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Am J Clin Dermatol 2003; 4 (7): 473-492REVIEW ARTICLE 1175-0561/03/0007-0473/$30.00/0

Adis Data Information BV 2003. All rights reserved.

Topical Acne DrugsReview of Clinical Properties, Systemic Exposure, and Safety

Arash Akhavan and Susan Bershad

The Mount Sinai School of Medicine, Department of Dermatology, New York, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4741. Introduction: Acne Prevalence, Pathogenesis, and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4742. Factors Affecting Percutaneous Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4763. Topical Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477

3.1 Tretinoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4773.1.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4773.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4773.1.3 Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478

3.2 Isotretinoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4793.2.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4793.2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4793.2.3 Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480

3.3 Adapalene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4803.3.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4803.3.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4803.3.3 Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481

3.4 Tazarotene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4813.4.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4813.4.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4813.4.3 Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481

4. Topical Benzoyl Peroxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4824.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4824.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4824.3 Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482

5. Topical Antibacterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4825.1 Clindamycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482

5.1.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4825.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4835.1.3 Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

5.2 Erythromycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4835.2.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4835.2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4845.2.3 Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484

6. Other Topical Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4846.1 Salicylic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484

6.1.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4846.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4856.1.3 Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485

6.2 Sulfur . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4856.2.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4856.2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4866.2.3 Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486

474 Akhavan & Bershad

6.3 Sodium Sulfacetamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4866.3.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4866.3.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4866.3.3 Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486

6.4 Azelaic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4866.4.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4866.4.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4886.4.3 Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488

7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488

This review examines the commonly available topical acne agents and factors that determine their percutane-Abstractous absorption. Reported and theoretical adverse effects from systemic exposure are detailed.

The topical retinoid class, which includes tretinoin, adapalene and tazarotene, and the topical antibacterials,clindamycin and erythromycin, are regulated by prescription in most countries. Used appropriately, theabove-mentioned drugs deliver, at most, miniscule amounts of active ingredient into the circulation. Clear-cutlinks to systemic toxicity in humans are practically nonexistent, except in the case of topical clindamycin, whichhas been associated with diarrhea rarely, and there have been 2 cases of pseudomembranous colitis reported.Birth defects have occurred in two patients treated with tretinoin and one patient treated with adapalene, butcausation was not proven. Another prescription drug, 20% azelaic acid, is associated with relatively highsystemic exposure, which is presumed innocuous because it is a normal dietary constituent whose endogenouslevels are not altered by topical use.

Benzoyl peroxide, salicylic acid, sulfur, and sodium sulfacetamide are available in concentrations of 2% ormore in over-the-counter acne treatments and some prescription products. All of these agents are known toexhibit some degree of percutaneous absorption. They remain largely unregulated because, other than skinirritation, only local allergic contact dermatitis from benzoyl peroxide in about 2.5% of patients and rare localand systemic hypersensitivity reactions from sodium sulfacetamide have been reported. Salicylism has occurredusing methyl salicylate ointments and high concentrations of salicylic acid on widespread areas of hyperkeratoticskin, but there are no known cases resulting from salicylic acid acne products.

Caution is advised in special circumstances, such as during childhood, pregnancy, lactation and concomitanttherapy with other drugs, because relevant studies are lacking. Animal data support avoidance of many topicalagents, particularly known teratogens such as retinoids and salicylic acid, in pregnant women. Salicylateavoidance is advised during lactation, because aspirin use carries the risk of bleeding disorders in nursing infants.

1. Introduction: Acne Prevalence, Pathogenesis, only partially understood. Follicular occlusion with adherent kera-and Treatment tinocytes and androgen-driven activation of sebum secretion result

in the formation of microcomedones. These may enlarge to formAcne is the commonest adolescent skin disorder, affecting 86% visible non-inflammatory acne lesions referred to as open and

of 17-year-olds in a large government survey[1] conducted in the closed comedones. Colonization of microcomedones and comedo-US. Teenage acne causes discomfort, disfigurement, emotional nes with Propionibacterium acnes, microaerophilic Gram-positivedistress and sometimes permanent scarring.[2] bacteria that metabolize sebaceous triglycerides, appears to be the

Many preadolescent children[3] and adults, mainly women,[4] event that transforms these follicular impactions into inflamedalso have acne. Besides diminishing the patient’s social and psy- acne lesions. One reasonable theory suggests that inherent hyper-chological well being,[5] acne in the pediatric age group and in sensitivity to P. acnes or its metabolic products is the mainpregnant and lactating women, presents therapeutic challenges, determinant of acne severity.[13,14]

due to a paucity of drug studies in such patients. Numerous acne medications are employed to target one or moreWhat is known of the etiology of acne is that heredity and of these processes. Topical retinoids are by far the most potent

hormones are involved,[6-9] but neither diet nor hygiene plays a comedolytic agents.[15] Benzoyl peroxide, salicylic acid, sulfur andmeaningful role.[10-12] The pathogenesis of acne is complex and azelaic acid are also used to inhibit comedo formation. Topical and

Adis Data Information BV 2003. All rights reserved. Am J Clin Dermatol 2003; 4 (7)

Topical Acne Drugs and Systemic Exposure 475

oral antibacterials, benzoyl peroxide, azelaic acid, and sulfur com- Oral therapy is chosen when the disease is resistant to topicalpounds combat colonization with P. acnes and reduce inflamma- therapy, covers large areas of the body, causes significant distresstion. Hormonal agents, including contraceptives and spirono- or requires rapid improvement. In suitable candidates, severelactone, act as anti-androgens. Oral isotretinoin is unique in its recalcitrant acne may be treated with oral isotretinoin, generallyability to shrink the sebaceous gland and profoundly diminish without concomitant topical acne therapy.sebum secretion.[16]

In addition to conventional medical care, there are two newClinical approaches to acne treatment may be found in compre-

FDA-approved approaches to non-drug treatment of acne. Thehensive reviews of this topic.[17,18]

first of these, used for moderate inflammatory acne, consists ofTopical therapy alone is usually preferred for mild acne. Often

high-intensity, enhanced blue-light phototherapy (ClearLight1,a topical comedolytic agent, particularly one from the retinoidLumenis Ltd).[19] The other is diode laser treatment (Smooth-group, is used in a daily sequence with benzoyl peroxide, a topicalbeam, Candela Corporation) for back acne and atrophic facialantibacterial agent, or a fixed-combination product containingacne scars.[20] These modalities are promising for drug-resistantboth. Topical therapy is also useful for moderate to severe acne,cases, but both are costly and lack the convenience and availabilitywhen combined with systemic antibacterial treatment (see figureof pharmaceutical remedies.1) or hormonal intervention.

a

dc

b

Fig. 1. (a) A 16-year-old boy with previously untreated moderate inflammatory acne at baseline, when therapy was initiated using short-contact therapywith 0.1% tazarotene gel once daily and 1% clindamycin lotion once daily; (b) at 1 month, showing pustular exacerbation characteristic of topical retinoidtherapy, treated with cefadroxil 500mg twice daily for 10 days while continuing topical drugs; (c) at 2 months, showing marked improvement 20 days afterstopping the oral antibacterial agent, using topical therapy alone; and (d) at 3 months, in near remission, on topical drug maintenance.

1 Use of tradenames is for product identification only and does not imply endorsement.



Table I. Safety of topical acne drugs during childhood, pregnancy and lactation[22]

Topical acne medications Safety in pediatric patients Safety in pregnancy/ Safety in nursing patients(<age 12 years) FDA pregnancy categorya

Retinoids

Adapalene Not established Not established/C Unknown

Isotretinoin Not established Not established/N/A Unknown

Tazarotene Not established contraindicated/X Unknown, probably unsafe

Tretinoin Not established Not established/C Unknown

Antibacterials

Clindamycin Not established Not established/B Unknown

Erythromycin Oral forms but not topical products are Not established/B Unknownsafe in all age groups

Others

Azelaic Acid Not established Not established/B Unknown, probably safeb

Benzoyl Peroxide Not established Not established/C Unknown

Salicylic Acid Safe in children over 2 years old Not established/C Unknown

Sodium- Sulfacetamide Not established Not established/C Unknown

Sulfur Not established Not established/C Unknown

a US Food and Drug Administration (FDA) Use-In-Pregnancy Rating Categories: A = Controlled studies show no risk; B = No evidence of risk inhumans despite adverse findings in animals, or, human studies lacking but animal studies show no risk. The chance of fetal harm is remote, butpossible; C = Risk cannot be ruled out. Data lacking in humans, animal studies positive or also lacking; D = Positive evidence of risk in humans,but benefit of use may outweigh the risk; X = Contraindicated in pregnancy.[22]

b Azelaic acid is a naturally occurring substance found in whole grain cereals and animal products.

N/A = not applicable.

Compared to oral therapy, topical drugs provide less aggressive grams.[23] When treatment includes the chest, shoulders and back,acne intervention but also have obvious advantages. Direct appli- up to 3 additional grams may be needed, depending on the extentcation to affected skin maximizes the proportion of drug delivered of body surface involved.to the pilosebaceous units and limits unnecessary systemic expo- Secondly, frequency of application influences systemic levels.sure,[21] thereby lessening the potential for internal adverse effects

For most topical acne drugs, once-daily administration is recom-and systemic drug interactions.

mended. Certain agents, particularly topical isotretinoin, benzoylThe purposes of this review are to determine the extent of

peroxide, clindamycin and erythromycin, may be used twice daily.percutaneous absorption of various topical acne agents and to

In such cases, serial administration increases systemic exposure,examine reported and possible consequences of such exposure.particularly when a drug and/or its metabolites have slow rates ofParticular attention is directed to acne treatment during childhoodabsorption or clearance.(under age 12 years), pregnancy, lactation, and concomitant ad-

Thirdly, the duration of application for certain drugs, includingministration of other drugs (see table I and table II).salicylic acid, is directly related to the dose absorbed.[24] While

2. Factors Affecting Percutaneous Absorption most agents are left on the surface for 8–12 hours, cleansers andmasks containing benzoyl peroxide, salicylic acid, sulfur andAside from the unique pharmacokinetic properties of eachsodium sulfacetamide are removed after a few minutes, presuma-drug, certain general principals influence systemic absorption afterbly lessening absorption. A short-contact method of tazarotenelocal application.application has also been described by one author (see figure 1).[25]

First, the dose absorbed is proportional to the amount applied.In a clinical study of 99 patients, 0.1% tazarotene gel applied forHigher systemic absorption will result from treating larger surface2–10 minutes daily produced significant acne improvement by 12areas or applying medications in an overgenerous manner. Theweeks.[26] To our knowledge, systemic tazarotene levels after suchusual amount of topical acne preparation recommended to coverbrief duration have not been studied.the facial surface has been estimated to be approximately 0.6



Fourthly, inherent skin characteristics determine the rate of 3.1 Tretinoinpenetration of some topical drugs into the stratum corneum, influ-encing their systemic absorption. The important work of Rougier

3.1.1 Backgroundand colleagues[27] in the 1980s showed that various agents pene-

Tretinoin, or all-trans retinoic acid, is a naturally occurringtrate forehead skin more rapidly than that of other anatomical sitesform of vitamin A. Typical formulations of topical tretinoin usedtested, including postauricular, abdomen, and arm. Of note, nofor acne (various tradenames and generics, numerous manufactur-racial variations in topical drug absorption were observed amongers) include 0.025–0.1% cream, 0.01–0.025% in standard gel, andAsian, Black and Caucasian skin.[28]

0.025–0.1% in vehicles designed to reduce the rate of drug release,Finally, drug vehicles influence both the rate and amount of

increase drug retention in the stratum corneum and inhibit deeperactive ingredient absorbed.[29,30] Generally, hydroalcoholic solu-

penetration. [30] The latter include the Microsponge Delivery Sys-tions and gels provide the most efficient drug delivery. In contrast,

tem (Enhanced Derm Technologies, division of RP Scherer Inc.)newer drug-delivery systems are designed to entrap active ingredi-

found in microsphere gel (Retin-A Micro, Ortho Dermatologi-ents in microsponges or polymers, reducing drug penetration

cal) and polyolprepolymer-2 (PP-2) found in delayed-release gelbeyond the avascular horny layer. In acne therapy, the latter are

and cream formulations (Avita, Bertek Pharmaceuticals). Treti-found in commercial tretinoin formulations (see section 3.1.1).

noin is generally applied once daily, at bedtime. The safety oftretinoin in patients aged under 12 years is not established.

3. Topical Retinoids The effectiveness of tretinoin for acne is well documented innumerous clinical trials using concentrations of 0.01–0.1%.[46-52] Itis among the most effective therapies currently available for theTopical retinoic acid was discovered for acne more than 3treatment of acne. The initial response to medication may be seendecades ago.[31] The term retinoids was originally used to describeat 2–3 weeks, but improvement is usually gradual. Most patientschemical analogs of vitamin A.[32] Starting in the late 1980s, withrequire 2–4 months to achieve notable success.[52-56] Long-termthe discoveries of nuclear retinoic acid receptors[33] and retinoid Xadherence until spontaneous remission is necessary, because topi-receptors,[34] the definition of retinoids evolved to include diversecal therapy controls rather than cures acne.molecules with the ability to bind to and activate these recep-

tors.[35] Topical tretinoin is available in emollient cream vehicle (Re-nova, Ortho Dermatological), with 0.02% or 0.05% active ingre-The retinoid class contains the well known agents tretinoin,dient, for palliation of signs of photodamage, including fine wrin-adapalene and tazarotene, which are used to treat acne and otherkles, tactile roughness and mottled hyperpigmentation.[36]common skin disorders, such as photoaging[36,37] and psoria-

sis.[38,39] Less familiar retinoids are alitretinoin for Kaposi’s sarco- Oral tretinoin is used for acute promyelocytic leukemia in dosesma,[40] and bexarotene for cutaneous T-cell lymphoma.[41] as high as 50 mg/m2/day.[57] Oral tretinoin has also been studied in

clinical trials for psoriasis, using doses of 1 mg/kg/day,[58] andSeveral mechanisms of action are likely to be responsible forhyperkeratotic skin diseases, using 20–60 mg/day.[59]the usefulness of topical retinoid agents as acne therapy. These

include modulation of keratinocyte proliferation,[42] induction oforthokeratosis,[43] comedolysis,[44] and inhibition of inflamma- 3.1.2 Pharmacokinetics

tion.[38] Oral isotretinoin also reduces sebaceous gland size and Orally, tretinoin is well absorbed, but percutaneous absorptiondecreases sebum production.[16] of topical tretinoin is low, slightly less than 1% after a single dose

Although over 5000 retinoids have been identified or synthe- of 0.1% tretinoin in microsphere gel and less than 2% of ansized,[45] only 4 topical retinoids are commonly employed as acne emollient cream formulation.[22] Following a single topical appli-treatment. Besides tretinoin, adapalene and tazarotene, which are cation of radiolabeled tretinoin, the blood concentration of retinoicapproved by the US FDA, topical isotretinoin is currently avail- acid was found to be unchanged from 2–48 hours.[60] Percutaneousable in Europe and Canada but is not FDA approved as of this absorption after topical application does not alter systemic retinoidwriting. levels, which remain within the range of the body’s natural endog-

enous levels.[61-63]While topical retinoids are the most effective anti-comedonalagents,[15] their principal drawbacks are local skin irritation, gradu- When taken orally, tretinoin is metabolized in the liver andal clinical improvement, and acne exacerbation, the so-called excreted by the kidney. Renal excretion is 63% over 72 hours.[22]

"retinoid flare" (see figure 1b), which occurs during the first month The half-life of the parent compound is 0.5–2.0 hours with theof treatment and may persist for several weeks. major metabolites being isotretinoin, 4-oxo trans retinoic acid,



Table II. Drug interactions from systemic and topical administration of agents found in acne products[22]

Agents Drug interactions reported from oral or parenteral administration Drug interactions reported withtopical application

Retinoids

Adapalene Oral/injectable/implantable contraceptives (may decrease efficacy) None known

Isotretinoina Vitamin A (additive toxic effects)

Tetracyclines (increased risk of pseudotumor cerebri)

Tazarotene None known None known

Tretinoin Potential drug interaction with inducers or inhibitors of hepatic CYP 450 None knownsystem although no data exists proving existence of such interactions

Inducers: rifampin, corticosteroids, phenobarbital, pentobarbital

Inhibitors: ketoconazole, cimetidine, erythromycin, verapamil, diltiazem,cyclosporine

Antibacterials

Clindamycin Neuromuscular blocking agents (may enhance their action) None known

Erythromycin (antagonism shown in vitro)

Erythromycin Theophylline (theophylline toxicity) None known

Digoxin (increased digoxin levels)

Oral anticoagulants (increased anticoagulant effects, especially in elderly)

Ergotamine/dihydroergotamine (peripheral vasospasm and dysesthesiafrom ergot toxicity)

Triazolam/midazolam (decreased clearance of these benzodiazepines)

Drugs metabolized by CYP 450 system such as carbamazepine,cyclosporine, tacrolimus, hexobarbital, phenytoin, alfenatil, disopyramide,lovastatin, bromocriptine, sodium valproate (elevation in serum levels ofthese drugs)

Clindamycin (antagonism shown in vitro)

Others

Azelaic Acid None known None known

Benzoyl Peroxide None known None known

Salicylic Acid Alendronate (gastrointestinal adverse effects with aspirin-containing None known. Interaction betweenproducts) topical methyl salicylate and oral

anticoagulants known to increaserisk of bleeding

Oral anticoagulants, heparin and heparinoids (increased risk of bleeding)

Varicella vaccine (increased risk of Reye’s syndrome if given within 6weeks of vaccination)

Sodium Sulfacetamide None known None known

Sulfur None known None known

a Topical form not available in the US.

CYP = cytochrome P.

4-oxo cis retinoic acid and 4-oxo trans retinoic acid glucuroni- These can be minimized by decreasing exposure to sunlight,de.[22] avoiding weather extremes such as cold and high wind, and using

non-comedogenic moisturizers.

3.1.3 Drug-Related Adverse Events Systemic toxicity has not been linked with topical tretinoin, butLocal adverse effects commonly occurring with topical appli- pharmacological doses of oral tretinoin cause the typical effects of

cation are peeling, erythema, dryness, burning and itching.[55,64] hypervitaminosis A, primarily dryness and inflammation of the



skin and mucous membranes. Oral therapy can also lead to serious 3.2 Isotretinoin

adverse reactions, including rapidly evolving leukocytosis in up to40% of patients,[22] hepatotoxicity,[65,66] and respiratory compro- 3.2.1 Backgroundmise.[22] Approximately 25% of patients with acute promyelocytic Oral isotretinoin greatly advanced the treatment of severe acneleukemia have experienced a retinoic acid-acute promyelocytic after an important discovery made by Peck et al.[72] in 1979.leukemia syndrome,[22] which can occur after the first oral treti- Although isotretinoin is commonly thought to be a syntheticnoin dose, and is characterized by fever, dyspnea, weight gain, retinoid, it is actually a natural isomer of vitamin A found in theradiographic pulmonary infiltrates, pleural and pericardial effu- body in small amounts.[73] This agent is available in topical formu-sions, hypotension and impaired myocardial contractility. lations in a number of countries outside the US.

A gel formulation containing 0.05% isotretinoin (Isotrex,Oral tretinoin is an FDA Pregnancy Category D drug, signify-Stiefel Laboratories) is typically applied to acne areas twice daily.ing a high risk of fetal abnormalities if taken during pregnancy, butThe oral form for severe cystic acne and disorders of keratinizationthe topical form is Category C, meaning that the benefits mustis given in twice-daily doses equaling 0.5–2.0 mg/kg/day. Dosesoutweigh the risks. Risk assessment is a matter of medical judg-as high as 8.2 mg/kg/day have been used orally to treat basal cellment, since the teratogenic blood level of tretinoin has not beencarcinoma.[74] At this time, neither oral nor topical isotretinoin hasdetermined.not been certified as safe for pediatric patients by the FDA.

In a reported case, a female patient with acne who was usingIn a double-blind study of 268 patients, topical isotretinointopical tretinoin gave birth to an infant born at 40 weeks gestation,

0.05% gel, applied twice a day for 14 weeks, was reported effec-weighing 2800 grams, with coarctation of the aorta, hypoplastic

tive in the treatment of mild-to-moderate acne, reducing bothleft hand, hypertelorism and small ear canals.[67] She had used

inflammatory and non-inflammatory lesions.[75] The drug was well0.05% topical tretinoin in an alcohol base and a 2.5% benzoyl

tolerated, with only 2 patients withdrawing due to the occurrenceperoxide topical preparation before conception and during the first

of irritation, a problem that was also seen in one patient in the2 months of gestation. The patient’s family history revealed no

control group using vehicle gel. Another randomized, controlledcongenital defects. There is a second case report of a congenital

study of 127 patients found that formulations of 0.05% or 0.1%ear malformation in the infant of a patient with acne who applied

isotretinoin cream containing standard sunscreens were effectivetopical tretinoin 1 month before pregnancy and during the first 11

and well tolerated in the treatment of patients with mild to moder-weeks.[68] While tretinoin was not proven to be directly related to

ate acne.[76]

the defects in either of these cases, they are troubling because earmalformation is typical of retinoid embryopathy.[69]

3.2.2 Pharmacokinetics

Some experts believe that topical tretinoin is not a risk factor Several studies have demonstrated little or no percutaneousabsorption of isotretinoin after local application. The first of thesefor congenital disorders.[70,71] Nevertheless, its use during preg-examined plasma levels after multiple applications of 0.05% iso-nancy is difficult to justify, because acne affects mainly appear-tretinoin gel,[23] and the second used serial applications of 0.1%ance and emotional well being, which are not easily quantified.isotretinoin in chemical sunscreens over 4 weeks.[77] In each, thereAvoidance of the topical form is advised during lactation.was a lack of measurable drug in plasma. A third study comparedSystemic exposure and adverse reactions in nursing infants cannotthe serum concentrations after topical isotretinoin application ver-be ruled out, because excretion via breast milk has not beensus oral ingestion of a US Recommended Daily Allowance ofstudied.[22]

5000 IU of vitamin A.[78] After a 42-day course of an excessiveCommon drugs having local adverse interactions with topical dose of isotretinoin cream (10 grams applied to 2300cm2 of

tretinoin include salicylic acid and benzoyl peroxide, which may photodamaged skin once daily), the increase in systemic levels ofpotentiate retinoid-induced skin peeling and erythema.[22]

retinoic acid was less than that reported after vitamin A supple-In theory, systemically absorbed tretinoin might interact with mentation. The authors concluded that the low systemic availabili-

drugs that alter hepatic cytochrome P (CYP) 450 enzymes, re- ty after isotretinoin application supports a lack of teratogenic riskquired for tretinoin metabolism.[22] Such drugs as cimetidine, from the topical cream.cyclosporine, diltiazem and erythromycin may potentially increase Following the oral administration of 80mg of isotretinoin toplasma tretinoin through CYP 450 inhibition. On the other hand, patients with acne, a mean peak serum level of 262 µg/L ispentobarbital, phenobarbital and rifampin have inducing effects on achieved in a mean time to peak of 2.9 hours.[79] Isotretinoin isthe same hepatic enzymes, thereby decreasing tretinoin levels.[22] 99.9% plasma protein bound and is excreted almost equally in



urine and feces. The drug is metabolized in the liver to 4-oxo- exist regarding topical isotretinoin use in nursing women and,isotretinoin, tretinoin and 4-oxo-tretinoin.[79] The elimination half- therefore, avoidance is prudent.life of isotretinoin is 10–20 hours, whereas the elimination half- Regarding drug interactions, topical isotretinoin can have addi-life of its major metabolite, 4-oxo-isotretinoin, is 24–29 hours.[79] tive local effects with other topical acne products, increasing the

risk of skin irritation.3.2.3 Drug-Related Adverse Events Taken concurrently with carbamazepine, oral isotretinoin hasLocal adverse events are similar to those of topical tretinoin, been shown to reduce levels of this commonly prescribed seizure

discussed previously. The finding that percutaneous absorption is medication.[94] Carbamazepine levels should be monitored duringundetectable suggests that the risk of internal effects is negligible. treatment with oral isotretinoin. Taking isotretinoin in combina-Topical isotretinoin has not been implicated as the cause of sys- tion with minocycline or tetracycline is avoided due to increasedtemic toxicity. In one case of inflammatory bowel disease follow- risk of pseudotumor cerebri.[95] Topical isotretinoin has not beening topical application of isotretinoin, a probable relationship was linked with such drug interactions.not established.[80]

3.3 AdapaleneOrally, isotretinoin is a potent teratogen. There have beennumerous detailed reports of congenital abnormalities associated

3.3.1 Backgroundwith its use.[69,81-83] In one investigation of 154 human pregnanciesOne of the most commonly used topical retinoid agents,with fetal exposure to oral isotretinoin, 12 patients had spontan-

adapalene (Differin, Galderma Laboratories), is a naphthoic acideous abortions and 21 infants had major malformations.[69] Amongderivative with a methoxyphenyl adamantyl side chain.the 21 malformed infants, a characteristic pattern of malformations

Adapalene is typically applied nightly to acne-prone skin as athat involved craniofacial, cardiac, thymic and CNS structures was0.1% gel, solution or cream. A thin film is recommended, takingobserved.care to avoid the eyes, lips and mucous membranes. The safety andThe FDA has designated oral isotretinoin a Pregnancy Cate-efficacy of the drug in children under the age of 12 years have notgory X drug. No dose of isotretinoin administered by mouth isbeen established.considered safe. Congenital defects have occurred with its use for

In a randomized, investigator-masked parallel European studyless than 4 days during the first trimester.[84] For this reason, evenof 268 patients with facial acne vulgaris receiving either adapalenetopical application of isotretinoin should be avoided in pregnancy0.1% gel or tretinoin 0.025% gel for 12 weeks, adapalene appearedand used with extreme caution in women of childbearing potential.to be as effective as tretinoin.[96] A large, multicenter clinical trialIn such patients, requirements for oral isotretinoin include manda-in the US showed a greater average reduction of inflammatory,tory use of 2 forms of contraception simultaneously unless absti-non-inflammatory and total acne lesions in the adapalene-treatednence is the chosen method of birth control, 2 negative pregnancygroup compared with the tretinoin-treated group.[97] In both stud-tests prior to treatment, monthly urine pregnancy tests duringies, patients who used adapalene experienced less erythema, burn-therapy, oral and written warnings of birth defects, and informeding, scaling and dryness than those using tretinoin.consent.[85]

Other adverse consequences of oral isotretinoin use are hyper- 3.3.2 Pharmacokineticslipidemias, most notably hypertriglyceridemia in about one-sixth Because adapalene is not used as an oral drug, some aspects ofof patients, and an increased ratio of low-density-lipoprotein cho- its pharmacokinetics are not as well known as those of otherlesterol to high-density-lipoprotein cholesterol, known to be unfa- retinoids. The adapalene microcrystal size was engineered within avorable toward cardiovascular disease risk.[86] Rarer adverse ef- range of 3–10µm, to deliver the drug preferentially into the follicu-fects include pseudotumor cerebri,[87] hyperostosis,[88,89] hepato- lar duct, with minimal penetration into the epidermis.[98] Analysestoxicity,[90] premature epiphyseal closure[91] and inflammatory of cryosections, radioactive tracing and fluorescence studies inbowel disease.[92] human skin samples have shown that adapalene gel is found in the

Depression, suicidal ideation and suicide have been reported in upper layers of the epidermis and rapidly enters the pilosebaceouspatients treated with oral but not topical isotretinoin[93] and, fur- units.[99-101]

thermore, a causal relationship is not clear. The FDA guidelines Minimal amounts (0.01% of an applied dose) of adapalene arefor oral isotretinoin require that patients be warned about possible systemically absorbed,[99] providing evidence of limited penetra-suicide risk and assessed for symptoms of mood disorders.[22] tion into the deep epidermis and dermis. This phenomenon may

Because the excretion of isotretinoin in breast milk is unknown, explain its relative lack of irritancy. In a pharmacokinetic study, inoral isotretinoin is contraindicated during lactation.[22] No data which 6 patients with acne were treated with 2 grams of 0.1%



adapalene cream applied once daily for 5 days, there were no was found to be effective for acne and reasonably well tolerated byquantifiable amounts of adapalene in the plasma of any of the most patients.[105] In another study comparing 0.1% tazarotene gelpatients, when assayed with a limit of quantification of 0.35 µg/ with 0.025% tretinoin gel, tazarotene was found to be moreL.[22] Based on animal data, excretion of adapalene appears to be effective in reducing noninflammatory lesions and similarly effec-primarily via the biliary route.[22] tive in reducing inflammatory lesions.[52] It is currently used

mostly as an alternative to tretinoin and adapalene in refractory3.3.3 Drug-Related Adverse Events

cases.Adverse effects associated with topical adapalene include ery-

thema, scaling, dryness, pruritus and burning.[22] These effects are 3.4.2 Pharmacokineticsmost common and pronounced in the first month of therapy and Tazarotene is converted by esterases to its active metabolite,decrease thereafter. Exposure to sunlight and other irritating topi- tazarotenic acid, following topical application to the skin. System-cal agents are best avoided. No serious adverse reactions have ic absorption of the active metabolite and the parent drug is lowbeen reported. following cutaneous application of 0.05% and 0.1% tazarotene gel

Adapalene is an FDA Pregnancy Category C drug. Although no formulations, at most reaching 6% of the administered dose ap-teratogenic effects were seen in animal studies with the drug, plied under occlusion.[103,106,107] Plasma levels of tazarotene andadequate and well-controlled studies in pregnant women are lack- tazarotenic acid are mostly below 0.15 µg/L and 6 µg/L, respec-ing. Given that adapalene binds to retinoic acid receptors and thus, tively.[108] There is no noticeable systemic accumulation of themay share the characteristic of teratogenicity with other com- drug following multiple topical applications.[109] Tazarotenic acidpounds in the retinoid family, its use is generally avoided during is further metabolized by the liver to a sulfone metabolite and apregnancy. There is a reported case of a woman treated with sulfoxide metabolite after it is systemically absorbed.[103] Tazaro-adapalene gel (0.3 mg/day) from the month before pregnancy until tenic acid and tazarotene are primarily excreted from the body in13 weeks gestation.[102] Therapeutically aborted at 22 weeks, the bile.[103] The plasma elimination half-life of the drug is 15–17fetus was small for its gestational age and had anophthalmia and hours.[110]

optic chiasma. It is not know whether a significant amount of the3.4.3 Drug-Related Adverse Eventsdrug is excreted through breast milk. Use during lactation isCommon adverse reactions following topical tazarotene appli-therefore not recommended.

cation are similar to those of other retinoids. They include itching,No systemic drug interactions are known to occur withburning, irritation and erythema.[22] Tazarotene is the most irritat-adapalene use.ing of the topical retinoids, with local skin irritation reported inabout half of patients applying it for only 2–10 minutes daily.[26]3.4 TazaroteneDue to increased risk of sunburn, protection from UV rays is

3.4.1 Background recommended. Systemic toxicity from topical use has not beenIntroduced in 1997, tazarotene is the newest topical agent in the reported. An oral form is currently under investigation for psoria-

retinoid class for acne. It is a synthetic acetylenic molecule that is sis, but dosages and adverse event data are not yet available.rapidly converted to its active metabolite, tazarotenic acid, in Topical tazarotene is designated as an FDA Pregnancy Cate-keratinocytes. Unlike the parent compound, tazarotenic acid has gory X drug, meaning its use is prohibited during pregnancy and inthe ability to bind and activate nuclear retinoic acid receptors.[103] sexually active patients without reliable contraception. There are

Tazarotene gel and cream formulations (Tazorac, Allergan reports of inadvertent pregnancies in tazarotene-treated patientsInc.) are available with 0.05% and 0.1% active ingredient. Only without ill effects,[111] including several female participants inthe more potent 0.1% products are approved by the US FDA for psoriasis clinical trials whose infants did not have any knownacne. These are typically used nightly at bedtime to treat mild or congenital defects. Other tazarotene clinical studies have includedmoderate facial acne. Acne therapy using tazarotene has been 6 pregnant women with uneventful outcomes,[111] but the timingstudied for periods as long as 15 weeks.[104] Tazarotene gel and and extent of exposure to tazarotene was unknown.cream formulations are also used for the treatment of plaque Because animal studies have shown high systemic levels ofpsoriasis,[39] and photoaging,[37] but tazarotene is not approved for tazarotene to be teratogenic,[22] additional studies on the maternal/pediatric use. fetal plasma levels of tazarotenic acid in humans must be done

Tazarotene gel and cream are effective in treating acne vulgaris before use of topical tazarotene in pregnancy can be deemed safe.when applied topically once daily. In a multicenter, double-blind, Whether or not tazarotene is excreted in human breast milk israndomized study of 375 patients with acne, 0.1% tazarotene gel unknown. Tests in lactating rats suggest that some drug is excreted



to the nursing offspring.[22] The drug is not recommended for up to 2.5% of patients.[22,122] During use, the patient should benursing mothers. advised to avoid other potential sources of skin irritation such as

UV radiation and topical acne medications except those recom-Topical tazarotene usage is not known to cause drug interac-mended by the physician. Serious adverse reactions have not beentions.reported with topical benzoyl peroxide use.

4. Topical Benzoyl Peroxide There are no known adverse effects in humans as a result ofsystemic exposure to benzoyl peroxide or its metabolites, butanimal studies have shown carcinogenicity.[22,123]

4.1 BackgroundBenzoyl peroxide is a Pregnancy Category C drug. It is not

Benzoyl peroxide is an agent with antibacterial[112] and known whether the drug causes fetal harm when given to pregnantcomedolytic[113] action. The usefulness of benzoyl peroxide for women, and it should only be used during pregnancy if clearlyacne is attributed primarily to its potent bactericidal effect against needed.[22] Data regarding benzoyl peroxide excretion in breastP. acnes.[114] The mechanism of action is thought to be degradation milk are lacking, and its safety in nursing infants is thereforeof bacterial proteins via release of free-radical oxygen. unknown.

Benzoyl peroxide acne products (many tradenames and gener- A noteworthy drug interaction caused by benzoyl peroxide isics, various manufacturers) are available in concentrations ranging inactivation of tretinoin when both are used simultaneously.[98] Infrom 2.5–10%, as lotions, creams, gels, masks, and cleansers, contrast, the newer retinoids adapalene and tazarotene are stable inwhich can be used once or twice a day. The frequency of applica- the presence of benzoyl peroxide. Interactions between benzoyltion and concentration of active ingredient may be adjusted to peroxide and systemic drugs have not been reported.control local adverse effects. Twenty percent benzoyl peroxide is a

5. Topical Antibacterialspotent formulation reserved for the treatment of cutaneous ulcers.Benzoyl peroxide is not specifically FDA approved for pediatricpatients, but its non-prescription status makes such use inevitable. 5.1 Clindamycin

Benzoyl peroxide is one of the most frequently used topicalpreparations for acne. When compared with other topical an- 5.1.1 Backgroundtimicrobials, 5% benzoyl peroxide was found to be at least as Clindamycin is a lincosamide antimicrobial agent that is aeffective for acne as clindamycin[115,116] and erythromycin formu- semi-synthetic derivative of lincomycin.[124] The antibacterial in-lations.[117] hibits bacterial protein synthesis by attaching to the 50S subunit of

Fixed-combination products containing benzoyl peroxide and the bacterial ribosome.either clindamycin (BenzaClin, Dermik Laboratories; Duac, Topical clindamycin, used for the treatment of acne vulgaris, isStiefel Laboratories) or erythromycin (Benzamycin, Dermik available as a 1% gel, lotion or solution (various tradenames andLaboratories) are more effective for acne than their individual generics, numerous manufacturers) and in fixed-combinationcomponents alone.[118,119] Further, such combinations are not asso- products. These are typically applied to affected areas once orciated with development of antibacterial-resistant bacteria,[120] oft- twice daily. Oral doses of clindamycin for other conditions rangeen seen with prolonged use of single-agent topical antibac- from 150–450mg every 6 hours.[22] Of note, oral clindamycin isterials.[121] FDA approved to treat infections in children under age 12 years,

but appropriate monitoring is required.4.2 Pharmacokinetics Clindamycin is found in a fixed-combination acne product

containing benzoyl peroxide, as described previously in sectionBenzoyl peroxide is well absorbed into the epidermis and

4.1. Application of this formulation is recommended twice dailyconcentrated in pilosebaceous units. After conversion to benzoic

after the skin is gently washed and dried. Another fixed-combina-acid in the skin, about 2% of the applied dose enters the systemic

tion product containing 0.025% tretinoin and 1% clindamycincirculation. [22] It is metabolized to benzoic acid and excreted as

phosphate (Velac, Yamanouchi Europe B.V.) is marketed inbenzoate in the urine.[22]

Europe and Canada[125] and is currently undergoing clinical inves-tigation in the US.4.3 Drug-Related Adverse Events

Although the phosphate compound of clindamycin is mostCommon adverse effects of benzoyl peroxide include skin commonly used in the treatment of acne, both the phosphate and

dryness, erythema and peeling. Contact sensitization may occur in hydrochloride salts have been shown to be effective. In an 8-week,



multicenter, placebo-controlled trial, topical clindamycin in both illness that results from the eradication of normal intestinal flora,its phosphate and hydrochloride salts was found to produce statis- allowing overgrowth of Clostridium difficile. This microbe pro-tically significant improvements in acne as compared with the duces two toxins that damage the intestinal wall, which in severevehicle alone.[126] Clindamycin gel[127] and lotion[128] are less irri- cases may be life-threatening.[141] Pseudomembranous colitis istating than the solution formula and are equally efficacious. The readily induced in hamsters with topical clindamycin applica-fixed-combination product containing 1% clindamycin and 5% tion[142] and has been documented in two patients with acnebenzoyl peroxide was significantly more effective than either of exposed to clindamycin topically.[143,144] In one case, pseudo-the two agents applied separately, when used to treat moderate membranous colitis developed in a patient applying topical 1%acne.[129] Fixed combination clindamycin phosphate and tretinoin clindamycin phosphate to facial acne intermittently over agel has been shown to reduce acne to a greater extent and produce 6-month period.[143] The patient’s stool assay was positive for C.a more rapid response than either agent used alone.[125] difficile. After successful colitis treatment, the patient resumed

topical clindamycin, leading to recurrent stool-positive C. difficile5.1.2 Pharmacokinetics

infection. Following a second course of treatment and completeTopically administered 1% clindamycin has been found to have cessation of clindamycin use, the patient remained symptom free

low bioavailability, with values differing considerably in different over an 18-month follow-up period.studies, including values from 4–5%[130] to less than 1%.[22]

Topical clindamycin is an FDA Pregnancy Category B drug.In one study, 2ml of 1% clindamycin solution applied to the Chances of harm to the fetus are remote, especially with the low

entire face twice daily for 4 weeks did not achieve detectable level of systemic exposure when the drug is applied topically.serum concentrations in an assay sensitive to 0.4 µg/m, but the

Systemically absorbed clindamycin from topical applicationdrug was observed in the urine of 10 of 13 patients.[130] There was

may be excreted in breast milk, although studies are lacking.a wide range of urinary recovery of the drug between participants,

Orally administered clindamycin has been reported in humansuggesting that different patients may absorb clindamycin to vary-

breast milk in the range of 0.7–3.8 µg/ml.[22] There are no clinicaling extents. In clinical trials evaluating topical clindamycin, de-

reports of adverse effects in infants whose mothers weretectable urine levels were noted following the application of

breastfeeding while using topical clindamycin.[145] It should betopical clindamycin hydrochloride, but not following topical clin-

noted that loose stools and diarrhea are common during infancy,damycin phosphate.[131] In another study, there was no detectable

allowing a possible association with maternal clindamycin use toserum level of clindamycin hydrochloride following the topical

be overlooked.application of a 1% hydroalcoholic solution.[132]

Reported drug interactions with oral clindamycin include thoseSystemically absorbed clindamycin has been determined to

with non-depolarizing neuromuscular blockers, whose effects mayhave a total protein binding of 60–95%.[133,134] After oral use, the

be potentiated, prolonging neuromuscular blockade.[146] This ef-drug is widely distributed throughout the body and is partially

fect is more common at higher doses of clindamycin and would bemetabolized in the liver to clindamycin sulfoxide and N-dimethyl

unlikely from percutaneous absorption. A laboratory observationclindamycin, and excreted by the kidney,[135] as well as through the

with possible clinical ramifications is that clindamycin and ery-biliary route and feces.[136]

thromycin have been shown to be antagonistic in vitro.[22,147] Theantibacterials are believed to compete for the same protein-binding5.1.3 Drug-Related Adverse Eventssites. It is therefore advisable to avoid concurrent use of the twoApplication-site erythema and dry skin are the most commonagents, either topically or by mouth.local events reported with topical clindamycin products.[22]Serious

adverse effects of orally administered clindamycin include leuco-5.2 Erythromycinpenia,[137] thrombocytopenia,[138] diarrhea,[139] pseudomembranous

colitis and hepatotoxicity.[140] Topical use is contraindicated in5.2.1 Backgroundpatients with a history of regional enteritis, ulcerative colitis or

antibacterial-associated colitis. During a multicenter, controlled Erythromycin is a macrolide antibacterial that attaches to thestudy of 358 patients using topical clindamycin versus vehicle for 50S subunit of bacterial ribosomes. It prevents the effective pro-acne, 12 episodes of diarrhea occurred in patients given active gression of the translocation reaction necessary for bacterial pro-therapy, with at least one episode thought to be treatment-relat- tein synthesis.[22]

ed.[126] Erythromycin is available in topical formulations for acneBesides its association with simple diarrhea, systemic exposure treatment as a 2% gel, solution, or ointment (various tradenames

to clindamycin may cause pseudomembranous colitis, a serious and generics, numerous manufacturers). A fixed combination gel



containing erythromycin and benzoyl peroxide (see section 4.1) is reactions have not been reported with topical administration, mostavailable in the US. An erythromycin-isotretinoin combination gel likely due to its low systemic absorption.(Isotrexin, Steifel Germany) is marketed elsewhere but is not With oral erythromycin use, abdominal cramping, nausea, andcurrently US FDA approved. Patients apply the medication to skin vomiting are commonly reported.[22] Less common adverse effectstwice daily following thorough washing and drying of skin. include cholestatic jaundice,[154] hepatitis,[155] ototoxicity,[156] and

Oral doses of erythromycin for adults range from 250mg every hypersensitivity.[157] Pseudomembranous colitis may occur rarely.6 hours to a maximum dose of 4 grams daily, reserved for serious Both oral and topical erythromycin formulations are designatedinfections.[22] Systemic therapy is used for a variety of infectious as FDA Pregnancy Category B. Animal reproductive studies withdiseases, including otitis media, Campylobacter enteritis, neonatal erythromycin have demonstrated no evidence of teratogenicity,conjunctivitis, Legionnaires disease, preoperative bowel prepara- but there are no well-controlled studies in pregnant women. Astion, and infections caused by gram-positive organisms, mycoplas- animal teratogenicity studies are not always predictive of effects inma, and chlamydia. humans, the drug should be considered during pregnancy only if

Efficacy of topical erythromycin for acne has been demonstra- the potential benefits outweigh the risks.ted in numerous randomized studies. Both gel[148] and solution[149] Oral erythromycin, even in moderate doses, is excreted in theforms of 2% erythromycin were superior to placebo in controlled breast milk of lactating women,[22] and there are reports of atrials of populations exceeding 150 patients. A study using 1% possible link between erythromycin administration during preg-erythromycin showed the drug to significantly reduce P. acnes in nancy and nursing with hypertrophic pyloric stenosis in in-the ducts of sebaceous glands in placebo-controlled tests.[150] In a fants.[158] It is not known whether topical erythromycin is excretedmore recent study of the anti-propionibacterium activity of the in breast milk. Because its safety in nursing women has not beendrug, the addition of 5% benzoyl peroxide to 3% erythromycin gel established, caution is advised.had greater effect than erythromycin alone in patients with acne As mentioned in section 5.1.3, erythromycin has been shown towith resistant strains of cutaneous propionibacterium.[120] In an- antagonize clindamycin in vitro, a finding to consider when select-other study, the combination of 3% erythromycin and 5% benzoyl ing a topical acne regimen.[22,147] In the past, oral erythromycinperoxide was found to be comparable in efficacy to the combina- was known to potentiate life-threatening ventricular arrhythmiastion of 1% clindamycin and 5% benzoyl peroxide, with both of and QT prolongation when combined with several drugs that arethese formulations proving more efficacious than 5% benzoyl no longer marketed. These include the non-sedating antihista-peroxide alone for acne.[151] And finally, a recent, randomized, mines astemizole and terfenadine and the gastrointestinal agentmulticenter, double-blind study of 157 patients showed a topical cisapride.[22] No such interactions have been reported in patientssolution containing 2.3% erythromycin and 1% bifonazole applied with acne using topical erythromycin. The low absorption ofonce daily was more effective for acne treatment than 2.3% erythromycin makes systemic effects unlikely.erythromycin solution applied twice daily.[152]

6. Other Topical AgentsTopical acne preparations containing erythromycin are notspecifically approved for pediatric patients, but oral erythromycinsuspensions are FDA approved in all age groups, including infan- 6.1 Salicylic Acidcy.

6.1.1 Background5.2.2 Pharmacokinetics

Salicylic acid is a topical keratolytic agent that works byPercutaneous absorption of erythromycin is very low afterdissolving the intercellular cement that holds epithelial cells to-topical application. In 2-month studies of topical 2% erythromycingether.[159] It is a component of a variety of over-the-counter acneuse, no serum levels were detected.[152,153]

remedies.After oral administration, the drug is widely distributed in body

Concentrations of salicylic acid ranging from 0.5–10% (varioustissues. Metabolism occurs in the liver by demethylation. Erythro-tradenames and generics, numerous manufacturers) have beenmycin is concentrated and excreted in its unchanged form in urine,recommended for acne,[160,161] but 2% is the maximum strengthbile and feces.allowed in non-prescription acne products in the US. This active

5.2.3 Drug-Related Adverse Events ingredient is commonly found in acne cleansers. It is also used inTopical erythromycin use is associated with occasional burn- concentrations of 3–6% as a keratolytic agent to treat hyperkera-

ing, peeling, dryness, pruritus and erythema. Oily skin has also totic skin disorders such as psoriasis, ichthyoses, palmoplantarbeen reported from erythromycin in certain vehicles.[22] Systemic keratosis, keratosis pilaris and pityriasis rubra pilaris,[162] and in



concentrations of 5–40% for wart and corn removal. Salicylic acid taining salicylate. There is also a report of a patient who developedis approved for use in pediatric acne. toxic inner ear damage after receiving salicylic acid treatment for

psoriasis.[172]Salicylic acid is not given orally because it causes severestomach irritation. Salicylate analgesia is given by mouth in the Salicylic acid can cause hypoglycemia by increasing glucoseform of acetylsalicylic acid (aspirin).[159] The standard dose of metabolism while impairing gluconeogenesis.[173] Refractory hy-aspirin for pain relief is 650mg, which can be given every 4 hours. poglycemia has been reported in a man with end-stage renal failureOne 650mg dose of aspirin is equivalent to 500mg of salicylic applying 10% salicylic acid cream to 80% of his body surfaceacid. area.[173] His serum salicylate level was 3.2 mmol/L. Following

hemodialysis and glucose infusions, the patient recovered and6.1.2 Pharmacokinetics

remained euglycemic.Percutaneous absorption of salicylic acid is quite efficient

Salicylic acid is an FDA Pregnancy Category C drug. There arecompared with that of most topical agents.[24] The bioavailability

no human studies of topical salicylic acid use during pregnancy,of topical salicylic acid application varies widely according to the

but systemic salicylic acid and aspirin are known to induce malfor-duration of contact[24] and the vehicle.[163] Prolonged application of

mations in rat embryos.[174]

Kerasal Ointment (polyethylene glycol, glycerol, petrolatum andThe excretion of salicylic acid in breast milk and its safety if

10% urea) led to absorption of approximately 9% of the activeconsumed by nursing infants are unknown. Of interest, it is recom-

ingredient, whereas application of 5% and 10% salicylic acidmended that aspirin use be avoided by nursing mothers, because

ointment (mineral oil and petrolatum) led to absorption of 25%salicylate is excreted in breast milk and may lead to rashes, platelet

and 20%, respectively.[163] The time to peak concentration follow-abnormalities and bleeding in nursing infants.[22]

ing topical application with occlusion is 5 hours.[162] In a study ofWith significant systemic exposure to salicylic acid, as can

topical methyl salicylate analgesic (2–6 mg/L), salicylic acidoccur following oral ingestion of aspirin, there is a risk of adverse

serum concentrations ranged from 0.3–0.9 mg/L one hour afterdrug reactions with oral anticoagulants and low-molecular-weight

application.[164]

heparins, both of which increase risk of bleeding.[22] In patientsSalicylate toxicity is associated with serum levels of 200–400

with diabetes mellitus treated with hypoglycemic drugs, aspirinµg/ml.[159,162] Systemic toxicity is therefore unlikely with topical

use may increase the effectiveness of the latter, leading to hypo-use of the drug, although toxicity is possible if the drug is applied

glycemia. Cases of Reye’s syndrome have occurred following theto a large surface area of the body for prolonged periods of time.

use of oral salicylates during varicella infection (chickenpox).[22]

Systemically absorbed salicylic acid is 50–80% albumin-bound inSalicylates should be avoided for at least 6 weeks after recovery

serum, and it is excreted mostly by the kidney.[162]

from chickenpox or receiving the varicella vaccine. Althoughsystemic toxicity has not been associated with topical acne prod-6.1.3 Drug-Related Adverse Eventsucts containing salicylic acid, the rapid and efficient percutaneousAt concentrations of 2% or greater, salicylic acid is likely toabsorption of the drug dictates a cautious approach.cause some degree of local skin peeling and discomfort. Adverse

reactions resulting from systemic exposure to the drug are possible6.2 Sulfurif it is used for prolonged periods over large areas of the body.

Possible adverse effects include salicylate toxicity, toxic inner ear6.2.1 Backgrounddamage, and hypersensitivity.[22]

The chemical element sulfur is considered a mild keratolyticSigns and symptoms that should alert the physician to theand bacteriostatic agent.[22] In keratinocytes, sulfur is reduced topossibility of salicylate toxicity include increased respiratory rate,form hydrogen sulfide by an unknown mechanism.[175] The hydro-dizziness, loss of hearing, lethargy, and symptoms of gastrointesti-gen sulfide formed from sulfur is thought to break down keratin.nal disturbance, including nausea, vomiting and diarrhea.[162]

Sulfur is also believed to have activity against P. acnes.[22]There are numerous reports of acute salicylate intoxication as aresult of topical salicylic acid use.[165-171] In one case, systemic Topical sulfur is available in lotions, creams, soaps and oint-salicylate toxicity was seen in a man who had used a methyl ments (various tradenames and generics, numerous manufactur-salicylate ointment analgesic on this thigh twice daily for several ers). Preparations containing 1–10% sulfur have been used as acneweeks.[164] He presented with a 3-day history of blurred vision, treatment for many decades. This element is more efficacioustinnitus, shortness of breath and was found to have a salicylate when used in combination with other drugs, including benzoylconcentration of 518 mg/L, with a mixed metabolic acidosis/ peroxide[176,177] and sodium sulfacetamide.[178] Sulfur is also foundrespiratory alkalosis. He had not taken any oral medications con- in over-the-counter and prescription acne products combined with



6.3.3 Drug-Related Adverse Eventsresorcinol or salicylic acid. Such topical preparations may beAdverse reactions associated with the topical use of sodiumapplied to acne-prone sites up to 3 times daily for several days,

sulfacetamide are infrequent and generally restricted to localdecreasing frequency as symptoms improve.events such as itching, erythema and discomfort.[22] Local contactsensitization has occurred. Very rare reactions reported include6.2.2 Pharmacokineticserythema multiforme[182] from topical use and its more severeThe bioavailability of topically applied sulfur is believed to beform, Stevens-Johnson syndrome,[183,184] from ophthalmic use. It isabout 1%.[175] In the skin, it is converted to hydrogen sulfideimportant to remember that hypersensitivity reactions may occurthrough a reaction between the sulfur element and keratino-whenever a sulfonamide is re-administered, regardless of the routecytes.[175]

of administration. Topical sodium sulfacetamide is contraindi-cated in any patient with a history of sensitivity to ‘sulfa’ drugs.6.2.3 Drug-Related Adverse Events

In rare cases, oral sulfonamides and sulfonylureas are asso-Adverse effects from topical administration of sulfur are rareciated with life-threatening events, including agranulocytosis, Ste-and are mainly limited to dryness and malodor of the skin.[175]

vens-Johnson syndrome, toxic epidermal necrolysis, fulminantSulfhemoglobinemia[179] and metabolic acidosis[180] are amonghepatic necrosis and aplastic anemia.[22] These have not beenthe more serious adverse reactions that can occur with oral inges-reported due to acne products that contain sodium sulfacetamide.tion of sulfur, but these have not been reported with topical use.

Although no problems associated with topical use of sodiumSulfur is an FDA Pregnancy Category C drug, meaning its usesulfacetamide during pregnancy have been reported, the drug is anin pregnant women should be reserved for cases where the benefitsFDA Pregnancy Category C drug. Neonatal jaundice can occur inof use clearly outweigh the potential harm to the fetus. Thenewborn infants of women given oral sulfonamides during preg-excretion of sulfur in breast milk is unknown.nancy.[22]

There are no known drug interactions with sulfur. Of note,It is not known whether topical application of sodiumpatients with sulfonamide sensitivity may generally use elemental

sulfacetamide is excreted in breast milk.[22] Systemically absorbedsulfur without untoward effect.sulfonamide antibacterials are typically excreted through lactation,and are capable of producing kernicterus in the nursing infant.[22]

6.3 Sodium SulfacetamideThere are no reported drug interactions due to topical sodium

sulfacetamide, but oral sulfonamides participate in several druginteractions. It has been reported that administration of sulfon-6.3.1 Backgroundamides may increase the prothrombin time in patients receivingSodium sulfacetamide is a bacteriostatic antibacterial in thewarfarin.[22] There is also a potential interaction with cyclosporine,sulfonamide group. It displays activity against several gram-nega-resulting in decreased cyclosporine concentrations.[185] Some sul-tive and gram-positive organisms.[124] Sulfonamides act throughfonamides have also been shown to decrease hepatic clearance ofcompetitive antagonism of para-aminobenzoic acid (PABA), halt-phenytoin.[186]ing bacterial DNA synthesis.[124]

Sodium sulfacetamide 10%, usually combined with 5% sulfur,6.4 Azelaic Acidis found in topical acne suspensions, lotions and creams (various

tradenames and generics, numerous manufacturers). This combi-6.4.1 Backgroundnation has been found to be synergistic in acne treatment.[22,181]

Sodium sulfacetamide is also available as an ophthalmic formula- Azelaic acid is a naturally occurring, saturated, straight-chainedtion for acute bacterial conjunctivitis and chronic blepharitis, and dicarboxylic acid found as a dietary constituent in whole grainit is found in intravaginal preparations for chlamydial and bacterial cereals and animal products.[22] For acne treatment, its mechan-vaginitis. isms of action are believed to be related to its mild antibacterial

and anti-keratinizing effects.[22,187]

6.3.2 Pharmacokinetics Azelaic acid is available as a 20% topical cream (Azelex,While the absorption of sodium sulfacetamide through intact Allergan Inc.), which is applied twice daily according to package

skin has not been determined, in vitro studies using human cadaver labeling. Improvement of symptoms are typically seen within 4skin found percutaneous absorption to be about 4%.[22] Systemi- weeks of starting azelaic acid therapy.[187-190] Safety and efficacycally administered sulfonamides are rapidly excreted in the have not been established in pediatric patients. It has also beenurine.[22] shown to be effective for melasma, reducing pigment intensity and


Topical A

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Table III. Estimated absorbed doses of topical acne drugs versus orally administered comparable agents

Topical acne Topical application, typical dose Estimated % of topical Estimated dose of topical drug absorbed Single oral dose oftherapy (mg) dose absorbed (mg) same or comparable

drug (mg)drug concentration (%) face onlya face + upper trunkb face onlya face + upper trunkb

Retinoids

Adapalene 0.1 0.6 3.6 0.01 Trace Trace N/A

Benzoyl peroxide 2.5–10 15–60 90–360 2 0.3–1.2 1.8–7.2 N/A

Isotretinoin 0.05 0.3 1.8 Undetectable Trace? Trace? 20–60

Tazarotene 0.1 0.6 3.6 2 0.012 0.072 N/Ac

Tretinoin 0.01–0.1 0.06–0.6 0.36–3.6 1–2 <0.012 < 0.072 20–40

Antibacterials

Clindamycin 1 6 36 1–5 0.06–0.3 0.36–1.8 150–450phosphate

Erythromycin 2–3 12–18 72–108 Undetectable Undetectable Undetectable 250–500

Others

Azelaic acid 20 120 720 4d 4.8 28.8 N/A

Salicylic acid 0.5–2 3–12 18–72 9–25 0.27–3 1.62–18 500e

Sodium 5–10 30–60 180–360 4f 1.2–2.4 7.2–14.4 N/Ag

sulfacetamide

Sulfur 2–10 12–60 72–360 1 0.12–0.6 0.72–3.6 N/A

a Based on 0.6g per application, the estimated amount to cover the face.[23]

b Based on 3.6g per application, the estimated amount to cover the face, chest, shoulders and back.[23]

c Oral tazarotene is under investigation. Dosage data are unavailable at this time.

d Based on commercial 20% azelaic acid cream. Percent absorbed may be 8% with gel vehicle.[187]

e Oral acetyl salicylic acid dose of 650mg.

f Based on studies in cadaver skin.[22]

g Oral sulfamethoxazole dose of 400–800mg.

NA = Not applicable; no comparable agent.


lesion size.[187,191] Of interest, hypopigmentation has occasionally 7. Conclusionsbeen reported as an adverse effect of the drug.[22]

Given the extraordinary prevalence of acne and the availabilityAzelaic acid is a useful adjunct to more conventional topicalof products to treat it, a reasonable assumption is that at least aacne therapies, particularly when there has been dissatisfactionhundred million patients worldwide have used such drugs over thewith standard regimens due to local irritation. The adverse effectpast half-century. Although local adverse effects are common-profile of azelaic acid, from both local and systemic administra-place, systemic toxicity appears to be remarkably low, based ontion, compares favorably with other more widely used acne thera-the handful of reported incidents.pies. Twelve-week placebo-controlled studies of the efficacy of

Aside from the obvious explanation that absorbed doses are tootopical 20% azelaic acid cream applied twice daily have shown itsmall to cause internal effects (see table III), there are other likelyto be successful in improving mild-to-moderate acne.[190,192]

reasons for the rarity of such cases.6.4.2 Pharmacokinetics First, patients are often unaware of systemic risks, particularlyAfter application of a single topical dose of azelaic acid cream, with non-prescription products. Second, physicians may be unac-

3–5% is retained in the stratum corneum, and up to 10% penetrates quainted with certain drug interactions and systemic events thatinto the epidermis and dermis.[22] Approximately 4% of the cuta- are theoretically possible. Finally, data in children and pregnantneously applied dose is absorbed systemically.[22] This percutane- women are lacking for most acne agents. Acne is rarely a threat toous absorption is increased to 8% when gel formulations are general health and, therefore, clinical studies in these vulnerableused.[187] Some of the systemically absorbed drug is metabolized populations are seldom undertaken.in the liver to glutaric acid and pimeric acid;[187,193] however, the The favorable historical safety record of topical agents does notdrug is eliminated mainly unchanged through renal excretion. The excuse drug makers and prescribers from their duties to minimizeelimination half-life is 45 minutes after oral administration and 12 potential risks. Every drug regimen requires vigilance, regardlesshours after topical application, indicating a slower rate of system of the route of administration.absorption and/or clearance with topical compared with oral ad-ministration.[22] Acknowledgements

Normal endogenous levels of azelaic acid are determined byThe manuscript received no commercial support. Dr Bershad has partici-dietary intake. Baseline serum and urine levels in humans have not

pated in clinical research studies funded by Roche Laboratories Inc. andbeen found to be altered with topical 20% azelaic acid treat- Allergan Inc.; she has served as a consultant and lecturer for Roche Laborato-ment.[22]

ries Inc. and Allergan Inc. and as a consultant to Warner Chilcott, division ofGalen Holdings. Dr Bershad holds US patents and reserves all rights to

6.4.3 Drug-Related Adverse Events international patents for the short-contact method of topical retinoid therapy toCommon adverse effects of topical azelaic acid include pruri- treat acne, photoaging and psoriasis.

tus, burning, stinging and tingling.[22] Erythema, dryness, peeling,hypopigmentation and hypertrichosis have also been reported.[22]

References1. Roberts J. Skin conditions of youths 12-17 years, United States. vital and healthDespite its relatively high concentration of active ingredient and

statistics: Series 11. Data from the National Health Survey, Data from the healthmoderate degree of percutaneous absorption, topical azelaic acidexamination survey; no. 157. DHEW publication no. (HRA) 76-1639, 1976

has not been linked with systemic effects.[187] Hypokalemia was 2. Krowchuk DP, Stancin T, Keskinen R, et al. The psychosocial effects of acne onadolescents. Pediatr Dermatol 1991 Dec; 8 (4): 332-8reported in one patient treated, experimentally, with high-dose oral

3. Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in premenarchal girls: anazelaic acid for malignant melanoma.[194]

early sign of puberty associated with rising levels of dehydroepiandrosterone.Arch Dermatol 1994; 130: 308-14Azelaic acid is an FDA Pregnancy Category B drug. Studies

4. Goulden V, Clark SM, Cunliffe WJ. Post-adolescent acne: a review of clinicalusing high oral doses in animals do not result in teratogenic effectsfeatures. Br J Dermatol 1997 Jan; 136 (1): 66-70

in the offspring, but controlled studies are lacking in humans.[22]5. Lasek RJ, Chren MM. Acne vulgaris and the quality of life of adult dermatology

patients. Arch Dermatol 1998 Apr; 134 (4): 454-8Passage of azelaic acid into milk has been demonstrated using6. Walton S, Wyatt EH, Cunliffe WJ. Genetic control of sebum excretion and acne: a

an in vitro equilibrium dialysis technique.[22] Since only about 4% twin study. Br J Dermatol 1988 Mar; 118 (3): 393-67. Imperato-McGinley J, Gautier T, Cai LQ, et al. The androgen control of sebumof the applied dose is absorbed, normal endogenous levels are not

production: studies of subjects with dihydrotestosterone deficiency and com-expected to be altered in human breast milk. Caution is advised inplete androgen insensitivity. J Clin Endocrinol Metab 1993 Feb; 76 (2): 524-8

nursing mothers. 8. Marynick SP, Chakmakjian ZH, McCaffree DL, et al. Androgen excess in cysticacne. N Engl J Med 1983 Apr 28; 308 (17): 981-6Azelaic acid has not been associated with drug interactions.

9. Lucky AW, McGuire J, Rosenfield RL, et al. Plasma androgens in women withSimilarly to other acne products, it might be expected to enhance acne vulgaris. J Invest Dermatol 1983 Jul; 81 (1): 70-4the irritative potential of concomitant topical therapy. 10. Rasmussen JE. Diet and acne. Int J Dermatol 1977 Jul-Aug; 16 (6): 488-92



11. Fulton Jr JE, Plewig G, Kligman AM. Effect of chocolate on acne vulgaris. JAMA creams with 0.05% tretinoin emollient cream applied once daily for 24 weeks.1969 Dec 15; 210 (11): 2071-4 Arch Dermatol 2001 Dec; 137 (12): 1597-604

12. Leyden JJ. Therapy for acne vulgaris. N Engl J Med 1997 Apr 17; 336 (16): 38. Duvic M, Nagpal S, Asano AT, et al. Molecular mechanisms of tazarotene action1156-62 in psoriasis. J Am Acad Dermatol 1997; 37 (2 Pt 3): S18-24

13. Webster GF. Inflammatory acne. Int J Dermatol 1990 Jun; 29 (5): 313-7 39. Weinstein GD, Krueger GG, Lowe NJ, et al. Tazarotene gel, a new retinoid, for14. Kersey P, Sussman M, Dahl M. Delayed skin test reactivity to Propionibacterium topical therapy of psoriasis: vehicle-controlled study of safety, efficacy, and

acnes correlates with severity of inflammation in acne vulgaris. Br J Dermatol duration of therapeutic effect. J Am Acad Dermatol 1997; 37 (1): 85-921980 Dec; 103 (6): 651-5 40. Walmsley S, Northfelt DW, Melosky B, et al. Treatment of AIDS-related cutane-

15. Mills Jr OH, Kligman AM. Assay of comedolytic activity in acne patients. Acta ous Kaposi’s sarcoma with topical alitretinoin (9-cis-retinoic acid) gel. PanretinDerm Venereol 1983; 63 (1): 68-71 Gel North American Study Group. J Acquir Immune Defic Syndr 1999; 22 (3):

16. Goldstein JA, Comite H, Mescon H, et al. Isotretinoin in the treatment of acne: 235-46histologic changes, sebum production, and clinical observations. Arch Derma- 41. Duvic M, Hymes K, Heald P, et al. Bexarotene is effective and safe for treatmenttol 1982; 118 (8): 555-8 of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase

17. Bershad SV. The modern age of acne therapy: a review of current treatment II-III trial results. J Clin Oncol 2001; 19 (9): 2456-71options. Mt Sinai J Med 2001; 68 (4-5): 279-86 42. Marcelo CL, Madison KC. Regulation of the expression of epidermal keratinocyte

18. Sykes Jr NL, Webster GF. Acne: a review of optimum treatment. Drugs 1994; 48 proliferation and differentiation by vitamin A analogs. Arch Dermatol Res(1): 59-70 1984; 276 (6): 381-9

19. Kawada A, Aragane Y, Kameyama H, et al. Acne phototherapy with a high- 43. Stadler R, Muller R, Detmar M, et al. Retinoids and keratinocyte differentiation inintensity, enhanced, narrow-band, blue light source: an open study and in vitro vitro. Dermatologica 1987; 175 Suppl. 1: 45-55investigation. J Dermatol Sci 2002; 30 (2): 129-35 44. Lavker RM, Leyden JJ, Thorne EG. An ultrastructural study of the effects of

20. Paithankar DY, Ross EV, Saleh BA, et al. Acne treatment with a 1,450 nm topical tretinoin on microcomedones. Clin Ther 1992; 14 (6): 773-80wavelength laser and cryogen spray cooling. Lasers Surg Med 2002; 31 (2): 45. Roos TC, Jugert FK, Merk HF, et al. Retinoid metabolism in the skin. Pharmacol106-14 Rev 1998; 50 (2): 315-33

21. Schaefer H. Penetration and percutaneous absorption of topical retinoids: a review. 46. Mills Jr OH, Kligman AM. Treatment of acne vulgaris with topically appliedSkin Pharmacol 1993; 6 Suppl. 1: 17-23 erythromycin and tretinoin. Acta Derm Venereol 1978; 58 (6): 555-7

22. Physicians’ desk reference. 56th ed. Montvale (NJ): Medical Economics Company 47. Amblard P, Bazex A, Beylot C, et al. The association tretinoin-erythromycin base:Inc, 2002 a new topical treatment for acne: results of a multicentric trial on 347 cases

23. Jensen BK, McGann LA, Kachevsky V, et al. The negligible systemic availability (authors transl). Sem Hop 1980; 56 (17-18): 911-5of retinoids with multiple and excessive topical application of isotretinoin 48. Gould DJ, Ead R, Cunliffe WJ. Oral tetracycline and retinoic acid gel in acne.0.05% gel (Isotrex) in patients with acne vulgaris. J Am Acad Dermatol 1991; Practitioner 1978; 221 (1322): 268-7124 (3): 425-8

49. Bucknall JH, Murdoch PN. Comparison of tretinoin solution and benzoyl peroxide24. Rougier A, Dupuis D, Lotte C, et al. The measurement of the stratum corneum

lotion in the treatment of acne vulgaris. Curr Med Res Opin 1977; 5 (3): 266-8reservoir: a predictive method for in vivo percutaneous absorption studies:

50. Swinyer LJ, Swinyer TA, Britt MR. Topical agents alone in acne: a blind assess-influence of application time. J Invest Dermatol 1985; 84 (1): 66-8ment study. JAMA 1980; 243 (16): 1640-3

25. Bershad S, Poulin YP, Berson DS, et al. Topical retinoids in the treatment of acne51. Krishnan G. Comparison of two concentrations of tretinoin solution in the topicalvulgaris. Cutis 1999 Aug; 64 (2 Suppl.): 8-20

treatment of acne vulgaris. Practitioner 1976; 216 (1291): 106-926. Bershad S, Kranjac Singer G, Parente JE, et al. Successful treatment of acne52. Webster GF, Berson D, Stein LF, et al. Efficacy and tolerability of once-dailyvulgaris using a new method: results of a randomized vehicle-controlled trial of

tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment ofshort-contact therapy with 0.1% tazarotene gel. Arch Dermatol 2002; 138 (4):facial acne vulgaris: a randomized trial. Cutis 2001; 67 (6 Suppl.): 4-9481-9

53. Ellis CN, Millikan LE, Smith EB, et al. Comparison of adapalene 0.1% solution27. Rougier A, Lotte C, Maibach HI. In vivo percutaneous penetration of some organicand tretinoin 0.025% gel in the topical treatment of acne vulgaris. Br J Dermatolcompounds related to anatomic site in humans: predictive assessment by the1998; 139 Suppl. 52: 41-7stripping method. J Pharm Sci 1987; 76 (6): 451-4

54. Grosshans E, Marks R, Mascaro JM, et al. Evaluation of clinical efficacy and28. Lotte C, Wester RC, Rougier A, et al. Racial differences in the in vivo percutane-safety of adapalene 0.1% gel versus tretinoin 0.025% gel in the treatment ofous absorption of some organic compounds: a comparison between black,acne vulgaris, with particular reference to the onset of action and impact onCaucasian and Asian subjects. Arch Dermatol Res 1993; 284 (8): 456-9quality of life. Br J Dermatol 1998; 139 Suppl. 52: 26-3329. Dupuis D, Rougier A, Roguet R, et al. The measurement of the stratum corneum

55. Lucky AW, Cullen SI, Funicella T, et al. Double-blind, vehicle-controlled,reservoir: a simple method to predict the influence of vehicles on in vivomulticenter comparison of two 0.025% tretinoin creams in patients with acnepercutaneous absorption. Br J Dermatol 1986; 115 (2): 233-8vulgaris. J Am Acad Dermatol 1998; 38 (4): S24-3030. Piacquadio D, Kligman A. The critical role of the vehicle to therapeutic efficacy

56. Lucky AW, Cullen SI, Jarratt MT, et al. Comparative efficacy and safety of twoand patient compliance. J Am Acad Dermatol 1998 Aug; 39 (2 Pt 3): S67-730.025% tretinoin gels: results from a multicenter double-blind, parallel study. J31. Kligman AM, Fulton Jr JE, Plewig G. Topical vitamin A acid in acne vulgaris.Am Acad Dermatol 1998; 38 (4): S17-23Arch Dermatol 1969; 99 (4): 469-76

57. Cortes JE, Kantarjian H, O’Brien S, et al. All-trans retinoic acid followed by32. Sporn MB, Dunlop NM, Newton DL, et al. Prevention of chemical carcinogenesischemotherapy for salvage of refractory or relapsed acute promyelocytic leuke-by vitamin A and its synthetic analogs (retinoids). Fed Proc 1976; 35 (6):mia. Cancer 1994; 73 (12): 2946-521332-8

58. Fritsch PO, Honigsmann H, Jaschke E, et al. Augmentation of oral methoxsalen-33. Petkovich M, Brand NJ, Krust A, et al. A human retinoic acid receptor whichphotochemotherapy with an oral retinoic acid derivative. J Invest Dermatolbelongs to the family of nuclear receptors. Nature 1987; 330 (6147): 444-501978; 70 (4): 178-8234. Mangelsdorf DJ, Ong ES, Dyck JA, et al. Nuclear receptor that identifies a novel

59. Stuttgen G, Ippen H, Mahrle G. Oral vitamin A acid in treatment of dermatosesretinoic acid response pathway. Nature 1990; 345 (6272): 224-9with pathologic keratinization. Int J Dermatol 1977; 16 (6): 500-235. Bershad S. Developments in topical retinoid therapy for acne. Semin Cutan Med

Surg 2001; 20 (3): 154-61 60. Lucek RW, Colburn WA. Clinical pharmacokinetics of the retinoids. ClinPharmacokinet 1985; 10 (1): 38-6236. Weiss JS, Ellis CN, Headington JT, et al. Topical tretinoin improves photoaged

skin: a double-blind vehicle-controlled study. JAMA 1988; 259 (4): 527-32 61. Latriano L, Tzimas G, Wong F, et al. The percutaneous absorption of topically37. Kang S, Leyden JJ, Lowe NJ, et al. Tazarotene cream for the treatment of facial applied tretinoin and its effect on endogenous concentrations of tretinoin and its

photodamage: a multicenter, investigator-masked, randomized, vehicle-con- metabolites after single doses or long-term use. J Am Acad Dermatol 1997; 36trolled, parallel comparison of 0.01%, 0.025%, 0.05%, and 0.1% tazarotene (3 Pt 2): S37-46



62. Van Hoogdalem EJ. Transdermal absorption of topical anti-acne agents in man; 89. Archer CB, Elias PM, Lowe NJ, et al. Extensive spinal hyperostosis in a patientreview of clinical pharmacokinetic data. J Eur Acad Dermatol Venereol 1998; receiving isotretinoin: progression after 4 years of etretinate therapy. Clin Exp11 Suppl. 1: S13-9 Dermatol 1989; 14 (4): 319-21

90. McElwee NE, Schumacher MC, Johnson SC, et al. An observational study of63. Buchan P, Eckhoff C, Caron D, et al. Repeated topical administration of all-trans-isotretinoin recipients treated for acne in a health maintenance organization.retinoic acid and plasma levels of retinoic acids in humans. J Am AcadArch Dermatol 1991; 127 (3): 341-6Dermatol 1994; 30 (3): 428-34

91. Marini JC, Hill S, Zasloff MA. Dense metaphyseal bands and growth arrest64. Clucas A, Verschoore M, Sorba V, et al. Adapalene 0.1% gel is better toleratedassociated with isotretinoin therapy. Am J Dis Child 1988; 142 (3): 316-8than tretinoin 0.025% gel in acne patients. J Am Acad Dermatol 1997; 36 (6 Pt

92. Martin P, Manley PN, Depew WT, et al. Isotretinoin-associated proctosigmoiditis.2): S116-8Gastroenterology 1987; 93 (3): 606-965. Shibata K, Shimamoto Y, Ishibashi S, et al. Life-threatening hepatic toxicity

93. Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide incaused by all-trans-retinoic acid in a patient with acute promyelocytic leukae-patients treated with isotretinoin. J Am Acad Dermatol 2001; 45 (4): 515-9mia. Clin Lab Haematol 1994; 16 (2): 191-5

94. Marsden JR. Effect of isotretinoin on carbamazepine pharmacokinetics. Br J66. Windhorst DB, Nigra T. General clinical toxicology of oral retinoids. J Am AcadDermatol 1988; 119 (3): 403-4Dermatol 1982; 6 (4 Pt 2 Suppl.): 675-82

95. Gottfried NS. Pseudo-tumor cerebri and acne [letter]. Mil Med 1991; 156 (8): A567. Navarre-Belhassen C, Blanchet P, Hillaire-Buys D, et al. Multiple congenital96. Cunliffe WJ, Caputo R, Dreno B, et al. Efficacy and safety comparison ofmalformations associated with topical tretinoin. Ann Pharmacother 1998; 32

adapalene (CD271) gel and tretinoin gel in the topical treatment of acne(4): 505-6vulgaris: a European multicentre trial. J Dermatol Treatment 1997; 8: 173-868. Camera G, Pregliasco P. Ear malformation in baby born to mother using tretinoin

97. Shalita A, Weiss JS, Chalker DK, et al. A comparison of the efficacy and safety ofcream [letter]. Lancet 1992; 339 (8794): 687adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a69. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Medmulticenter trial. J Am Acad Dermatol 1996; 34 (3): 482-51985; 313 (14): 837-41

98. Shroot B. Pharmacodynamics and pharmacokinetics of topical adapalene. J Am70. Caron GA. Tretinoin and pregnancy [letter]. Lancet 1993; 341 (8861): 1664Acad Dermatol 1998 Aug; 39 (2 Pt 3): S17-2471. Jick SS, Terris BZ, Jick H. First trimester topical tretinoin and congenital disorders.

99. Allec J, Chatelus A, Wagner N. Skin distribution and pharmaceutical aspects ofLancet 1993; 341 (8854): 1181-2adapalene gel. J Am Acad Dermatol 1997; 36 (6 Pt 2): S119-2572. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and

100. Rolland A, Wagner N, Chatelus A, et al. Site-specific drug delivery to piloseb-conglobate acne with 13-cis-retinoic acid. N Engl J Med 1979; 300 (7): 329-33aceous structures using polymeric microspheres. Pharm Res 1993; 10 (12):73. Tang GW, Russell RM. 13-cis-retinoic acid is an endogenous compound in human1738-44serum. J Lipid Res 1990; 31 (2): 175-82

101. Jamoulle JC, Grandjean L, Lamaud E, et al. Follicular penetration and distribution74. Peck GL. Retinoids in dermatology: an interim report. Arch Dermatol 1980; 116

of topically applied CD 271, a new naphthoic acid derivative intended for(3): 283-4

topical acne treatment. J Invest Dermatol 1990; 94 (5): 731-275. Chalker DK, Lesher Jr JL, Smith Jr JG, et al. Efficacy of topical isotretinoin 0.05%

102. Autret E, Berjot M, Jonville-Bera AP, et al. Anophthalmia and agenesis of opticgel in acne vulgaris: results of a multicenter, double-blind investigation. J Am

chiasma associated with adapalene gel in early pregnancy [letter]. Lancet 1997;Acad Dermatol 1987; 17 (2 Pt 1): 251-4

350 (9074): 33976. Langner A, Stapor W, Donald AE, et al. Double-blind, placebo-controlled study of

103. Chandraratna RA. Tazarotene: first of a new generation of receptor-selectivethe efficacy and safety of isotretinoin cream (0.05% w/w and 0.10% w/w) with

retinoids. Br J Dermatol 1996; 135 Suppl. 49: 18-25sunscreens in the treatment of mild to moderate acne vulgaris. J Dermatolog

104. Leyden J, Lowe N, Kakita L, et al. Comparison of treatment of acne vulgaris withTreat 2000; 11: 7-14

alternate-day applications of tazarotene 0.1% gel and once-daily applications of77. Cunliffe WJ, Glass D, Goode K, et al. A double-blind investigation of the potential adapalene 0.1% gel: a randomized trial. Cutis 2001; 67 (6 Suppl.): 10-6

systemic absorption of isotretinoin, when combined with chemical sunscreens,105. Shalita AR, Chalker DK, Griffith RF, et al. Tazarotene gel is safe and effective in

following topical application to patients with widespread acne of the face andthe treatment of acne vulgaris: a multicenter, double-blind, vehicle-controlled

trunk. Acta Derm Venereol 2001; 81 (1): 14-7study. Cutis 1999; 63 (6): 349-54

78. Chen C, Jensen BK, Mistry G, et al. Negligible systemic absorption of topical 106. Chandraratna RA. Tazarotene: the first receptor-selective topical retinoid for theisotretinoin cream: implications for teratogenicity. J Clin Pharmacol 1997; 37 treatment of psoriasis. J Am Acad Dermatol 1997; 37 (2 Pt 3): S12-7(4): 279-84

107. Duvic M. Pharmacologic profile of tazarotene. Cutis 1998; 61 (2 Suppl.): 22-679. Brazzell RK, Colburn WA. Pharmacokinetics of the retinoids isotretinoin and 108. Marks R. Early clinical development of tazarotene. Br J Dermatol 1996; 135 Suppl.

etretinate: a comparative review. J Am Acad Dermatol 1982; 6 (4 Pt 2 Suppl.): 49: 26-31643-51

109. Tang-Liu DD, Matsumoto RM, Usansky JI. Clinical pharmacokinetics and drug80. Reniers DE, Howard JM. Isotretinoin-induced inflammatory bowel disease in an metabolism of tazarotene: a novel topical treatment for acne and psoriasis. Clin

adolescent. Ann Pharmacother 2001; 35 (10): 1214-6 Pharmacokinet 1999; 37 (4): 273-8781. Rappaport EB, Knapp M. Isotretinoin embryopathy: a continuing problem. J Clin 110. Marks R. Pharmacokinetics and safety review of tazarotene. J Am Acad Dermatol

Pharmacol 1989; 29 (5): 463-5 1998; 39 (4 Pt 2): S134-882. Benke PJ. The isotretinoin teratogen syndrome. JAMA 1984; 251 (24): 3267-9 111. Menter A. Pharmacokinetics and safety of tazarotene. J Am Acad Dermatol 2000;83. Braun JT, Franciosi RA, Mastri AR, et al. Isotretinoin dysmorphic syndrome. 43 (2 Pt 3): S31-5

Lancet 1984; I (8375): 506-7 112. Kligman AM, Leyden JJ, Stewart R. New uses for benzoyl peroxide: a broad-84. Hersh JH, Danhauer DE, Hand ME, et al. Retinoic acid embryopathy: timing of spectrum antimicrobial agent. Int J Dermatol 1977; 16 (5): 413-7

exposure and effects on fetal development. JAMA 1985; 254 (7): 909-10 113. Cunliffe WJ, Stainton C, Forster RA. Topical benzoyl peroxide increases the85. Roche Laboratories Inc. SMART guide to best practices: system to manage sebum excretion rate in patients with acne. Br J Dermatol 1983; 109 (5): 577-9

accutane related teratogenicity. Nutley (NJ): Roche Laboratories Inc, 2001 114. Nacht S, Gans EH, McGinley KJ, et al. Comparative activity of benzoyl peroxide86. Bershad S, Rubinstein A, Paterniti JR, et al. Changes in plasma lipids and and hexachlorophene: in vivo studies against propionibacterium acnes in

lipoproteins during isotretinoin therapy for acne. N Engl J Med 1985; 313 (16): humans. Arch Dermatol 1983; 119 (7): 577-9981-5 115. Tucker SB, Tausend R, Cochran R, et al. Comparison of topical clindamycin

87. Roytman M, Frumkin A, Bohn TG. Pseudotumor cerebri caused by isotretinoin. phosphate, benzoyl peroxide, and a combination of the two for the treatment ofCutis 1988; 42 (5): 399-400 acne vulgaris. Br J Dermatol 1984; 110 (4): 487-92

88. Tangrea JA, Kilcoyne RF, Taylor PR, et al. Skeletal hyperostosis in patients 116. Swinyer LJ, Baker MD, Swinyer TA, et al. A comparative study of benzoylreceiving chronic, very-low-dose isotretinoin. Arch Dermatol 1992; 128 (7): peroxide and clindamycin phosphate for treating acne vulgaris. Br J Dermatol921-5 1988; 119 (5): 615-22



117. Burke B, Eady EA, Cunliffe WJ. Benzoyl peroxide versus topical erythromycin in 145. [No authors listed]. The transfer of drugs and other chemicals into human breastthe treatment of acne vulgaris. Br J Dermatol 1983; 108 (2): 199-204 milk. Pediatrics 1983; 72 (3): 375-83

118. Chalker DK, Shalita A, Smith Jr JG, et al. A double-blind study of the effective- 146. Al Ahdal O, Bevan DR. Clindamycin-induced neuromuscular blockade. Can Jness of a 3% erythromycin and 5% benzoyl peroxide combination in the Anaesth 1995; 42 (7): 614-7treatment of acne vulgaris. J Am Acad Dermatol 1983; 9 (6): 933-6 147. Igarashi K, Ishitsuka H, Kaji A. Comparative studies on the mechanism of action of

119. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a lincomycin, streptomycin, and erythromycin. Biochem Biophys Res Communcombination clindamycin/benzoyl peroxide gel compared with clindamycin 1969; 37 (3): 499-504gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind 148. Pochi PE, Bagatell FK, Ellis CN, et al. Erythromycin 2 percent gel in the treatmentinvestigations. J Am Acad Dermatol 1997; 37 (4): 590-5 of acne vulgaris. Cutis 1988; 41 (2): 132-6

120. Eady EA, Bojar RA, Jones CE, et al. The effects of acne treatment with a 149. Jones EL, Crumley AF. Topical erythromycin vs blank vehicle in a multiclinic acnecombination of benzoyl peroxide and erythromycin on skin carriage of erythro- study. Arch Dermatol 1981; 117 (9): 551-3mycin-resistant propionibacteria. Br J Dermatol 1996; 134 (1): 107-13 150. Puschmann M, Meyer-Rohn J. The efficacy of a topical preparation containing

121. Leyden JJ, McGinley KJ, Cavalieri S, et al. Propionibacterium acnes resistance to erythromycin in the treatment of acne. Dermatologica 1982; 164 (5): 343-9antibiotics in acne patients. J Am Acad Dermatol 1983; 8 (1): 41-5 151. Leyden JJ, Hickman JG, Jarratt MT, et al. The efficacy and safety of a combination

122. Morelli R, Lanzarini M, Vincenzi C, et al. Contact dermatitis due to benzoyl benzoyl peroxide/clindamycin topical gel compared with benzoyl peroxideperoxide. Contact Dermatitis 1989; 20 (3): 238-9 alone and a benzoyl peroxide/erythromycin combination product. J Cutan Med

123. Zbinden G. Scientific opinion on the carcinogenic risk due to topical administration Surg 2001; 5 (1): 37-42of benzoylperoxide for the treatment of acne vulgaris. Pharmacol Toxicol 1988; 152. Schmidt JB, Knobler R, Neumann R, et al. [External erythromycin therapy of63 (5): 307-9 acne]. Z Hautkr 1983; 58 (24): 1754-60

124. Mandell GL, Bennet JE, Dolin R, eds. Principles and practice of infectious 153. Schmidt JB, Thurner J, Poitscheck C, et al. [Local acne therapy with erythro-diseases. 5th ed. Philadelphia (PA): Churchill Livingstone, 2000: 394-7 mycin]. Z Hautkr 1982; 57 (2): 69-77

125. Cambazard F. Clinical efficacy of Velac, a new tretinoin and clindamycin phospha- 154. Zafrani ES, Ishak KG, Rudzki C. Cholestatic and hepatocellular injury associatedte gel in acne vulgaris. J Eur Acad Dermatol Venereol 1998; 11 Suppl. 1: S20-7 with erythromycin esters: report of nine cases. Dig Dis Sci 1979; 24 (5): 385-96

126. Becker LE, Bergstresser PR, Whiting DA, et al. Topical clindamycin therapy for 155. Avila P, Capella D, Laporte JR, et al. Which salt of erythromycin is mostacne vulgaris: a cooperative clinical study. Arch Dermatol 1981; 117 (8): 482-5 hepatotoxic [letter]? Lancet 1988; I (8594): 1104

127. Parker F. A comparison of clindamycin 1% solution versus clindamycin 1% gel in 156. Haydon RC, Thelin JW, Davis WE. Erythromycin ototoxicity: analysis and conclu-the treatment of acne vulgaris. Int J Dermatol 1987; 26 (2): 121-2 sions based on 22 case reports. Otolaryngol Head Neck Surg 1984; 92 (6):

678-84128. Goltz RW, Coryell GM, Schnieders JR, et al. A comparison of Cleocin T 1 percentsolution and Cleocin T 1 percent lotion in the treatment of acne vulgaris. Cutis 157. Jorro G, Morales C, Braso JV, et al. Anaphylaxis to erythromycin. Ann Allergy1985; 36 (3): 265-8 Asthma Immunol 1996; 77 (6): 456-8

129. Ellis CN, Leyden J, Katz HI, et al. Therapeutic studies with a new combination 158. Cooper WO, Griffin MR, Arbogast P, et al. Very early exposure to erythromycinbenzoyl peroxide/clindamycin topical gel in acne vulgaris. Cutis 2001; 67 (2 and infantile hypertrophic pyloric stenosis. Arch Pediatr Adolesc Med 2002;Suppl.): 13-20 156 (7): 647-50

130. Barza M, Goldstein JA, Kane A, et al. Systemic absorption of clindamycin 159. Gilman AG, Rall TW, Nies AS, et al., eds. Goodman and Gilman’s the pharmaco-hydrochloride after topical application. J Am Acad Dermatol 1982; 7 (2): logical basis of therapeutics. 8th ed. New York (NY): Pergamon Press, 1990208-14 160. Olsen TG. Therapy of acne. Med Clin North Am 1982; 66 (4): 851-71

131. Stoughton RB, Cornell RC, Gange RW, et al. Double-blind comparison of topical 161. Hjorth N. Traditional topical treatment of acne. Acta Derm Venereol Suppl1 percent clindamycin phosphate (Cleocin T) and oral tetracycline 500 mg/day (Stockh) 1980; Suppl. 89: 53-6in the treatment of acne vulgaris. Cutis 1980; 26 (4): 424-5, 429 162. Olin B, editor. Facts and comparisons. St Louis (MO): JB Lippincott Co, 1990

132. Thomsen RJ, Stranieri A, Knutson D, et al. Topical clindamycin treatment of acne: 163. Schwarb FP, Gabard B, Rufli T, et al. Percutaneous absorption of salicylic acid inclinical, surface lipid composition, and quantitative surface microbiology res- man after topical administration of three different formulations. Dermatologyponse. Arch Dermatol 1980; 116 (9): 1031-4 1999; 198 (1): 44-51

133. Gordon RC, Regamey C, Kirby WM. Serum protein binding of erythromycin, 164. Morra P, Bartle WR, Walker SE, et al. Serum concentrations of salicylic acidlincomycin, and clindamycin. J Pharm Sci 1973; 62 (7): 1074-7 following topically applied salicylate derivatives. Ann Pharmacother 1996; 30

134. Bennett WM, Aronoff GR, Golper TA, et al. Drug prescribing in renal failure. 3rd (9): 935-40ed. Philadelphia (PA): American College of Physicians, 1994 165. Pertoldi F, D’Orlando L, Mercante WP. [Acute salicylate intoxication after

135. Fass RJ, Saslaw S. Clindamycin: clinical and laboratory evaluation of parenteral trancutaneous absorption]. Minerva Anestesiol 1999; 65 (7-8): 571-3therapy. Am J Med Sci 1972; 263 (5): 368-82 166. Candy JM, Morrison C, Paton RD, et al. Salicylate toxicity masquerading as

136. DeHaan RM, Metzler CM, Schellenberg D, et al. Pharmacokinetic studies of malignant hyperthermia. Paediatr Anaesth 1998; 8 (5): 421-3clindamycin phosphate. J Clin Pharmacol 1973; 13 (5): 190-209 167. Germann R, Schindera I, Kuch M, et al. [Life threatening salicylate poisoning

137. Fleming GF, Crowe GR. Granulocytopenia due to clindamycin [letter]. Med J Aust caused by percutaneous absorption in severe ichthyosis vulgaris]. Hautarzt1976; 1 (3): 70 1996; 47 (8): 624-7

138. Swenson RM, Michaelson TC, Daly MJ, et al. Clindamycin in infections of the 168. Chiaretti A, Schembri Wismayer D, Tortorolo L, et al. Salicylate intoxicationfemale genital tract. Obstet Gynecol 1974; 44 (5): 699-702 using a skin ointment. Acta Paediatr 1997; 86 (3): 330-1

139. Vikenes K, Lund-Tonnesen S, Schreiner A. Clostridium difficile-associated diar- 169. Poe TE, Scott RB, Keith Jr JF. Drug interactions with furosemide [letter]. J Famrhea after short term vaginal administration of clindamycin. Am J Gastroenterol Pract 1984; 18 (2): 2041999; 94 (7): 1969-70 170. Pec J, Strmenova M, Palencarova E, et al. Salicylate intoxication after use of

140. Elmore M, Rissing JP, Rink L, et al. Clindamycin-associated hepatotoxicity. Am J topical salicylic acid ointment by a patient with psoriasis. Cutis 1992; 50 (4):Med 1974; 57 (4): 627-30 307-9

141. Poxton IR, McCoubrey J, Blair G. The pathogenicity of Clostridium difficile. Clin 171. Davies MG, Briffa DV, Greaves MW. Systemic toxicity from topically appliedMicrobiol Infect 2001; 7 (8): 421-7 salicylic acid. BMJ 1979; 1 (6164): 661

142. Feingold DS, Chen WC, Chou DL, et al. Induction of colitis in hamsters by topical 172. Cross SE, Anderson C, Thompson MJ, et al. Is there tissue penetration afterapplication of antibiotics. Arch Dermatol 1979; 115 (5): 580-1 application of topical salicylate formulations [letter]? Lancet 1997; 350 (9078):

143. Parry MF, Rha CK. Pseudomembranous colitis caused by topical clindamycin 636phosphate. Arch Dermatol 1986; 122 (5): 583-4 173. Raschke R, Arnold-Capell PA, Richeson R, et al. Refractory hypoglycemia

144. Milstone EB, McDonald AJ, Scholhamer Jr CF. Pseudomembranous colitis after secondary to topical salicylate intoxication. Arch Intern Med 1991; 151 (3):topical application of clindamycin. Arch Dermatol 1981; 117 (3): 154-5 591-3



174. Yokoyama A, Takakubo F, Eto K, et al. Teratogenicity of aspirin and its 187. Fitton A, Goa KL. Azelaic acid: a review of its pharmacological properties andmetabolite, salicylic acid, in cultured rat embryos. Res Commun Chem Pathol therapeutic efficacy in acne and hyperpigmentary skin disorders. Drugs 1991;Pharmacol 1984; 46 (1): 77-91

41 (5): 780-98175. Lin AN, Reimer RJ, Carter DM. Sulfur revisited. J Am Acad Dermatol 1988; 18

188. Mackrides PS, Shaughnessy AF. Azelaic acid therapy for acne. Am Fam Physician(3): 553-81996; 54 (8): 2457-9176. Danto JL, Maddin WS, Stewart WD, et al. A controlled trial of benzoyl peroxide

and precipitated sulfur cream in acne vulgaris. Appl Ther 1966; 8 (7): 624-5 189. Cunliffe WJ, Holland KT. Clinical and laboratory studies on treatment with 20%

azelaic acid cream for acne. Acta Derm Venereol Suppl (Stockh) 1989; 143:177. Wilkinson RD, Adam JE, Murray JJ, et al. Benzoyl peroxide and sulfur: founda-tion for acne management. CMAJ 1966; 95 (1): 28-9 31-4

178. Breneman DL, Ariano MC. Successful treatment of acne vulgaris in women with a 190. Hjorth N, Graupe K. Azelaic acid for the treatment of acne: a clinical comparisonnew topical sodium sulfacetamide/sulfur lotion. Int J Dermatol 1993; 32 (5):

with oral tetracycline. Acta Derm Venereol Suppl (Stockh) 1989; 143: 45-8365-7191. Verallo-Rowell VM, Verallo V, Graupe K, et al. Double-blind comparison of179. Pandey J, Chellani H, Garg M, et al. Congenital sulfhemoglobin and transient

azelaic acid and hydroquinone in the treatment of melasma. Acta Derm Venere-methemoglobinemia secondary to diarrhoea. Indian J Pathol Microbiol 1996;39 (3): 217-20 ol Suppl (Stockh) 1989; 143: 58-61

180. Blum JE, Coe FL. Metabolic acidosis after sulfur ingestion. N Engl J Med 1977; 192. Katsambas A, Graupe K, Stratigos J. Clinical studies of 20% azelaic acid cream in297 (16): 869-70

the treatment of acne vulgaris: comparison with vehicle and topical tretinoin.181. Olansky S. Old drug – in a new system – revisited. Cutis 1977; 19 (6): 852-4

Acta Derm Venereol Suppl (Stockh) 1989; 143: 35-9182. Genvert GI, Cohen EJ, Donnenfeld ED, et al. Erythema multiforme after use of

193. Passi S, Nazzaro-Porro M, Picardo M, et al. Metabolism of straight saturatedtopical sulfacetamide. Am J Ophthalmol 1985; 99 (4): 465-8medium chain length (C9 to C12) dicarboxylic acids. J Lipid Res 1983; 24 (9):

183. Rubin Z. Ophthalmic sulfonamide-induced Stevens-Johnson syndrome. Arch Der-1140-7matol 1977; 113 (2): 235-6

194. Willshaw HE, Rubinstein K. Azelaic acid in the treatment of ocular and adnexal184. Gottschalk HR, Stone OJ. Stevens-Johnson syndrome from ophthalmic sulfonam-ide. Arch Dermatol 1976; 112 (4): 513-4 malignant melanoma. Br J Ophthalmol 1983; 67 (1): 54-7

185. Spes CH, Angermann CE, Stempfle HU, et al. Sulfadiazine therapy for toxoplas-mosis in heart transplant recipients decreases cyclosporine concentration. ClinInvestig 1992; 70 (9): 752-4 Correspondence and offprints: Dr Susan Bershad, 28 South Mountain Ave-

186. Hansen JM, Kampmann JP, Siersbaek-Nielsen K, et al. The effect of different nue, Montclair, New Jersey 07042, USA.sulfonamides on phenytoin metabolism in man. Acta Med Scand Suppl 1979;624: 106-10 E-mail: [email protected]


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