICLE
`
`Am J Clin Dermatol 2008; 9 (6): 369-381
`1175-0561/08/0006-0369/$48.00/0
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Topical Retinoids in Acne Vulgaris
`Update on Efficacy and Safety
`
`Anja Thielitz and Harald Gollnick
`
`University Clinic of Dermatology and Venereology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
`
`Contents
`
`3.
`
`Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
`1. Mode of Action of Topical Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
`1.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
`1.2 Biologic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
`2. Tretinoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
`2.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
`2.2 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
`2.3 Safety and Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
`Isotretinoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
`3.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
`3.2 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
`3.3 Safety and Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
`4. Adapalene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
`4.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
`4.2 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
`4.3 Safety and Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
`5. Tazarotene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
`5.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
`5.2 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
`5.3 Safety and Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
`6. Retinaldehyde and Retinol (Vitamin A) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
`7. Maintenance Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
`8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
`
`Abstract
`
`Topical retinoids represent a mainstay of acne treatment because they expel mature comedones, reduce
`microcomedone formation, and exert anti-inflammatory effects. The first-generation retinoid tretinoin (all-trans
`retinoic acid) and the synthetic third-generation polyaromatics adapalene and tazarotene are approved for acne
`treatment by the US FDA, whereas topical tretinoin, isotretinoin (13-cis retinoic acid), and adapalene are
`accredited in Canada and Europe. Topical retinoids have a favorable safety profile distinct from the toxicity of
`their systemic counterparts. Local adverse effects, including erythema, dryness, itching, and stinging, occur
`frequently during the early treatment phase. Their impact varies with the vehicle formation, skin type, frequency
`and mode of application, use of moisturizers, and environmental factors such as sun exposure or temperature.
`The broad anti-acne activity and safety profile of topical retinoids justifies their use as first-line treatment in most
`types of non-inflammatory and inflammatory acne. They are also suitable as long-term medications, with no risk
`of inducing bacterial resistance, for maintenance of remission after cessation of initial combination therapy.
`
`The sequence of events leading to acne initiation is still incom-
`pletely understood and the subject of controversial discussion;[1-3]
`however, the most notable pathophysiologic factors are sebaceous
`
`gland hyperplasia with hyperseborrhea, alterations in the growth
`and differentiation of follicular keratinocytes, Propionibacterium
`acnes colonization of the follicle, and inflammation and immune
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`Thielitz & Gollnick
`
`reactions. Clinical experience and evidence from various studies
`have shown that parallel targeting of these major pathogenetic
`factors represents the most effective approach in the treatment of
`acne.[4,5]
`The primary acne lesions are the microcomedones, which are
`invisible to the naked eye but require special attention with regard
`to the development of therapeutic strategies because they represent
`the central precursor lesions evolving into either non-inflamma-
`tory comedones or inflammatory papules and pustules. The patho-
`genetic factors that induce microcomedones are hyperseborrhea
`and hyperproliferation and aberrant differentiation of the follicular
`epithelium; however, on a microscopic level, the beginning of
`microcomedone formation is also associated with vascular endo-
`thelial cell activation and inflammatory events.[6] Targeting
`microcomedone formation is not only essential in the prevention
`and therapeutic control of acne but also a prerequisite to mainten-
`ance of long-term remission of this chronic disease.
`Retinoids play a crucial role in the treatment of acne because
`they inhibit the formation of and reduce the number of both non-
`inflammatory microcomedones[7-9] and inflammatory acne lesions,
`with several retinoids having been shown to exert direct anti-
`inflammatory activity.[10] These agents are synthetic derivatives of
`retinol (vitamin A) and those used in topical form for the treatment
`of acne include tretinoin (all-trans retinoic acid), isotretinoin
`(13-cis retinoic acid), adapalene (derived from naphthoic acid),
`and tazarotene (acetylenic retinoid), whereas retinaldehyde, reti-
`nol, and retinyl esters are used in cosmetic preparations for acne
`skin.[11] Motretinide is a topical retinoid in an aromatic ester form
`available in Switzerland only. Tazarotene is not approved for acne
`treatment in Europe, and topical isotretinoin is not US FDA
`approved (table I).
`The aim of the article is to provide a systematic review of the
`available evidence of the efficacy and safety of topical retinoids
`
`Table I. Overview of available topical retinoids/combination products in
`different countries
`
`Japan
`Adapalenec
`
`Europe
`US/Canada
`Tretinoin
`Tretinoin
`Adapalene
`Adapalene
`Isotretinoin
`Tazarotene
`Retinaldehyde
`Retinaldehyde
`Isotretinoin + erythromycin
`Tretinoin + clindamycin
`Tretinoin + erythromycin Adapalene + benzoyl
`peroxidea
`Tretinoin + erythromycin
`Motretinideb
`a Available in most European countries.
`b Available in Switzerland only.
`c Will be introduced in December 2008.
`
`used as monotherapy or as part of combination therapies in the
`treatment of acne vulgaris.
`A MEDLINE database search was performed via PubMed to
`extract all topics dealing with topical retinoids using the search
`term ‘topical retinoids and acne’. The search period was 1963 to
`January 2008. After reviewing the titles and abstracts, articles
`were excluded if they addressed an excluded topic (chloracne,
`rosacea, acne venenata, acne fulminans, acne necrotica), were not
`in English or German, or contained news, letters, or citations
`without an abstract.
`
`1. Mode of Action of Topical Retinoids
`
`1.1 Pharmacology
`
`The biologic effects of topical retinoids are mediated and
`regulated by nuclear hormone receptors (retinoic acid receptors
`[RARs] and retinoid X receptors [RXRs]) and cytosolic binding
`proteins.[12] A retinoid is currently defined as a molecule that binds
`to and activates RARs either directly or by metabolic conversion
`and thereby elicits transcription of retinoic acid-responsive
`genes.[13] This clear definition overcomes previous limitations
`related to the fact that some molecules structurally similar to
`retinol had no biologic effects, whereas other synthetic compounds
`with no resemblance to retinol had retinol-like activity. Each
`receptor family includes three subtypes (α, β, γ) that form homo-
`or heterodimers that bind to a DNA stretch called a ‘responsive
`element’ (RARE and RXRE) and induce the expression or
`downregulation of target genes in a ligand-dependent manner. The
`most frequently distributed receptors in human skin are RARγ and
`RXRα, and a heterodimer formed by the two transduces the
`retinoid effects in human skin.[14,15] The discovery of nuclear
`RARs provided clues to a rational design of new synthetic recep-
`tor-selective agonists with different or improved physiochemical
`profiles and tolerability.[12] Tretinoin, the first topical retinoid
`approved for acne, binds with equal affinity to all RARs, and its
`metabolite 9-cis retinoic acid binds to RXRs. Furthermore, treti-
`noin upregulates and binds to the cellular retinoic acid binding
`protein II (CRABP II), the predominant intracellular binding pro-
`tein in skin. This non-selective action and binding to CRABP II
`has been proposed as the reason for the high irritative potential of
`tretinoin. Another drawback of tretinoin is its high instability when
`exposed to light and oxygen.[16]
`This limitation of tretinoin was overcome by the development
`of new synthetic third-generation retinoids. The three aromatic
`rings of adapalene, which was approved for acne treatment in
`1996, render this molecule more stable to light and oxygen.[16] Its
`lipophilic structure and low solubility enable penetration into the
`sebaceous follicle rather than through the skin, which may contrib-
`ute to better tolerability. Adapalene binds selectively to RARβ and
`
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`RARγ and activates gene expression through all RARs but not
`RXRs.[17] Despite being a strong inducer of CRABP II messenger
`RNA, adapalene does not bind to this protein, which might also
`help explain its improved tolerability.[18]
`Tazarotene, which was approved for treatment of acne in 1997,
`was designed as a polyaromatic molecule with higher conforma-
`tional rigidity than tretinoin as a means of reducing unwanted side
`effects. Tazarotene is RAR selective and activates gene expression
`through RARβ and RARγ, but antagonizes the activity of the
`nuclear transcription factor activator protein (AP)-1[19,20] through
`all RARs; this action is believed to mediate anti-inflammatory and
`anti-proliferative effects in psoriasis.
`Retinaldehyde is a natural metabolite of retinol that does not
`bind to RARs; its biologic activity results from conversion to
`tretinoin by epidermal keratinocytes.[11,21] The same holds true for
`retinol and retinyl esters, which are used in cosmetic preparations.
`
`1.2 Biologic Effects
`
`influence proliferation and differentiation of
`Retinoids
`cells[12,22,23] and reverse abnormal desquamation by increasing
`follicular epithelial turnover and accelerating the shedding of
`corneocytes, resulting in expulsion of mature comedones (open
`and close type) and suppression of microcomedone formation.[7-9]
`RARγ in particular has been shown to mediate both the efficacy
`and irritation potential of retinoids,[15] whereas RARα agonist
`activity has no impact on irritation. Furthermore, retinoids modu-
`late the expression of the transcription factors, such as AP-1,[19]
`which regulate the genetic expression of growth factors (e.g.
`vascular endothelial growth factor) and degradative enzymes (e.g.
`matrix metalloproteases) involved in inflammatory responses.
`Moreover, retinoids stimulate collagen synthesis[24,25] and prevent
`oxidative stress and thereby exert an anti-aging effect.[11] They are
`also involved in the induction of apoptosis by a variety of mechan-
`isms either associated with binding of retinoid receptors or inde-
`pendent of receptor binding.[26]
`The change in the microclimate of the pilosebaceous follicle by
`prevention of hypercornification promotes an inhospitable aerobic
`environment for P. acnes and is likely to enhance the penetration
`of other topical drugs. A specific direct antibacterial effect against
`P. acnes has been shown for retinaldehyde only.[27]
`In addition to an indirect anti-inflammatory effect resulting
`from changes in the follicular environment, various in vitro and
`in vivo studies have demonstrated a direct immunomodulatory
`activity for topical retinoids.[10,17,28-30] In vitro assays have re-
`vealed that adapalene is associated with greater inhibition of
`lipoxygenase pathways and leukotriene production than tretinoin,
`isotretinoin, and etretinate.[17,28] Furthermore, adapalene and treti-
`noin, and to a lesser extent isotretinoin, inhibited release of oxygen
`free radicals from polymorphonuclear leukocytes derived from
`rabbits.[17] However, adapalene was less effective than tretinoin
`
`and isotretinoin in inhibiting human polymorphonuclear leukocyte
`chemotaxis.[17] Both adapalene[10,30] and tretinoin[29] modulate the
`innate immune response by inhibiting expression of toll-like re-
`ceptor-2 on monocytes and keratinocytes, respectively.
`In vivo, tretinoin, isotretinoin, and adapalene significantly de-
`creased UV-induced erythema, whereas in other in vivo models of
`inflammation including croton oil, arachidonic acid ear edema
`(mouse), and carrageenan-induced paw edema (rat), the anti-
`inflammatory effect of adapalene was superior to that observed
`with tretinoin.[10,28] However, a recent study performed in rats
`demonstrated a significant anti-inflammatory effect in car-
`rageenan-induced rat paw edema in favor of tretinoin.[31] These
`results support and provide an additional theoretic background for
`the significant reduction in inflammatory lesions that has been
`observed in well controlled clinical trials of various formulations
`of adapalene, tretinoin, and tazarotene (see following sections).
`
`2. Tretinoin
`
`2.1 Monotherapy
`
`Tretinoin was the first topical retinoid to be described in reports
`by St¨uttgen and Beer in 1962.[32] It has been a mainstay of acne
`therapy for more than 35 years and was approved by the FDA in
`1971. Numerous trials have demonstrated that tretinoin is effective
`as a single-agent therapy in patients with mild-to-moderate
`comedonal or inflammatory acne,[33-35] in whom it significantly
`reduces the numbers of both comedones and inflammatory acne
`lesions. Tretinoin has shown in several trials that treatment for at
`least 12 weeks results in reductions in lesion counts ranging
`between 32% and 81% for non-inflammatory lesions and between
`17% and 71% for inflammatory lesions, i.e. 22–83% of the total
`lesion count.[36] Bikowski[37] recently proposed a simple way of
`comparing the efficacy of different acne treatments by calculating
`the mean percentage reductions in lesion counts extracted from
`two well controlled, phase III trials published in the prescription
`information and adjusting for the vehicle effect. Using this
`method, the reported absolute mean percentage reductions for
`0.1% and 0.04% tretinoin microsphere gel were 38.5% and 37.5%,
`respectively. The initial response to topical tretinoin may be
`observed after 2–3 weeks, but substantial clinical improvement
`can be achieved after 4–6 weeks of continuous therapy, and
`maximum improvement occurs after 3–4 months.[38] An ultrastruc-
`tural study demonstrated significant reductions in microcome-
`dones of 50% after 6 weeks and 80% after 12 weeks of treatment
`with 0.1% tretinoin cream,[7] while another study showed a 35%
`reduction in microcomedones[8] after 12 weeks of treatment with
`0.025% tretinoin gel. These findings emphasize the need for long-
`term adherence to obtain complete remission.
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`Thielitz & Gollnick
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`Tretinoin is available as a gel (0.01%, 0.025%, and 0.05%),
`cream (0.025%, 0.05%, 0.1%, and 0.4%), liquid (0.025%, 0.05%,
`and 0.1%), lotion (0.1%), ointment (0.05%), compress (0.05%),
`microsphere gel (0.04% and 0.1%), and prepolyolprepolymer-2
`gel or cream (0.025%). Use of tretinoin has been limited by
`cutaneous irritation, including erythema, desquamation, burning,
`and pruritus, particularly in patients with sensitive skin. To over-
`come such tolerability problems, tretinoin has been reformulated.
`New preparations with similar effectiveness but improved cutane-
`ous tolerability[39-42] include tretinoin trapped within copolymer
`microspheres (Retin-A Micro®, OrthoNeutrogena)1 or prepolyol-
`prepolymer-2 gel or cream (Avita®, Bertek Pharmaceuticals),
`which gradually release the active ingredient over time. Further-
`more, the microsphere formulation offers marked protection
`against tretinoin photodegradation, even in the presence of a
`strong oxidizing agent such as benzoyl peroxide.[43,44] After 12
`weeks of treatment, 0.04% tretinoin microsphere gel was no better
`tolerated than the 0.1% formulation, but was less effective against
`inflammatory lesions at week 2.[45]
`Two studies have reported that liposomal encapsulation of
`tretinoin allows a reduction in the concentration of the active agent
`without decline in efficacy for acne vulgaris compared with
`0.025% or 0.05% tretinoin gel after once-daily topical application
`for 10 (or 12) weeks, but has a much better cutaneous tolerability
`and improved efficacy with respect to reduction in come-
`dones.[46,47] However, liposomal preparations of tretinoin are not
`yet commercially available. Furthermore, a recent study demon-
`strated improved efficacy and tolerability of a new topical retinoid
`acid/cyclodextrin complex formulation (0.025%) compared with
`the double-strength conventional preparation (0.05%).[48]
`
`2.2 Combination Therapy
`
`Because of the multi-factorial nature of acne pathogenesis,
`combination therapies have been developed to target two or more
`causative elements of the disease, for example, a retinoid with
`comedolytic and anti-inflammatory potential combined with an
`antibacterial to arrest P. acnes growth and related immune re-
`sponse.[5,49] An early trial published in 1978 reported that a twice-
`daily application of 2% erythromycin base in a hydroalcoholic
`solution accompanied by once-daily use of 0.05% tretinoin solu-
`tion was substantially more effective than tretinoin or erythro-
`mycin alone for treatment of moderate inflammatory acne.[50]
`Subsequently, the high efficacy and tolerability of a fixed gel
`preparation containing 0.025% tretinoin and 4% erythromycin for
`acne vulgaris was confirmed in an open-label multicenter study of
`1337 patients,[51] and a combined alcoholic erythromycin/tretinoin
`solution showed good efficacy and tolerability in a multicenter
`
`study that included >6500 patients.[52] In a comparative study of
`combination treatments, 3% erythromycin/5% benzoyl peroxide
`achieved a significantly greater reduction in both physician- and
`patient-rated severity of acne symptoms than 0.025% tretinoin/4%
`erythromycin after 2 weeks of treatment.[53]
`The improved efficacy of tretinoin in combination with benzoyl
`peroxide compared with either ingredient alone has been shown in
`several trials.[54-56] Both substances must be applied alternately
`(e.g. tretinoin in the morning and benzoyl peroxide in the evening)
`to avoid oxidative degradation of tretinoin. Tretinoin microsphere
`gel has been shown to have improved stability towards UV- and
`oxidative-induced degradation.[44] Its combination with a 6% ben-
`zoyl peroxide cleanser resulted in a greater reduction in inflamma-
`tory acne lesions than monotherapy with 0.1% tretinoin micro-
`sphere gel, without increased skin irritation.[56]
`The combinations of 1% clindamycin and 0.025% tretinoin
`hydrogel (Velac®, Connetics) and 1.2% clindamycin and 0.025%
`tretinoin gel (Ziana®, Medicis) were well tolerated and signifi-
`cantly more effective than clindamycin, tretinoin, or its vehicle for
`the treatment of acne vulgaris in large trials involving 2219[57] and
`>4500[58] patients, respectively. A previous study reported that a
`fixed formulation of 1.2% clindamycin and 0.025% tretinoin in a
`gel base (a different formulation of ‘Velac®’ than that currently
`marketed by Connetics) was statistically significantly more effec-
`tive than tretinoin in reducing mean papular and total inflamma-
`tory lesion counts as well as mean overall acne severity score, with
`no difference in tolerability.[59]
`A combination of clindamycin and benzoyl peroxide with
`tretinoin was reported to be well tolerated and showed improved
`efficacy compared with tretinoin combined with clindamycin;
`however, in this study, addition of tretinoin to the combination of
`clindamycin and benzoyl peroxide had no additional benefit in
`terms of efficacy.[60] A study investigating a 1% clindamycin/5%
`benzoyl peroxide topical gel in combination with either tretinoin
`microsphere gel at concentrations of 0.04% or 0.1%, or 0.1%
`adapalene gel, revealed good tolerability and a trend toward better
`resolution of hyperpigmentation in individuals with dark ethnic
`skin receiving the clindamycin/benzoyl peroxide topical gel in
`combination with the 0.04% tretinoin microsphere gel.[61] The
`good tolerability and safety of triple combination regimens of
`clindamycin/benzoyl peroxide topical gel and tretinoin micro-
`sphere gel 0.1% or 0.04% (or 0.1% adapalene) were confirmed in
`another community-based, 12-week, investigator-blinded, paral-
`lel-group, multicenter study involving 353 subjects.[62] The combi-
`nation regimens with tretinoin microsphere gels were equally
`effective and well tolerated.
`
`1 The use of trade names is for product identification purposes only and does not imply endorsement.
`
`© 2008 Adis Data Information BV. All rights reserved.
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`2.3 Safety and Tolerability
`
`compared with 389 similarly and prospectively identified women
`with no topical tretinoin exposure during pregnancy.[75] The study
`supported the notion that topical tretinoin is not associated with an
`increased risk of minor malformations consistent with retinoic
`acid embryopathy.
`Topical tretinoin is an FDA pregnancy category C drug, which
`means that a risk cannot be ruled out because data in humans are
`lacking and animal studies are either positive or data are also
`lacking. Topical tretinoin may be prescribed when the benefits
`outweigh the risks; however, administration during pregnancy is
`difficult to justify because safer treatments are available and acne
`is not a life-threatening disease. During lactation, avoidance of
`topical tretinoin is advised because excretion via breast milk has
`not been studied and adverse reactions in nursing infants have not
`been ruled out. The safety and effectiveness of topical tretinoin in
`children aged <12 years have not been established.
`
`3. Isotretinoin
`
`3.1 Monotherapy
`
`The major adverse effect of tretinoin and other topical retinoids
`is local skin irritation,[63] including erythema, peeling, dryness,
`burning, and itching. Some individuals might also experience a
`pustular flare. The irritative potential depends on the concentration
`and formulation of the product. A study comparing the tolerability
`of adapalene gel with six different formulations of tretinoin report-
`ed three groups of descending order of irritancy: 0.1% tretinoin
`cream and 0.05% tretinoin cream; 0.025% tretinoin gel, 0.01%
`tretinoin gel, and 0.025% tretinoin cream; and 0.1% adapalene gel
`and petrolatum (control).[41,64] The irritative potential of 0.1%
`tretinoin microsphere gel and 0.05% tretinoin emollient cream was
`similar to that of 0.025% tretinoin cream.[65] Another study com-
`paring 0.1% tretinoin microsphere gel with 0.1% adapalene gel
`found similar erythema and peeling rates slightly in favor of
`adapalene.[66] Retinoid-induced skin irritation can be relieved by
`regular use of a gentle moisturizing cream as an adjunctive treat-
`ment.[67] It is advisable to decrease sun exposure and avoid weath-
`er extremes such as cold wind and hot humidity during retinoid
`treatment. When exposed to light, 50% degradation of tretinoin
`was observed after 2 hours and 95% after 24 hours.[16] Therefore,
`Isotretinoin is the 13-cis isomer of retinoic acid and is available
`tretinoin should be applied once daily at bedtime. In contrast, 89% in topical formulations (0.05% gel or cream, 0.1% cream) in
`of tretinoin microsphere gel remained stable after 2 hours of
`countries outside the US. Its binding activity to RAR is low and
`simulated solar radiation, even in combination with clindamycin
`isotretinoin does not bind to RXRs or CRABP. Some of the effects
`and benzoyl peroxide, rendering 86% undegraded tretinoin after
`seen with isotretinoin in sebocytes might be related to its isomer-
`2 hours.[43]
`ization to tretinoin.[76,77] Topical 0.05% isotretinoin gel was effec-
`The percutaneous absorption of topical 0.05% tretinoin applied
`tive compared with its vehicle in 268 patients with mild-to-
`as emollient cream or cream is low and ranges between 1% and
`moderate acne.[78] A significant anti-acne efficacy was observed
`2%, even after long-term application.[68] Topical administration of
`after 8–12 weeks. In comparative trials, 0.05% isotretinoin gel was
`tretinoin acid did not significantly increase systemic retinoid plas-
`as effective as 0.05% tretinoin cream,[79] and slightly less effective
`ma concentrations, which remained in the range of natural endoge-
`than 0.1% adapalene gel,[80] although the differences were not
`nous levels and were more influenced by nutritional and diurnal
`statistically significant. Benzoyl peroxide had a superior effect
`factors.[68-70] In terms of risk assessment, a pharmacokinetic model
`compared with isotretinoin on inflamed lesions in the sense that
`predicts that topical application of tretinoin results in an internal
`improvement occurred earlier.[81]
`exposure that is four to six orders of magnitude lower than a
`minimally teratogenic dose.[71] Conversely, several case reports
`have suggested that fetal congenital abnormalities consistent with
`retinoid embryopathy following topical application of tretinoin in
`the first trimester are possible.[72,73] However, in a study evaluating
`the risks of birth defects in mothers exposed to topical tretinoin
`during early pregnancy, 215 exposed women were compared with
`430 age-matched control individuals.[74] A relative risk of 0.7
`(95% CI 0.2, 2.3) for a major congenital anomaly after topical
`tretinoin exposure was estimated, a finding that excluded any
`increased risk and rather suggested a protective effect of topical
`tretinoin. The results of this study were confirmed by those of
`another study in which 106 pregnant women with first-trimester
`exposure to topical tretinoin were prospectively identified and
`followed up with regard to birth outcomes, including pregnancy
`loss, major structural defects, and pre- and postnatal growth,
`
`3.2 Combination Therapy
`
`A study of 160 patients with mild-to-moderate acne revealed
`that a fixed combination of 0.05% isotretinoin and 2% erythro-
`mycin (Isotrexin®, Stiefel) was significantly better in terms of
`reducing inflammatory lesions than isotretinoin alone at week 4
`and than erythromycin alone at week 12.[82] Isotretinoin/erythro-
`mycin (‘double-strength Isotrexin®’) gel applied only once daily
`showed comparable efficacy to benzoyl peroxide/erythromycin
`applied twice daily in the treatment of mild-to-moderate acne
`vulgaris of the face.[83]
`
`3.3 Safety and Tolerability
`
`0.05% isotretinoin produces symptoms of irritative dermatitis,
`including erythema, scaling, burning, and dryness, in a range
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Am J Clin Dermatol 2008; 9 (6)
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`comparable to that seen with 5% benzoyl peroxide gel.[81] In terms
`of tolerability, isotretinoin was slightly better than 0.05% tretinoin
`cream but significantly worse than 0.1% adapalene gel.[80,81] Sta-
`bility investigations revealed that 80% of topical isotretinoin re-
`mained stable after 4 hours of exposure to incandescent light, and
`that 60% remained stable after 2 hours of exposure to fluorescent
`light.[84]
`Although topical isotretinoin does not reduce sebaceous gland
`size and sebum production, a penetration study of five different
`formulations applied to human skin in vitro showed that substan-
`tial amounts of topically applied isotretinoin were delivered via
`the follicular route to the sebaceous glands.[85] However, several
`reports have indicated that percutaneous systemic absorption is
`negligible after topical application of 0.05% isotretinoin gel, even
`after multiple applications at doses approximately 12 times greater
`than normal daily use,[86] as well as after topical application of
`0.1% isotretinoin cream with or without topical sunscreens.[87,88]
`These results suggest that systemic absorption of topical isotreti-
`noin is less than the US recommended daily allowance of retinol
`supplementation.
`Because oral isotretinoin is a potent teratogen and designated
`pregnancy category X, use of topical isotretinoin, which is not
`FDA designated, is contraindicated during pregnancy and the drug
`should be used with caution in women of childbearing potential.
`Furthermore, topical isotretinoin is contraindicated during lacta-
`tion because excretion via breast milk has not been studied and
`adverse reactions in nursing infants have not been ruled out. The
`safety and effectiveness of topical isotretinoin in children aged
`<12 years have not been established.
`
`4. Adapalene
`
`4.1 Monotherapy
`
`Adapalene is a new synthetic, third-generation topical retinoid
`derived from naphthoic acid and available as 0.1% gel, cream, and
`solution and as 0.3% gel (Differin®, Galderma). Numerous studies
`have assessed the clinical efficacy of adapalene, used either as
`monotherapy or as part of combination therapies.[89,90] Most
`sources of direct information regarding the relative safety and
`efficacy of 0.1% adapalene gel derive from comparative studies