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`ARTICLES
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`ROSACEA: WHERE ARE WE Now?
`JOSEPH 8 8JKOWSKJ MD', MITCHEL P GOLDMAN MD 2
`
`BIKOWSKI SKIN CARE CENTER, SEWICKLEY, PENNSYLVANIA
`
`2 DEPARTMENT OF DERMATOLOGY/MEDICINE, UNIVERSITY OF CALIFORNIA, SAN DIEGO,
`
`CALIFORNIA, AND DERMATOLOGY/COSMETIC LASER ASSOCIATES OF LA JOLLA, INC.,
`
`LA JOLLA, CALIFORNIA
`
`Abstract
`
`Adv<mces continue to be made in the classification and treatment of rosacea, a chronic dermatologic syndrome. A new empiric clas(cid:173)
`sification system identifies 4 rosacea subtypes (erythematotdangiectatic, papulopustular, phymatous, and ocular) that may aid in more
`precise diagnosis. Several new therapies have recently been approved for treatment of rosacea. Azelaic acid 15% gel is a new first(cid:173)
`tier topical agent proven effective in reducing inflammatory lesions and erythema. New formulations of metronidazole and sulfac(cid:173)
`eramide 10%/sulfi.Jr 5% that offer cosmetic or tolerability advantages are now available. Intense pulsed light therapy has demonstrat(cid:173)
`ed effectiveness in reducing flushing, erythema, and telangiectases, with greater tolerability than existing laser systems. Other treat(cid:173)
`ments under investigation include low-dose doxycycline hyclate (which may provide greater safety than existing oral antibiotics). ben(cid:173)
`zoyl peroxide/clindamycin gel, and tacrolimus ointment (for steroid-induced rosacea). With this expanded armamentarium of med(cid:173)
`ical and light-based therapies, clinicians can now implement a multifaceted approach to treatment, crafting new treatment combina(cid:173)
`tions to address the unique and evolving features of rosacea in each individual patient.
`
`Introduction
`
`To date, there is no clearly identified cause for rosacea and no
`recognized cure'-'· Rosacea is a condition that is managed. For
`many of the 14 million Americans diagnosed with this derma(cid:173)
`tologic syndrome, the marked stigmata of rosacea contribute to
`low self-esteem, stress on the job, and wcial isolation'·1
`• Thus,
`the paramount gml of all rosacea management strategies must
`be to improve quality of life for patients. Fortunately, new
`advances in the understanding of rosacea and an expanding
`<may of treatment options are making it possible to more fine(cid:173)
`ly tune treatment to address the individual needs of each
`patient, leading to improved outcomes. This article will review
`advances in the classification and treatment of rosacea that
`have occurred over rhe lust few years and will suggest a multi(cid:173)
`faceted approach to treatment of each recognized ~ubtype of
`rosacea.
`
`A More Precise Classification System
`Rosacea is not a disease hut rather a syndrome wirh an individ(cid:173)
`ual presentation in each patient'. Most patients experience
`
`ADDRESS FOR CORRESPONDENCE:
`Joseph B Bikowski MD
`l3ikowski Skin Care Center
`500 Chadwick St
`~~wicklcy, PA 15143
`£'hone: (412) 741-2810
`
`t:• 2004, Journal of Drugs In Dermatology
`
`flushing and/or erythema; many present with inflammatory
`papule:; and pustules, edema, telangiectasia, or ocular symp(cid:173)
`toms; a few (mostly men) develop rhinophymau.
`In each
`patient, these characteristic signs and symptoms appear in dif(cid:173)
`ferent configurations that often change over time, as Hare-ups
`interrupt periods of rcmbsion'-;. Historically, rosacea has been
`described in terms of 4 stages: prerosacea (intcmlittent episodes
`of flushing or blushing); stage I (erythema persisting for hours
`or days and tiny telangiectases); stage 2 (inflammatory papules
`and pustules, persistent erythema, more telangiectasia); and
`stage 3 (moderate to severe erythema, inflammatory lesions,
`and/or telangiectasia, appearance of phymas)'-;-7
`• Many practi(cid:173)
`tioners, as well as the published literature and clinical trial
`evaluations, continue to rely on this staging system. However,
`stages imply a progressive diseL,se course, suggesting that flush(cid:173)
`ing leads to persistent erythema, then eventually to the appear(cid:173)
`am:c of inflammatory lesions, worsening telangiectasia, and in
`some cases phymatous growth. This ~volutionary progression,
`while observed in some patients, is not congruent with clinical
`findings by dermatologists in many patients.
`
`A st<~ndard, empiric classification system, developed by an
`expert commitree of the 1\:atiomll Rosacea Society and pub(cid:173)
`lished in 2002, aims to establish a more scientifically prcci>e
`paradigm for diagnosis of rosacea'. Because there is no clear eti(cid:173)
`ology or pathogenesis of rosacea, the classification is betsed on
`morphologic characteristics. Four primary features of ros<lcea
`are identified: tlushing, nontransient erythema, papules and
`pustules, and telangiectasia. At least 1 of these features, with a
`centml f<~ce distribution, is required for a diagnosis of wsacea.
`
`.J Drugs Dermatol 2004: 3(3):251-261
`
`251
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`-·-··· -------------··--·------··----
`Supplied by the British Library- "The world's knowledge" www.bl.uk
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`1
`
`Galderma Laboratories, Inc. Ex 2003
`Dr. Reddy's Labs v. Galderma Labs., Inc.
`IPR2015-01782
`
`
`
`ROSACEA: WHERE ARE WE NOW?
`
`JDD 3:3: MAY/JUNE, 2004
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`Secondary features that may be present include burning/sting(cid:173)
`ing, plaqut:, dry appearance, edema, ocular manifestations,
`peripheral location, and phymatous changes. Common pat(cid:173)
`terns of features are grouped into 4 subtypes (erythematotelang(cid:173)
`iectatic, papulopustular, phymatous, and ocular) and 1 varia(cid:173)
`tion (granulomatous), described in Table F. Differences in
`severity may occur within each subtype, and some patients may
`have features of more than one subtype simultaneously1
`.
`
`This standard classification has not yet been universally
`embraced hy dermatologists, in part because it is perceived to
`be complex. However, this complexity reflects the attempt to
`
`remain in the investigational stage. The following section will
`review both newly approved therapies for rosacea and investi(cid:173)
`gational agents that have shown early promise.
`
`Oral Therapies
`
`There have not been any major advances in systemic treat(cid:173)
`ments for rosacea for several decades. The oral antibiotics
`(tetracycline, doxycycline, minocyciine, erythromycin, and
`metronidazole) that arc used off-label to treat rosacea, primari(cid:173)
`ly the papulopustular subtype, have heen available for the past
`30 to 40 years'·•. While their efficacy is well established, the
`
`Table I. Characteristics of 4 rosacea subtypes and a variantl
`
`Erythema to telangiectatic
`
`Papulopustular
`
`Phyma to us
`
`Ocular
`
`Flushing and persistent central facial erythema with or
`without
`Persistent central facial erythema with transient,
`or both.
`central facial
`or
`Thickening skin, irregular surface nodularities, and
`enlargement. May occur on the nose, chin, forehead,
`
`Noninflammatory; hard; brown, yellow, or red
`· or nodules of uniform size.
`cutaneous
`
`precisely describe the numerous features of the rosacea syn(cid:173)
`drome and systematically organize them into definable sub(cid:173)
`types. More time is needed to determine the validity and prac(cid:173)
`tical relevance of this classification in patient diagnosis and
`treatment. Nevertheless, careful assessment of each patient's
`disease features and determination of the relevant rosacea sub(cid:173)
`type(s) under the new classification can be useful in developing
`an effective inJividualized treatment plan for each patient, as
`discussed later in this article.
`
`New Therapies for Rosacea
`
`Several new a!;ents have recently become available or are cur(cid:173)
`rently being explored for use in the treatment of rosacea. As
`shown in Table II, the Food and Drug Administration has
`approved a number of new or reformulated topical agents and
`light-h<Jsed therapies for use in rosacea, while other agents
`
`possible associated adverse events generally make long-term use
`undesirable. This is a serious problem given the chronicity of
`rosacea, which requires long-tem1 maintenance therapy or
`repeated treatment of recurrences. Efforts to improve systemic
`therapy are currently focused on improving safety to permit
`extended use.
`
`Early results suggest that a low, suhantimicrobial dose of doxy(cid:173)
`cycline may provide efficacy in rosacea with a reduced inci(cid:173)
`dence of adverse events10
`• The tetracycline doxycycline hyclate
`is currently used as first- or second-tier therapy for rosacea at a
`daily dose of 100 - 200 mg"". Though it is generally well tol(cid:173)
`erated, known adverse events include skin rash, gastrointestinal
`distress, esophageal irritation, and (rarely) photosensitivity'· 1w.
`Tetracyclines, including doxycycline, have been discovered ro
`have nonantimicrobial properties (i.e., inhibition of Imltrix(cid:173)
`degrading mctallorrotcimses (~'llv!P:;) ). At subantimicrobial
`doses, they have been shown to rwvide activity ag:-~inst chronic
`
`.J Drug,; Dermatul 2004; 3(3);251-261
`
`252
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`Supplied by the British Library- "The world's knowledge" www.bl.uk
`
`2
`
`Galderma Laboratories, Inc. Ex 2003
`Dr. Reddy's Labs v. Galderma Labs., Inc.
`IPR2015-01782
`
`
`
`(Page 3 of 11)
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`ROSACEA: WHERE ARE WE NOW?
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`JDD 3:3: MAY/JUNE, 2004
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`Table II. New treatments recently FDA approved or under investigation for the treatment of rosacea
`
`I I
`
`outputs
`t---"'--'----~------l of 560-900 nm, spot sizes ranging
`from 4 8 mm to 10 50 mm,
`Existing therapeutic classes
`and maximum fluence ranging
`1--::--:------------l from 10-90 J/cm2
`Metronidazole
`Aurora SRTM and SR/DSTM
`Topical emulsion 0.75% (RozexTM)
`D-Light SRTM
`1 - : : : - - - - - - - - - - - - - - l EsteLux™
`Sulfacetamide 10%/sulfur 5%
`Lux Y™ and Lux G™
`Green tinted gel (Avar'rM Green)
`IPL™ Quantum HR and SR
`Untinted gel and cleanser (AvarTM)
`Multilight® HR
`Aqueous gel and cleanser in 10%
`OmniLight™ FPL
`urea vehicle (Rosula®)
`Photodenn® VUPL
`Alcohol-free emoJlient cream and
`Platinum HR/SR
`foaming wash (Clenia™)
`ProliteTM
`pH neutral cleanser (Rosanil™)
`SpectrPulse®
`Combination cream with two
`Vasculight1M Elite, HR, SR, and VS
`sunscreens (Rosac®)
`
`Tacrolimus
`0.1% ointment (Protopic®)
`
`perioduntitis and acne without an effect on the bacterial
`microflora. Thus, efficacy is achieved with a low incidence of
`side effects and reduced risk of development of bacterial resist(cid:173)
`ance10.
`
`Low-dose doxycycline hyclate (Periostat®) has recently shown
`promise in treatment of rosacea. An 8-week open-label study
`evaluated monutherapy with duxycycline 20 mg twice daily in
`patients with all stages of rosacea (N=SO); most patients had
`received no prior treatment. At an average of 4 weeks, patients
`showed an 80% to 100% reduction in inflammatury lesions, a
`50% decrease in erythema, and a decrease in the size and diam(cid:173)
`eter of telangiectases. These outcomes are consistent with
`those reported for conventional doses of tetracyclines. No inci(cid:173)
`dence of nausea, vomiting, headache, diarrhea, vaginitis, or
`photosensitivity was reported, even in patients who had previ(cid:173)
`ously reported such events while taking higher doses of doxycy(cid:173)
`cline10.
`
`A phase 3 multicenter, double-blind, placebo-controlled trial
`(N = 150) to evaluate rhe effectiveness of mono therapy with
`subantimicrobial-dose doxycycline (doxycycline hyclate 20 mg
`twice daily) for 4 munths is currently being conducted. Results
`frum this trial, expected in 2004, may help determine the future
`m\e of low-dose antibiotic therapy in the long-term treatment
`of rosacea.
`
`Another possible new oral therapy for the management of
`rosacea is prophylactic use of baby aspirin. Migraine headaches
`
`are reported 2 to 3 times more frequently in rosacea patients,
`perhaps due to the vascular instability associated with buth
`conditions14•15 • Some neurologists recommend use of baby
`aspirin (81 mg enteric coated) as prophylaxis against migraine
`headaches. In Dr. Bikowski's personal experience over a 2-year
`period among approximately 100 patients who took 1 baby
`aspirin nightly, the majority reported a subjectively significant
`decrease in flushing and subsequent erythema after 1 to 3
`months of treatment. However, to date there have been no
`controlled trials validating use of aspirin in rosacea.
`
`Topical Agents
`
`Over the pru;t decade, improvements in the topical therapy arena
`have been limited to the development of new formulations (i.e.,
`creams, lotions, gels, emulsions, cleansers) and different dose
`concentrations (e.g., 0.75% vs. 1 %) of existing therapeutic
`agents, such as metronidazole and sulfacetamide 10%/sulfur 5%.
`This fine-tuning has contributed to improved delivery of the
`active agent into the skin, enhanced cosmetic acceptability of
`medications, and some reduction in skin irritation'". However,
`introduction of new topical agents that provide improved
`efficacy and/or tolerability can ultimately be expected w have a
`greater impact overall on patient well-being.
`
`Azelaic acid gel
`Azelaic acid is a naturally occurring dicarboxylic acid that has
`shown anti·inflammatory effects in vitro"· 1'.
`It has recently
`been developed as a polyacrylic-acid-based aqueous 15% gel
`
`J Drugs Dermatol 2004: 3(3):251-261
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`253
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`
`Galderma Laboratories, Inc. Ex 2003
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`IPR2015-01782
`
`
`
`(Page 4 of 11)
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`ROSACEA: WHERE ARE WE NOW?
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`JDD 3:3: MAY/JUNE, 2004
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`with several advantages over the 20% cream formulation,
`including improved dmg release and aboorption. The gel incor(cid:173)
`porates a higher percentage of micronized azelaic acid (25%)
`than the cream (3%). In vitro, 25.3% of the azelaic acid pen(cid:173)
`etrated into viable skin when the gel was applied to hairless
`mouse skin in a Franz flow-through diffusion cell study, com(cid:173)
`pared with only 3.4% of the cream19
`• The pH of the gel
`:
`(approximately 4.8) is the optimum for maintaining formula(cid:173)
`tion conoistency and does not interfere with the skin acid man(cid:173)
`tle (pH approximately 5.5), in contraot to the more acidic
`cream (pH 3.3)"'.
`
`0
`
`Azelaic acid 15% gel (Finacea TM) is the first new class of med(cid:173)
`ication to be approved for the treatment of rosacea in more
`than 10 years. The effectiveness of azelaic acid 15% gel in
`reducing inflammatory papules and pustules and erythema has
`been demonstrated in 3 large phase .3 randomized, multicenter,
`double-blind trials: two pivotal 12-week vehicle-controlled
`studies (N =664 )11 which formed the basis ofFDA approval, and
`a 1 5-week comparative study vs. metronidazole 0. 75% gel
`(MetroGel'"), currently the most widely used topical agent for
`rosacea (N=25l)n. Treatment with azelaic acid gel resulted in
`significant percent reductions in inflammatory lesions, ranging
`from 51% to 73%. The percentage of patients whose erythema
`severity improved ranged from 44% to 56% in these 3 trials. In
`all trials, treatment with azelaic acid gel resulted in continuous
`improvement from visit to visit, and the differences vo. the
`comparator (vehicle or metronidazole gel) at the end of study
`were significant (PS.02). At the end of each study, close to two
`thirds of patients (61% and 62% pivotal; 69% comparative)
`achieved "ouccess" as defined by a new 7-point investigator's
`global assessment"'". Figures lA and 1 B illustrate the symptom
`resolution in a patient with papulopustular rosacea after just 4
`weeks of treatment with azelaic acid gel.
`
`Figure lA: Patient with papLllopustular rosacea at baseline.
`Figure 1 B. Same pHtient after 4 weeks of twice-daily treatment with
`azelaic acid Wa gel.
`
`j Drugs Dermatol 2004; 3(31:251-261
`
`254
`
`In all trials, a higher incidence of patiento treated with azelaic
`acid experienced adverse events, such as burning, stinging,
`tingling, or itching, which were mild and transient in the
`majority of patients21
`• Nevertheless, in clinical trials, around
`22
`'
`90% of patients rated local tolerability good or acceptable
`despite minor irritation21
`, and tolerability has not been
`21
`'
`reported to be a major patient concern in clinical use.
`
`Based on its established efficacy against inflammatory lesions
`and erythema, demonstrated vs. both vehicle and metronida(cid:173)
`zole 0. 75% gel, azelaic aCld 15% gel is now considered a first(cid:173)
`tier agent for the treatment of rosaceal1,24 •
`
`Metronidazole
`Metronidazole has been used as a topical therapy for rosacea
`• Numerous clinical trialo have
`since its approval in 198825
`established its efficacy in reducing inflammatory papules and
`improvement, both as
`pustules and producing overall
`monotherapy and maintenance therapy26,27. Metronidazole is
`available in a variety of formulations (gel, lotion, cream) and
`strengths (0. 75% and 1 %), which have been shown to have
`equivalent efficacyu'· 27 •
`In 2003, a water-based 0.75% topical
`emulsion (Rozex "'),applied twice daily, was approved for top(cid:173)
`ical treatment of papules and pustules of rosacea". Although
`presented as a new product, its ingredients are identical to
`the metronidazole 0.75%
`topical
`cream
`those
`in
`(MetroCream") formulation'"''". Because no clinical trial
`results have been reported, efficacy is expected to be similar to
`that of metronidazole cream. The most frequently reported
`adverse events ( <3% of patients) with the emulsion are the
`same as with the cream: burning and stinging, erythema, skin
`irritation, pruritus, and worsening of rosacea'8
`·'".
`
`Sulfacetamide 10%/Sulfur 5%
`
`Sodium sulfacetamide 10%/sulfur 5% is a supplemental option
`for topical treatment of rosacea that is generally us~:d in addi(cid:173)
`tion to, or afrer, oral or first-line topical therapies. It is used for
`the topical control of acne vulgaris, rosacea, and seborrheic der(cid:173)
`matitisl0. The efficacy of the sulfacetamide 10%/sulfur 5%
`combination in the treatment of rosacea was first established in
`the !950s'0·11 • Since then, a plethora of different formulations
`of sulfacetamide/sulfur have become available, many in the last
`year alone. The first to be developed were lotions (currently
`marketed as Nicosyn'" and Sulfacet-R" tinted and tint-free),
`followed by topical suspensions and cleanoers (Plexion~, Avar··,
`Rosula"', Rosanil'", Clenia"'), creams (Plexion'' SCT, Clenia~,
`Rosacg), and gel formulations (Avar Green'", Avar~, Rosula"').
`
`Because of its pre-1962 regulatory otatus, the sulfacetamide
`10%/sulfur 5% combination is known as a DES! (Dmg Efficacy
`• As a result, information on the
`Study Implementation) drttg 11
`status of new agents and rhe drug approval process is not avail(cid:173)
`able through the FDA's Electronic Orange Book, which lists
`
`j
`
`I
`
`l
`'~
`r ,.
`
`1
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`Supplied by the British Library- 'The world's knowledge" www.bl.uk
`
`4
`
`Galderma Laboratories, Inc. Ex 2003
`Dr. Reddy's Labs v. Galderma Labs., Inc.
`IPR2015-01782
`
`
`
`(Page 5 of 11)
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`ROSACEA: WHERE ARE WE NOW?
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`JDD 3:3: MAY/JUNE, 2004
`
`only products approved based on safety and effectiveness".
`Moreover, the core content of the prescribing information for
`each of these different formulations is identical and does not
`contain any supporting clinical data that would permit a criti(cid:173)
`cal or comparative analysis of the efficacy of these agents. The
`efficacy of the lotion and cleanser formulations has been estab(cid:173)
`lished in a few small 8-week clinical studies ( < 100 patients
`each), which showed that treatment with sulfacetamide/sulfur
`reduced inflammatory lesion count, erythema severity, and
`overall rosacea severity"'. Safety and tolerability are good, w~th
`mre reports of skin irritation, dryness, or redness.
`
`Within the past year, 3 new water-based gels, an emollient
`cream, 3 cleansers, a foaming wash, and a cream with sun(cid:173)
`:;creens, all containing sulfacetamide 10%/:;ulfur 5% as active
`ingredients, have become available for use in rosacea. Water(cid:173)
`bCJ.sed gel formulations represent the latest technological
`advance in topical therapies, offering less irritation and better
`skin aesthetics"'. A green-tinted sulfacetamide/sulfur gel (Avar
`Green'") may provide some patients with an additional imme(cid:173)
`diate cosmetic benefit by masking the appearance of erythema.
`Green co:;metics have long been recognized as useful tools for
`the redness of flushing and erythema".
`camouflaging
`Overlaying green onto red creates the perception of a more
`neutral flesh tone; however, the extent and duration of the per(cid:173)
`ceptual effect in this sulfacetamide/sulfur gel have not been
`measured. Unlike cosmetics, the gel contains an active agent,
`so it should only be applied as directed, 1 to 3 times daily. A
`similar untinted gel and cleanser (Avar'") are also available 34
`•
`
`Two other new formulations, an aqueous gel and a cleanser
`(Rosula"'), are based in a 10% urea vehicle. The humectant
`properties of urea may help minimize irritation and dryness';. A
`new alcohol-free emollient cream and a foaming wash
`(Clenia'") also may have moisturizing effects that would be ben(cid:173)
`eficial in patients with sensitive or dry skin36
`• An additional
`new cleanser formulation (Rosanil'") is fragrance free and pH
`neurral37
`• A small open-label study (N=31) of this sulfac(cid:173)
`etamide 10%/sulfur 5% cleanser, used in combination with
`twice-daily metronidazole 0. 75% gel for 4 weeks, established its
`tolerability and showed a trend toward improvement in lesion
`count, erythema severity index, and overall rosacea severity''.
`
`Finally, a new sulfacetamide 10%/sulfur 5% cream combined
`with two non-PABA sunscreen agents (Rosac'") has also recent(cid:173)
`ly become available. The inclusion of avobenzone, a UVA fil(cid:173)
`ter, and octinoxate, a UVB filter, helps protect patient:; against
`sun exposure, which is a primary rosacea trigger factor". In an
`investigator-blinded, randomized, parallel-group study (N =50)
`vs. metronidazole 0.75% cream (MetroCream"), 12 weeks of
`treatment with this sulfacetamide/sulfur/sunscreen cream
`resdted in a significantly greater improvement in the investi(cid:173)
`gator's global severity rating (83% vs. 58% with metronidazole
`cream). In addition, significant differences in percent reduc(cid:173)
`tion in inflammatory lesions (82% vs. 68%) and percent of
`
`patient:; with improved erythema (63% v:;. 42%) were ob:;erved
`with sulfacetamide/sulfur/sunscreen cream compared with
`metronidazole cream, respectively'".
`
`While each of these formulations is unique, the active ingredi(cid:173)
`ents are
`identical
`to each other and
`to existing
`sulfacetamide/sulfur agents. With the exception of the com(cid:173)
`bined sunscreen formulation, no new clinical data is available
`for these new products, thus efficacy can be expected to be sim(cid:173)
`ilar to that of other sulfacetamide/sulfur products currently in
`use. Clinical experience will rem8in pmamount in distinguish(cid:173)
`ing between thc:;e products and determining how they can best
`be used to benefit patients.
`
`Investigational Treatments
`
`The following topical agents are not yet approved for use in
`ro5acea but have shown some activity against it in exploratory
`investigations. L8rger controlled trials will be needed to con(cid:173)
`firm their efficacy and safety in ro:;acea patients.
`
`Benzoyl peroxide/clindamycin gel
`
`Topical clindamycin 1% has shown efficacy in rosacea38 and
`is currently available as both a lotion (Cleocin T") and a gel
`(Clindagel"'); It is considered a second-tier treatment option".
`Combination gels containing clindamycin 1% and benzoyl per(cid:173)
`oxide (BP) 5% (BcnzaClin", Duac") arc an approved treatment
`·"". A small exploratory trial has investigated
`for acne vulgaris39
`the utility of BP/clindamycin, applied once daily, for the treat(cid:173)
`ment of moderate rosacea. In a 12-week, randomized, double(cid:173)
`blind, multicenter, placebo-controlled trial (N=S3), a >70%
`reduction in inflammatory lesions was achieved with BP/clin(cid:173)
`damycin (PS.02 vs. placebo) by week 6, and was maintained
`through week 12. Reductions in erythema, flushing and blush(cid:173)
`ing, and overall severity of rosacea were also observed in
`patients treated with BP/clindamycin (PS.OO l ). Treatment
`with BP/clindamycin resulted in a .30% improvement in over(cid:173)
`all rosacea severity vs. 10% with placebo"A'.
`
`Tacrolimus ointment and pimecrolimus cream
`
`Tacrolimu:; and pimecrolimus are nonsteroidal immunomodula(cid:173)
`rors that act by calcineurin inhibition. They prevent inflam(cid:173)
`mation primarily by inhibiting cytokine production and block(cid:173)
`ing T-cell activation in a manner similar
`to that of
`cyclosporine""· Tacrolimus 0.1% ointment (Protopicl) and
`pimecrolimus 1% cre8m (ElideF) have recently been approved
`for the treatment of atopic dermatitis when conventional ther(cid:173)
`apy is inadvis8ble4w. Because of its anti-inflammatory proper(cid:173)
`ties, tacrolimus is currently being evaluated for use in a variety
`of other int1ammatory skin conditions, including rosacea".
`
`Several case studies have suggested that tacrolimus 0.075% or
`J Drugs Dermatol 2004: 3(3):251-261
`
`255
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`(Page 6 of 11)
`
`ROSACEA: WHERE ARE WE NOW?
`
`JDD 3:3: MAY/JUNE, 2004
`
`0.1% ointment, twice daily, given with or without oral tetracy(cid:173)
`cline, is effective in resolving the signs and symptoms of
`steroid-induced rosacea, including pmritus, tenderness, and
`• Tacrolimus appears to have a rapid onset of
`erythema46,.
`7
`action, with :;igns of improvement often observed within a few
`day:; and marked improvement achieved after several weeks of
`treatment"'-''. Because pimecrolimus has a :;imilar mechanism
`of action and anti-inflammatory activity in other dermatologic
`disorders, its efficacy in steroid-induced rosacea also deserves
`investigation.
`
`Light-Based Therapies
`Laser therapy can be effective in treating the vascular symp(cid:173)
`toms of rosacea, especially those rhat are not responsive to
`either systemic or topical therapy such as telangiectasia and
`persistent erythema. Until recently, pulsed dye laser (PDL) at
`585 nm or 595 nm has been the treatment of choice for these
`Its effectiveness was
`symptoms, especially telangiectasia"·".
`recently confirmed in a prospective controlled study (N= 12),
`which reported highly significant reductions in telangiectasia
`(75%), flushing (55%), and erythema (50%) scores (P<.Ol)'R.
`However, patient acceptability of PDL has been limited by
`inconsistent results and the frequent occurrence of purpura,
`which can last for several weeks and is difficult to conceal by
`51
`most patients4950
`·".
`•
`
`The advent of intense pulsed light (IPL) therapy has broadened
`the treatment possibilities for patiems with vascular symptoms.
`IPL employs selective photothermolysis with a broad spectrum
`of light, unlike the single wavelength of a laser. Like lasers, IPL
`focuses sufficient heat on targeted vessels in a specific time
`interval to destroy them by coagulation while leaving the sur(cid:173)
`rounding tissue undamaged'0
`• Advantages of IPL include the
`51
`•
`ability to select a wavelength within a broader spectrum rang(cid:173)
`ing from visible to infrared light; sequential pulsing (with sys(cid:173)
`tems manufactured by Lumenis Inc), which permits epidermal
`cooling between pulses; and a variable pulse duration, which
`enables different-sized vessels located at different deprhs to be
`effectively targeted - an advantage in treating small facial
`telangiectases••·". Most IPL systems have a spot size much larg(cid:173)
`er than lasers, which facilitates treatment of the entire face
`quickly - an advantage in addressing erythema and flushing'9
`•
`
`Recent srudit:s have shown reductions in redness, flushing, and
`In a large study conducted
`telangiectasia with IPL therapy.
`over 2 years, 188 evaluable patients (74 with rosacea) were
`treated with IPL (PhotoDerm" VL), with a median of 2 treat(cid:173)
`ments per patient". Facial clearing of 75% to 100% was noted
`in the majority (93%) of patients. These results were achieved
`after only 1 treatment in 68% of patients, although full clear(cid:173)
`ance of the diffuse facial veins associated with rosacea occasion(cid:173)
`ally required 2 treatments. In .3 rosacea patients who had been
`unsuccessfully treated with pulsed dye or copper laser, a single
`trearmenr with IPL resulted in 75% to 100% clearing. Adverse
`
`] Drugs Dermatol 2004; 3(3):251-261
`
`events, reported by 18% of patients, included bruising, persist(cid:173)
`ent edema, and transient hypopigmentation".
`
`In another study, .32 patients with predominantly moderate
`rosacea of subtype ] or ll who had plateaued on conventional
`therapy received 1 to 7 lPL treatments
`(Vasculighf" Plus/
`Vusculight~ SR)49
`• A 2.4 ms/4.0 ms double pulse was adminis(cid:173)
`tered with a 20 ms delay time, and fluences were 32 J/cm2 to 36
`J/cm' with a 570 nm filter or 27 J/cm1 to 32 J/cm'with a 560 nm
`filter". Among 28 evaluable patients, 83% rated their redness
`better or much better, 75% rated flushing and skin texture bet(cid:173)
`ter or much better, and 64% noted that acneiform breakouts
`were better or much better••. Very few adverse events were
`reported ( 1 purpura, 1 peeling, 1 postinflammatory hyperpig(cid:173)
`mentation), and all were reversible"'.
`
`In one attempt to objectively quantify the effectiveness of IPL
`(PhotoDcnn"' VL) in 4 patients, scanning laser Doppler and
`computer image analysis revealed decreases in blood flow
`(30%), telangiectasia area (29%), and erythema intensity
`(21 %) 14
`• Fi~:ure 2A and 2B illustrate the response of a rosacea
`patient presenting with telangiectasia and erythema 6 months
`after completion of three IPL treatments. This patient was
`treated with PhotodermVL using a 550 nm cutoff filter with a
`double pulse of 2.5 and 4.0 ms with a 10 ms delay at .38 J/cm'.
`
`Figure 2A: Rosacea patient with cemrofacial telan!,tiectaSia and erythema.
`Figure 2B: Same patient 6 months after completion of 3 IPL treat·
`ments with Photoderm VL using a 550 nm cutoff filter with a double
`pulse of 2.5 and 4.0 ms with a 10 ms delay at 3B]/cm,.
`
`Other approaches to laser treatment of telangiectasia and ery(cid:173)
`thema have been tried in rosacea patients with limited success.
`Long-pulse KTP laser and long-pulse PDL have been used at
`lower fluences to eliminate red vessels associated with erythe(cid:173)
`ma with minimal purpura", but these have not proven as effec(cid:173)
`tive as !PL. Longer wavelength devices for deeper vessels, such
`as the Nd:YAG laser, ,1o not work as well for treating the super(cid:173)
`ficial, sm<~ller, bright red vessels found in patients with rosacea.
`"Stacking"- using multiple pulses of PDL m the same time or
`
`I,
`
`t ,,,
`
`256
`
`Supplied by the British Library - "The world's knowledge" www.bl.uk
`
`6
`
`Galderma Laboratories, Inc. Ex 2003
`Dr. Reddy's Labs v. Galderma Labs., Inc.
`IPR2015-01782
`
`
`
`(Page 7 of 11)
`
`ROSACEA: WHERE ARE WE NOW?
`
`JDD 3:3: MAY/JUNE, 2004
`
`making multiple passes- can be more effective in treilting filcial
`telangiectasia, though purpura remains a concern and the tech(cid:173)
`nique is more time comuming;J. Another advance in treating
`photodamage and rosacea involves the use of 5-aminolevulinic
`acid (ALA; Levulan"' Kerastick') applied for 15 to 60 minutes
`nrior to laser or IPL treatment. Studies have demonstrated that
`ALA selectively penetrates into sebaceous glands and is then
`activated by the laser or JPL to damage or destroy them"·".
`
`A Multifaceted Approach to Treatment
`
`Because of the variable presentation of rosacea, its treatment
`
`has long been considered as much an art as a science"·' 2• Each
`patient is a unique case requiring an individualized treatment
`plan that must be adjusted over time based on the patient's suc(cid:173)
`cess with lifestyle management, response to therapies, and the
`unpredictable course of the disease.
`
`Patient education is the necessary first step in effective manage(cid:173)
`ment of all rosacea subtypes. Medical interventions alone may
`have limited effectiveness if not combined with patient self(cid:173)
`care. Physicians must explain to patients the importance of
`proper skin care and the myriad factors that can trigger rosacea
`symptoms, particularly flushing. New patients should be
`encouraged to keep notes identifying their own personal trip(cid:173)
`wires and then urged to make every e