June 2003 Current Treatment & Prevention of Acne H01

Transcription

1 W-F Professional Associates, Inc. 400 Lake Cook Rd., Suite 207 Deerfield, IL June 2003 Current Treatment & Prevention of Acne H01 MISSING A LESSON? IT S EASY TO GO TO OUR WEBSITE & DOWNLOAD WHAT YOU NEED. ( LESSONS ARE USUALLY ON THE WEBSITE BY THE FIRST DAY OF EACH MONTH. THIS MONTH Treatment of Acne ALWAYS KEEP A COPY OF YOUR QUIZZES. YOU MAY MAIL QUIZZES TO US, FAX THEM ( ), OR SEND US A CONVENTIONAL WITH YOUR ANSWERS. (info@wfprofessional.com) HAVE YOU RECENTLY MOVED? PLEASE NOTIFY US. Every year or 2, we find it useful to review & update the topic of Acne Treatment. Our goals are to present methods of prevention and to review current and new treatment options. This lesson provides 1.25 hours (0.125 CEUs) of credit, and is intended for pharmacists in all practice settings. The program ID # for this lesson is H01. Pharmacists completing this lesson by June 30, 2006 may receive full credit. To obtain continuing education credit for this lesson, you must answer the questions on the quiz (70% correct required), and return the quiz. Should you score less than 70%, you will be asked to repeat the quiz. Computerized records are maintained for each participant. Complete List of 2003 Topics: See Page 13. If you have any comments, suggestions or questions, contact us at the above address, or call toll free (In Alaska and Hawaii phone ). Please write your ID Number (the number that is on the top of the mailing label) in the indicated space on the quiz page (for continuous participants only). The objectives of this lesson are such that upon completion the participant will be able to: 1. Discuss the importance of patient education related to acne treatment & prevention. 2. Outline the factors associated with acne onset. 3. Identify the factors that serve as targets for drug action in antiacne therapies. 4. List the goals for non-drug, topical & systemic treatment of acne. 5. Compare the benefits & risks of topical versus systemic acne treatment. 6. List the advantages & disadvantages of topical versus systemic therapies. 7. Identify herbal & alternative acne treatments. 8. Recognize the pharmacist s role in acne management. All opinions expressed by the author/authors are strictly their own and are not necessarily approved or endorsed by W-F Professional Associates, Inc. Consult full prescribing information on any drugs or devices discussed.

2 INTRODUCTION AND BACKGROUND In this lesson, we will discuss therapies used in the treatment of acne vulgaris, also referred to as common acne (1,2,3). The economics involved in treating this often chronic condition are substantial. In the year 2000, an approximate 16% sales increase in acne treatment prescriptions was attributed to adult women seeking anti-acne therapies. A National Ambulatory Medical Care Survey indicated that acne treatment related visits to primary care providers increased more than two-fold to 900,000 between the early eighties and the early nineties (2). Acne has been reported in patients of all ages (1,2,3,4,5). It is estimated that nearly 80% of people get acne at least once between the ages of 11 and 30 years, and that about 17 million people in the USA seek treatment. The peak incidence for acne occurs in 18 year olds. More than 8% of patients are between the ages of 25 and 34, and over 3% are between the ages of 35 and 44 years. Severe acne is more common in males between the ages of 18 and 28 years. One source estimates that up to 50% of adult women experience some form of persistent acne (8). The psychosocial impact of acne conditions cannot be underestimated (1,2,3,6). Chronic acne can persist for years. Physically it causes embarrassment, disfigurement and permanent scarring and/or hyperpigmentation. Socially it has been linked to diminished self-esteem, social isolation, depression and unemployment. These psychosocial issues often make patients hesitate to seek treatment and support. Pharmacists can dispel misconceptions about the acne condition (2,5,6,9). First, patients should not blame themselves. It is not caused by diet or poor hygiene. Harsh, vigorous washings can aggravate acne. Second, diet cannot cause acne. Occasionally, some patients note flare ups are associated with certain foods, but these foods do not cause the condition. Third, topical treatments do not heal existing lesions, but work by preventing the formation of new lesions. They must be applied to all affected skin areas, not just lesions that are present. Some circumstances aggravate acne (1,2,5,7,9). Traumatizing existing acne lesions by picking them, or irritation from wearing athletic gear or clothing over them prolongs the lesion healing and increases the chances for scarring. The application of cosmetics and moisturizers that have high oil content can worsen acne. This is particularly common when hair pomades are applied to skin along the hairline. Premenstrual flare ups are common in patients sensitive to the androgenic effects of progesterone in the last half of the menstrual cycle. Patients working at auto repair shops or fast-food restaurants may have acne exacerbations due to contact with environmental grease. Finally, medications known to exacerbate acne include (1,2,16): systemic exposure to drugs such as androgens, barbiturates, bromides, carbamazepine, corticosteroids, ethionamide, haloperidol, iodides, isoniazid, lithium, phenytoin, phenobarbital, quinidine, or oral contraceptives containing high progestin content. Topical corticosteroid use can exacerbate acne also. CE PRN (ISSN ) is owned and published by W-F Professional Associates, Inc. 400 Lake Cook Road, Suite 207, Deerfield, Illinois William J. Feinberg, President CE PRN is published eleven times per year, monthly, January through November. Subscription rate is $90.00 per year. Second-Class Postage paid at Deerfield, Illinois and at additional mailing offices by W-F Professional Associates, Inc. All rights reserved. None of the contents of this publication may be reproduced in any form without the written permission of the publisher. POSTMASTER: Send all address changes to W-F Professional Associates, Inc., 400 Lake Cook Road, Suite 207, Deerfield, IL June

3 ETIOLOGY AND PATHOGENESIS OF ACNE There is no consensus on the exact cause of acne, but it is generally accepted that at least 4 factors contribute to its onset (1,2,4,5,6,8,9): 1. Increases in sebum production, which typically is attributed to androgen hormone activity. 2. Follicular obstruction, particularly of vellus hair ducts located on the face, chest, back, and upper arms. 3. Proliferation of Propionibacterium acnes, an anaerobic diphtheroid bacteria. 4. An inflammatory response to Propionibacterium acnes. Sebum is an oily substance that is secreted by the sebaceous gland. When secreted, it is released into a duct that is associated with a hair follicle (1,2,4,5,6,8,9). The gland-duct-follicle unit is called the pilosebaceous unit. During puberty, the sebaceous glands enlarge, while the hair follicles they are associated with remain small. The sebum flows from the duct to condition skin and hair. Pilosebaceous ducts are most numerous on the face, back, shoulders, and chest. Acne lesions most commonly occur on the face, but outbreaks also arise on the back, chest, shoulders, and upper arms of some patients. An acne lesion starts when the sebum flow is blocked (1,2,4,5,6,8,9). The process by which the innermost live skin cells transition into dead external stratum corneum cells is called keratinization. Altered keratinization results in skin cells that are shed and adhere to each other and the lining of the pilosebaceous duct. Research is ongoing to understand what causes the cells to adhere to the duct to create an obstruction (4,5). Findings to date report patients with acne have abnormal cell differentiation and hyperproliferation. In addition, acne-prone patients have sebum that is deficient in linoleic acid, and possibly higher in free fatty acids, squalene, and squalene oxide. It is hypothesized that sebum content alterations cause cell cohesion, leading to follicular blockage. The anaerobic bacteria Propionibacterium acnes, referred to as P. acnes, is a part of the normal flora of the skin, and thrives in obstructed follicles. The volume of sebum, degree of obstruction, activity of P. acnes, and the patient s immune response to substances released by P. acnes or the rupture of the pilosebaceous duct, determine the type and severity of lesions that form. Non-inflammatory acne presents as either closed or open comedones (1,2,4,5,6,8,9). When the pilosebaceous duct becomes blocked, a microcomedone forms, which cannot be observed. As sebum and cells continue to collect in the duct and form a plug, a visible closed lesion forms. This closed lesion is commonly called a whitehead because of its color. As the plug grows in size, it swells out of the duct to form an open comedone. The dark color of the plug in an open comedone results from oxidation of the plug contents. An open comedone is called a blackhead. Inflammatory acne occurs when the immune system responds to an acne lesion (1,2,4,5,6,8,9). The comedone becomes red and forms a papule, which may contain pus. If the papule spreads into surrounding tissues, a cyst, pustule, or nodule forms. Scarring commonly occurs from untreated cysts, pustules and nodules. Squeezing the lesions can further rupture the ducts, and aggravate the condition. Most acne patients typically have a mixture of different types of acne lesions. The details of immune activity associated with acne are under study (4). The possible mechanisms involved are numerous and complicated. A previous hypothesis states that the P. acnes associated lipase cleaves sebum triglycerides to produce glycerol, which is processed into free fatty acids. The free fatty acids were thought to be comedogenic, and promote the inflammatory response. It is now known that inhibiting bacterial lipase does not improve inflammatory acne. A new thought is that the altered follicular epithelium in a blocked duct signals an immune response. Depending on the level of immune activity, neutrophils, CD4+ lymphocytes, histamine-like compounds, antibodies, and other immune factors are involved in the response. Additional laboratory research demonstrated that comedones are produced in association with interleukin- 1a, and inhibited by the corresponding receptor antagonist. Although implications of these findings are unknown at this time, it is clear that the immune response to acne seems to propagate inflammatory lesions in some patients. Increases in serum androgen levels result in larger, more active sebaceous glands (1,2,4,5,6,10). Hence, acne is often associated with the onset of puberty. This appears to be a simple cause and effect relationship; however, the correlation between androgen levels and acne for males is variable, and for females is inconsistent. 3

4 Mean female serum androgen hormone profiles for acne patients are generally the same as for normal patients (4,10). Thus, androgens promote the development of acne, but they are not a prerequisite for the condition in all patients. Potent androgen compounds, including testosterone (T), are produced via complicated metabolic pathways (4,10). Research has shown that T circulates in the bloodstream either free, or bound to plasma proteins called sex hormone-binding globulin (SHBG)(10). A slight shift in the binding of T to SHBG can significantly affect the androgenic state of a patient. Androgen shifts either via hormonal production or changes in SHBG can impact acne. One theory is that sebaceous glands in certain patients are hypersensitive to the presence of androgens. Hence, high androgen levels may not be necessary for acne conditions. Shifts in SHBG levels may be enough to precipitate it. ACNE TREATMENT REGIMEN The goals of acne treatment are to heal lesions already present, prevent new lesions from forming, prevent skin scarring, and prevent psychological suffering (1,3,7,). Acne is slow to respond to therapy because lesions start developing long before they are visible (5,6,9). Thus, treatment regimens should be assessed over a 2 month period of time, and should remain as simple as possible. If symptoms do not show any improvement between 4 and 8 weeks after initiating therapy, completely new medications should be considered, rather than adding more medications onto an ineffective regimen. Complicated regimens typically cause increased irritation and reduce patient compliance. Patients need to understand that it can take 8 months or more for lesions to resolve with an effective treatment. It is critical that they regularly use the indicated regimen throughout this time, and to speak with their pharmacist or physician when discouraged. There are a variety of grading systems for acne (1,4,5,6,8). In 1990, the Consensus Conference on Acne Classification stressed the importance of acne classification into 3 categories: 1) Mild: few to several papules or pustules and no nodules; 2) Moderate: several to many papules or pustules and few to several nodules; and 3) Severe: numerous to extensive papules or pustules and many nodules (4,5). A nodule is a palpable, solid, circumscribed lesion that is cm in size (9). To determine a therapy, a physician should classify the condition, consider the psychosocial impact of the condition on the patient, consider the failure of previous treatments, and the occupational disability of the patient (4). Some physicians argue that classifications are helpful for grading clinical studies, but generally do not impact outcomes (6). The traditional treatment approach of initiating topical therapy, maximizing it, then progressing to oral therapy is well known. Physicians, however, admit that there are numerous alternative approaches to treating acne, and seldom do 2 physicians have the same approach (5). Due to the severe psychosocial consequences, one alternative approach suggests evaluating the most severe lesions, and selecting a therapy accordingly (6). The less severe lesions will be cleared in the process, and the patient will have a quicker recovery. A general consensus approach suggests that an initial assessment include an approach for treatment, patient education, and a follow up visit scheduled for 2 months later (5). Patients should call the physician or pharmacist with questions in the interim to reinforce the importance of adhering to the treatment regimen and decrease the chances of noncompliance. If acne does not respond to treatment after 2 months, the first inquiry must be about patient compliance (6). A non-drug treatment regimen is designed to promote healthy skin, prevent new acne lesions from forming, and support the healing of existing lesions (1,9). The cornerstone of a non-drug regimen includes cleansing the skin at least twice daily using warm water and a gentle, non-abrasive cleanser or soap. Additional cleansing may be required for patients who are exposed to environmental triggers, or produce excessive amounts of sebum or sweat. The skin must be gently washed, and patted dry, as friction or local irritation may aggravate acne. Abrasive cleansers should only be used under a physician s supervision. Astringents may help gently remove oily residues from the skin, but can cause excessive skin dryness and irritation. Squeezing or picking acne lesions can aggravate their condition and cause scarring. Water based make-ups are best, and it may be necessary to try more than one brand of cosmetic to determine which one will not exacerbate acne. Patients using cosmetics must thoroughly remove all make-up at the end of each day. Finally, a nondrug treatment regimen requires that patients monitor their lifestyle. Circumstances that correlate to a flare-up 4

5 in acne should be noted and discussed with pharmacists and physicians. Problem solving discussions can focus on how to minimize triggers such as certain foods, stress, and those that are activity related. Patients must understand that the non-drug treatment regimen often determines the success of OTC drug treatment. Pharmacists can help patients choose OTC drug therapies based on the severity and duration of the acne lesions. It is critical for patients to understand that it takes an average of 2 months for noticeable improvement once non-drug and OTC therapy have started, and possibly months more for lesions to completely resolve. If the acne lesions are progressing despite following a non-drug and OTC treatment regimen, the patient must be referred to a physician. TOPICAL ACNE THERAPIES The topical drug treatment of acne is recommended for mild to moderate, non-inflammatory lesions of the face (1,2,5,6,7). Topical treatments do not affect the amount of sebum produced, and must be initiated at low doses to avoid skin irritation. As tolerance to the topical medication increases, the dose or frequency of application for the medication can be increased as needed. Often lesions that do not respond to one topical treatment will respond to combination therapy (2). If two different topical medications are recommended, they should be applied in an alternating fashion at different times of the day, unless otherwise instructed by a physician or pharmacist. Topical medication should be applied over the whole area that is affected, and not just to distinct acne lesions. Topical anti-acne medications should not be applied to mucous membranes, damaged skin, or sunburned skin. If they come in contact with such areas, they should be immediately removed with water. In 1991, the Food and Drug Administration Advisory Panel for OTC Antimicrobial (II) Drugs issued a final monograph that states the regulations for OTC anti-acne products (11). There are two conditions for anti-acne drug product use in the regulations: Monograph conditions and Non-monograph conditions. Monograph conditions essentially correspond to the former Category I products that are recognized as safe and effective, and correctly labeled. After August 1992, no anti-acne non-monograph condition drug could be introduced to market without going through the FDA drug approval process. Existing products that are considered non-monograph condition drugs can remain on the market until data demonstrates that they should no longer be sold. Benzoyl Peroxide is the only OTC non-monograph drug currently marketed because of questions regarding its safety. Anti-acne drug vehicles impact the drug effectiveness (1,2,11). Gel-type formulations are very effective, but may cause irritation to patients with dry or sensitive skin. Gel formulations containing high water content dry more slowly than products that have a high alcohol content. Alcohol based products are the most irritating and drying to the skin. Cream and lotion products are less irritating than gel products. They are good choices for patients with dry or sensitive skin, or patients exposed to dry atmospheric conditions. Solution products are helpful when treating a large body surface area. The following summary outlines key points for topical acne treatments. For complete dispensing information, see reference 12. Benzoyl Peroxide (BP) BP efficacy primarily is due to its bactericidal activity, but it also reduces the fatty acid content in the pilosebaceous duct, promotes skin desquamation and cell turnover, and helps dissolve plugs in the pilosebaceous duct (1,7,9,11,13). It is an oxidizing agent that works by releasing free-radical oxygen into the skin and pilosebaceous ducts. Studies indicate that BP penetrates into the pilosebaceous duct within a few hours of application (13). In 1991, preliminary reports suggesting that BP may promote tumor growth in mice prompted the FDA to study the drug more carefully. To date, there is no indication that BP promotes skin cancer in humans, so it remains marketed as a non-monograph drug. BP has been clinically shown to improve acne papules and pustules, thus is beneficial in treatment of inflammatory and non-inflammatory acne (1,2,7,11,12,13). Within 3 months, 50% to 75% of inflammatory lesions can be healed (1). A number of prescription and OTC BP products are available in drug strengths between 2.5% and 10% (5,9,11,12,13). Studies report that the concentration of BP in OTC products does not impact the number of inflammatory lesions healed (13). It also has been shown that a 2.5% OTC BP product 5

6 and a 10% OTC BP product deliver comparable amounts of drug into the skin. The value of the higher concentration products is questionable, and may only serve to cause greater skin irritation (5,13). The product vehicles impact BP delivery into the skin. Patients not having success with one BP product can try a BP product in a different vehicle. BP products often irritate skin (1,2,5,6,7,11,12). Mild irritation causes enhanced blood flow and vasodilatation to the application site, thus may speed acne healing (1). Due to the potential for skin irritation, it is recommended that patients start therapy with a low dose cream applied every other day, and the frequency of application can increase as tolerated. If needed, higher dose products are available in more drying vehicles, such as gels. If moderate irritation occurs, the patient can apply cool compresses to the site, followed by a non-irritating emollient cream or lotion. Once healed, BP treatment can resume. Severe irritation requires discontinuing the BP product, and contacting a physician. Concurrent exposure to sunlight, or use of other topical acne medications may promote BP skin irritation. Less than 1% of patients are reported to experience allergic contact dermatitis caused by BP. Patients allergic to cinnamon may be cross-sensitized to BP. BP products can bleach hair and fabrics. BP cleansers are used 1 to 2 times daily (12). The area for cleansing should be wet before applying the cleanser, and rinsed well after cleaning. BP washes and cleansers may be particularly helpful to patients having large areas of back or chest acne. Patients should be advised to apply other BP products every other day after cleansing the skin with a non-bp containing cleanser. The frequency of application for leave-on BP products can be increased as tolerated to 3 times a day. BP is often used in combination with other anti-acne medications ((2,5,6,9,11). Due to resistance, it is almost a given that BP and topical antibiotic therapy are combined. It can inactivate tretinoin via oxidation if applied at the same time, so it is best if BP is applied in the morning and tretinoin at night. Keratolytics Sulfur, salicylic acid, and resorcinol are classified as keratolytics, and they facilitate the sloughing of epithelial cells in the lining of the follicle (2,9,14,15). All are used either alone or in combination, and are available in OTC and prescription formulations. Individually, they are generally less effective than BP. Sulfur is most commonly found in OTC anti-acne products at concentrations between 2% and 10% (9,11,12,14,15). It causes skin drying and peeling. It speeds the resolution of inflammatory lesions, and is recognized as having weak antimicrobial activity. Cream, lotion, soap, and mask products are available, and can be used up to 3 times daily. Sulfur containing products may tint the skin a yellow color, and have the characteristic odor of rotten eggs. Salicylic acid (SA) controls cell shedding in the duct to prevent plug formation (2,9,14,15). For the treatment of mild to moderate acne, it primarily is used between 0.5% and 2% in OTC leave-on products, washes and cleansers. Below 1%, SA has an acidifying effect on the skin. Between 1-4% it produces a surface keratolytic effect. At 5% and above, SA has a deep keratolytic action. It can increase skin irritation when used concurrently with other anti-acne medications, and has the potential for systemic toxicity when used over large areas for prolonged periods of time. Salicylic acid and sulfur are synergistic when used in combination. Resorcinol is an anti-acne medication that is seldom used due to its characteristic odor and comparable efficacy to other OTC anti-acne actives (2,9,14,15). It is an alkyl-substituted phenol that has mild antibacterial effects, and is used at a level of 1% to 2%. It is most often used in combination with sulfur. A dark-brown scaling of the skin may occur after resorcinol therapy, particularly in patients with dark complexions. Resorcinol should not be used over extensive areas of the body due to possible systemic toxicity. Retinoids For over 50 years, vitamin A and vitamin A derivatives have been used to treat acne (1). They work by increasing cell turnover, and decreasing cell cohesiveness, thus normalizing follicular keratinization 6

7 (1,2,5,6,7,11,12). Tretinoin (TR), also known as all-trans-retinoic acid or vitamin A acid, works to heal all phases of the acne process. It prevents comedone rupture, thus suppressing the migration of immune mediators to the acne site. Even severe acne can clear within a few months of TR use (6). It can normalize the hyperpigmentation in African American patients resulting from inflamed lesions (7); however, TR therapy that causes excessive irritation can cause hypopigmentation that may last several months (5). Tretinoin is available to treat acne in liquid, cream and gel formulations by prescription at 0.01%, 0.025%, 0.05%, and 0.1% concentrations (12). The most recent cream formulations, called Retin-A Micro, are at 0.04% and 0.1% concentrations. The 0.1% Micro was clinically tested to show equal efficacy with less irritation than other 0.1% formulations, due to microsphere and liquid polymer technologies (2,5,9). The clinical results achieved after TR therapy are a function of both the drug concentration, and the type of drug vehicle (2). Topical TR is applied daily at bedtime to the affected area. Acne may appear worse in the first few weeks of therapy because previously non-visible lesions often surface at the onset of therapy. An overall improvement in lesion appearance should be noted after 3 to 6 weeks of therapy, but maximal clinical improvements may take as long as 4 months. If it is necessary to use TR in combination with other topical anti-acne medications, the application times must be substantially staggered. TR often causes skin peeling and redness, which can be controlled by changing the frequency of application or medication strength (1,2,5,6,7,11,12). Patients should minimize exposure to sunlight and sunlamps, and apply a sunscreen to exposed areas. Skin irritation is greater if TR is used in combination with other topical anti-acne medications. Patients should be instructed to cleanse the area before TR application. TR is a powerful teratogen (2,13). It is in pregnancy category C. Since the possibility of TR absorption into the systemic blood stream exists, it is advised that topical TR be used cautiously in women who may become pregnant, and not used during pregnancy unless absolutely necessary. Adapalene(AD, Differin ). AD is a drug that binds to certain retinoic acid nuclear receptors to decrease cell turnover in the pilosebaceous duct, and reduce inflammation (11,12). AD 0.1% gel heals non-inflammatory lesions better than TR 0.025% gel, and works as well as TR with less irritation in patients having mild to moderate acne inflammation with lesions (2,5,7,11). AD effectiveness is more erratic than TR (7). AD is sold as a 0.1% cream, gel, or solution (12). It is applied daily at bedtime to clean skin. Initially, acne may appear to get worse, but positive results should occur within 3 months. AD should not be applied to sunburned skin, and ultraviolet exposure should be avoided once therapy is started. The most common adverse complaints associated with AD use are related to skin drying, burning and irritation. Altering the frequency of application or product type may help alleviate these reactions. AD should not be used with other anti-acne topical medications or skin irritants. It is in pregnancy category C. It is advised that topical AD be used cautiously in women who may become pregnant, and not used during pregnancy unless absolutely necessary. Tazarotene (TA, Tazorac ). TA is a retinoid prodrug that becomes an active metabolite after esterase hydrolysis in the skin (12). It is marketed as a 0.1% gel or cream to treat mild to moderately severe acne, and psoriasis. The 0.05% gel or cream are indicated for the treatment of wrinkling or skin pigment changes. It is effective, but is more expensive and has higher irritation rates reported, than TR or AD (5). TA is in pregnancy category X, so it is contraindicated for use in women who may become or are pregnant. Skin irritation and photosensitivity are common with TA. It is applied to clean skin daily at bedtime. Azelaic acid (AA, Azelex ) AA is a dicarboxylic acid that has antimicrobial activity against P. acnes and Staph. epidermidis, and prevents plug formation in the duct (2,5,6,11,12). It often is used in patients who cannot tolerate TR (5). Clinical testing reports AA is as effective as 0.05% TR, 5% BP, or 2% erythromycin, in healing non-inflammatory acne lesions, but in practice, results are discouraging (2,5). The most notable adverse effect associated with AA is that it decreases skin pigment, especially in patients with dark complexions, due to it inhibiting melanin production (2,5,6,11,12). Patients with light or freckled skins do not note such changes. AA is marketed as a 20% cream. Skin irritation is common when therapy is initiated (12). Antibiotics Topical antibiotics usually are prescribed if mild inflammatory acne lesions fail to respond to BP, TR, or AD (1,2,5,6,7). Topical antibiotics are thought to penetrate into the pilosebaceous duct to minimize P. acnes 7

8 counts, reduce inflammatory mediators, and decrease the duct free fatty acid content (5,11,12). Clindamycin and erythromycin are reported to significantly decrease the number of inflammatory acne lesions (2). Up to 6 weeks of therapy may be needed to lower the P. acnes count in severe inflammatory acne. Once no new acne lesions appear, the antibiotic can be gradually discontinued. There is much concern about the resistance of P. acnes to antibiotic therapy (2,6,11,12). Resistance is reported most frequently with erythromycin. Bacterial resistance to erythromycin is suspected to be cross resistant to clindamycin (11). Many clinicians feel that topical antibiotics should always be prescribed with a second medication, most commonly BP or TR (2,5,6,7). This greatly increases the effectiveness of therapy, but also increases the cost of therapy. Using 2 separate products simultaneously may be more cost effective than using one combination product; however, patient compliance must be evaluated. Either BP or TR therapy may be combined with the topical antibiotic therapy. Several different topical antibiotic products are available in different vehicles (12). The vehicles may vary the clinical response to the antibiotic. Improvements in inflammatory papules and pustules may be noted after 3 weeks to 9 weeks of therapy (1,2,5,6,7). It is recommended that topical antibiotics be used twice daily, in the morning and evening, after washing the affected areas. The pledget delivery form for clindamycin and erythromycin is a disposable single use applicator that must be thrown away after each use (11,12). Systemic side effects from topical antibiotics have not been reported (11). Note that topical tetracyclines, erythromycin and clindamycin are antagonistic, and should not be used concurrently (12). Topical erythromycin and clindamycin are more effective than topical tetracycline (2,7). Erythromycin is the only topical antibiotic that is offered as a combination product with BP (11,12). This product must be mixed using ethyl alcohol prior to dispensing, refrigerated, and used within 3 months. Convenience is the only real advantage to having erythromycin and BP combined into a single product. The individual products each can be separately applied to get the same effect. Clindamycin can cause skin redness, dryness, burning and peeling (12). Topical metronidazole is indicated for the treatment of inflammatory rosacea, but has been prescribed for acne therapy. Topical tetracycline is the least popular anti-acne antibiotic in the USA (2). It can cause skin stinging or burning, and a yellow discoloration of the skin and clothing may appear, which can be removed with washing (11,12). It also causes skin fluorescence under ultraviolet lights. Topical meclocycline is less irritating than tetracycline, causes less skin staining, and does not cause fluorescence. Patients with formaldehyde allergy or sulfite sensitivity should use topical tetracycline and meclocycline cautiously. SYSTEMIC ACNE THERAPIES The systemic treatment of acne is considered when: topical therapy fails, a patient suffers from moderate to severe inflammatory acne and is at risk for permanent scarring of the skin, a patient has acne on large body areas, or if resistance to other anti-acne therapies occurs (1,2,5,6,7). The long term goal of systemic therapy is to resolve acute acne lesions and gain control over the condition so that topical therapies can resume (7). The following summary outlines key points for systemic acne treatments. For complete dispensing information, see reference 12. Antibiotics Tetracycline, doxycycline, minocycline, erythromycin, and sulfamethoxazole-trimethoprim inhibit P. acnes proliferation (2,5,6,7,12). Although oral clindamycin also inhibits P. acnes proliferation, it rarely is used because it can cause pseudomembranous colitis as a side effect (2). Clinical efficacy should be noted within 8 weeks of starting therapy, wherein new lesions are significantly reduced or are no longer appearing (6). Maximum effects are not seen for as long as 4 months, and therapy should be discontinued after 6 months (2). If lesions get worse or do not improve after 6 months, it may be a sign of either bacterial resistance or a gram-negative bacterial infection, and alternative therapy is required. Effective therapy will yield signs of acne improvement within 4 months, after which the oral antibiotic dose can be reduced (1,2,5). The lower dose therapy should continue for 1 to 3 months, and the oral dose either reduced again or discontinued as acne improves. A topical therapy should replace oral therapy. Acne may periodically flare up with low-dose oral antibiotic therapy, or once oral antibiotics are discontinued. Either an increase in the oral antibiotic dose, or use of a topical antibiotic concurrently with low-dose oral antibiotics, 8

9 usually is sufficient to control the flare-ups. Although controversial because of emerging bacterial resistance, some physicians keep patients on long-term low-dose oral antibiotic therapy for years to maintain acne control (5,6). Current guidelines recommend either using isotretinoin or hormonal therapies for patients requiring long-term therapy (7). Because of its low cost and efficacy, tetracycline is the oral antibiotic prescribed most frequently (2,5,11). The starting dose commonly is 500 mg to 1 gram divided into 2 doses daily (5,6). Some physicians feel tetracycline is not effective enough due to resistance, and start therapy with either doxycycline or minocycline (6,7). Doxycycline usually is dosed at 100 mg twice a day, and minocycline usually is dosed at 50 mg to 100 mg twice a day (5,6,12). They are not prescribed as frequently as tetracycline, however, due to high cost and potential for increased side effects with minocycline. Tetracycline has the highest number of gastrointestinal complaints among the tetracyclines. It should be taken on an empty stomach 1 hour before or 2 hours after eating. Doxycycline and minocycline can be taken without regard to food (12). Tetracycline has decreased absorption when administered with dairy products, or calcium, magnesium, aluminum, or zinc containing products. Coadministration of iron products decreases the absorption of most tetracyclines. The two most bothersome adverse responses to the tetracycline class of antibiotics include photosensitivity, and the potential for decreased effectiveness of oral contraceptives (2,5,6,12). They should not be used during pregnancy due to potential adverse effects on fetal skeletal development, or in children under 9 years of age due to potential discoloration of the teeth. Minocycline is cited for the most severe side effects, which include lupus, Stevens-Johnson s syndrome, blue-gray pigment changes, or vestibular disturbances (6,12). Vaginal candidiasis frequently occurs with tetracycline use. Erythromycin is a second-line oral anti-acne treatment because of a higher incidence of bacterial resistance related to unsuccessful acne treatment (2,5,6,12). It usually is dosed at 500 mg twice a day for acne therapy, and causes disturbing gastrointestinal side effects in many patients. Sulfamethoxazole-trimethoprim usually is dosed as the double strength at 800mg SMX, 160 mg TMP twice a day for acne therapy. It is a second-line oral anti-acne treatment because of the potentially serious adverse effects of photosensitivity, rash, allergy, and bone marrow suppression, and it is contraindicated during pregnancy and lactation. In rare cases, ciprofloxacin has been used for acne therapy. Cephalosporins and penicillins are not effective in acne treatment (6). Isotretinoin (Accutane ) Isotretinoin, also known as 13-cis-retinoic acid, is a metabolite of vitamin A (1,2,6,9,12,16). Its introduction about 20 years ago revolutionized the treatment of severe acne (6). It is the only anti-acne drug that is effective against all the pathological factors that cause acne, including sebum production. It decreases sebum production by 80% within a month of therapy (16). It heals all types and severity of acne, and reduces the severity of scarring. Over 70% of patients obtain long-term acne remission after one course of therapy (16). Most relapses happen within 18 months after therapy is stopped, and those restarting therapy rarely experience a second relapse. Low dose therapy and noncompliance are the main causes for relapse. Patients prone to relapse include young men with extensive truncal acne, patients with acne sinus tracts, hemorrhagic crusted acne, and hyperandrogenic women. Due to its efficacy, it can be more cost effective than other therapies that require longer treatment periods or multiple products. (2,16). While there is no dispute over the benefits of isotretinoin therapy, physicians differ in their opinions about its appropriate use due to the potential side effects and potent teratogenicity (16). While is it indicated for the treatment of severe recalcitrant nodular acne (12), it is prescribed for moderate to severe acne if physicians feel the benefits outweigh the risks. Teratogenicity is the most severe side effect. Over an 18-year period of time, almost 2000 pregnancies were exposed to isotretinoin, with 71 reports of infants having congenital malformations as a result. The prime reason for pregnancy exposure is lack of contraception. Hence, patient education in pregnancy prevention is strictly mandated before isotretinoin can be prescribed. The FDA requires only dermatologists prescribe isotretinoin under the System to Manage Accutane Related Teratogenicity (S.M.A.R.T.) program. Once enrolled in the program, dermatologists must assure the patients meet education guidelines as well as the following requirements, and apply yellow qualification stickers to every isotretinoin 9

10 prescription. The patient must fill the prescription within 7 days. A maximum of a 30-day supply is dispensed with each prescription. Patients must receive a medication guide with each prescription filled. Men have fathered healthy children when taking isotretinoin despite slight changes in spermatogenesis. It is recommended that males avoid isotretinoin therapy when trying to conceive a child. Female patients must: understand verbal and written warnings about isotretinoin s impact on pregnancy; be willing and able to comply with using 2 reliable forms of contraceptive therapy at least 1 month prior to therapy, starting isotretinoin therapy on day 2 or 3 of the menstrual cycle following the second negative serum pregnancy test, and continue contraceptive measures at least 1 month after isotretinoin therapy is stopped; have a second negative pregnancy test confirmed at least 11 days after the last act of unprotected intercourse if experiencing amenorrhea; have a negative pregnancy test prior to receiving each monthly prescription; agree not to donate blood while taking isotretinoin or within 1 month of stopping therapy; avoid substances that may decrease the effectiveness of oral contraceptives, including Saint John s wort. Severe systemic side effects occur in about 2% of patients (16). Some of these side effects continue after it is stopped (12). Before starting therapy, and about monthly after therapy begins, the following laboratory tests should be evaluated: serum triglycerides, cholesterol, liver function tests, and a complete blood count. Most side effects are dose related. Mucocutaneous side effects are reduced if doses are started as low as 0.1 mg/kg/day, and titrated up as tolerated (2,16). Inflammation of the lips (cheilitis) occurs in about 90% of patients, and noncompliance or poor absorption should be suspected if cheilitis is not observed. Skin irritation and exfoliation are bothersome in more than 50% of patients. Approximately 30% of patients experience dry nose or nose bleeding, along with possible brittle nails, dry mouth and thirst. Asthma exacerbations occur from pulmonary mucosa dryness. Permanent alopecia is reported with long term therapy. About 16% of patients report pain or stiffness in joints, bones, and muscles. This usually subsides when isotretinoin is discontinued, and may be managed with nonsteroidal anti-inflammatory drug therapy. Ocular effects include dry eyes, blepharitis, and conjunctivitis, which resolve within 2 months of stopping therapy. Decreased dark vision adaptation and color vision, however, may be irreversible on rare occasion. About 25% of patients have an increase in triglycerides, which usually can be controlled by monitoring dietary intake. Reports of increased cholesterol and decreased high density lipoprotein levels are cited. Up to 15% of patients have increased liver function test levels, and a decrease in red and white blood cell counts have been reported. Patients must wait at least 18 months after therapy before scheduling surgical or laser procedures to repair acne scars due to cheloid formation. Studies indicate there is not a causal relationship between isotretinoin use and major depression or suicide (16). Dermatologic patients have an inherent 10% higher suicidal risk versus nondermatologic patients, so it was concluded that psychological challenges are due to severe acne conditions rather than isotretinoin. However, since the potential for adverse psychological effects cannot be ruled out, it is very advisable to evaluate a patient s emotional status before initiating therapy, and to monitor the patient for psychological shifts throughout treatment. Isotretinoin therapy is started at a dose of 0.5 to 1.0 mg/kg/day for a single 20 - week course (16). The 0.5 mg/kg/day dose is reported to have higher acne relapse rates than higher doses, particularly for nodular acne (1,2,12,16). After treatment is stopped, improvement may continue for 4 to 5 months. If a patient relapses, higher doses of 1.5 mg/kg/day to the maximum recommended daily dose of 2 mg/kg/day are recommended. Isotretinoin has increased bioavailability when taken with food, so it is dosed twice a day with meals. A new micronized formulation of isotretinoin is under review by the FDA (16). It has better bioavailability at lower doses, and can be taken once a day. Carbamazepine, phenytoin, and valproic acid lower the blood concentrations and efficacy of isotretinoin. Patients having a Staph. aureus colonization in addition to acne require oral antibiotic therapy. In rare cases, isotretinoin can cause acne fulminans, in which patients should stop isotretinoin therapy and begin a course of systemic corticosteroids. 10

11 Hormonal Therapy The rationale behind using hormonal therapy to treat women with acne is centered on patients having symptoms of hyperandrogenism, primarily hirsutism, adult onset acne, premenstrual flare ups, irregular menses, and treatment failures with standard therapies (7,10). Patients without these overt signs of hyperandrogenism, however, have also benefited from oral contraceptives improving their acne condition. Oral contraceptives reduce excessive androgens from ovarian and adrenal sources (10). There are over 40 different oral contraceptive products in the USA. All combination products contain both an estrogen and a progestin component. Monophasic products have a uniform hormonal dose throughout the pill cycle. Multiphasic products shift either the progestin and/or estrogen dose throughout the cycle. Historically, there has been much published literature on the relative androgenicity of the progestin components of oral contraceptives. The studies conducted employed methods that were state of the art at the time, but flawed by today s standards. In addition, it has been found that for combination products, the combination must be tested for androgen activity, not just the progestin, because the estrogen component alters the progestin androgenicity. More recent research indicates that all low dose combination oral contraceptives are estrogen dominant, and will benefit hyperandrogenic women in need of acne treatment. Even though the FDA specifically indicates certain products for anti-acne use (Ortho Tri-Cyclen and Estrostep), studies fail to show a statistical difference in acne response between these and other products(9,10). Hormonal therapy begins to improve acne in candidate patients after 2 to 4 months of use (2,7). The FDA s Fertility and Maternal Health Drugs Advisory Committee recommends that products be selected by choosing the lowest dose of estrogen and progestin suitable for the patient (10). This provides acne improvement and minimizes the probability of adverse thrombotic events, nausea, vomiting, breast tenderness, weight gain, headache, and breakthrough bleeding related to noncompliance (7,10). Patients that smoke cigarettes or have a family or personal history of hypercoagulability should not begin oral contraceptive therapy. Spironolactone prevents androgen binding to receptors, and may be used in combination with oral contraceptives (7,12). Side effects to spironolactone are dose related, so therapy should start at 25 mg/day, and be slowly increased to a maximum of 200 mg/day. Side effects reported for spironolactone associated with acne therapy include gynecomastia and tenderness in the breasts, hyperkalemia, and menstrual irregularities. Hyperkalemia is usually not clinically significant in young healthy women. Excessive adrenal androgen production may be treated using oral corticosteroid therapy (7). Oral corticosteroids may be used to manage excessive ovarian androgen production when other hormonal therapies are unsuccessful in treating acne. Patients requiring oral corticosteroids should take a maximum bedtime dose of 7.5 mg prednisone or 0.5 mg dexamethasone until improvements are noted. Corticosteroid injections suppress acute inflammation in severe acne lesions. See reference 12 for a complete outline of corticosteroid adverse effects and dispensing information. NONTRADITIONAL Therapies Some patients prefer trying herbal or alternative therapies prior or in parallel to traditional therapies (17,18). In 1997, the number of visits to alternative medicine practitioners exceeded the number of visits to all primary care physicians at 629 million, and $27 billion was spent for alternatives therapies and over $3 billion for herbal therapies (17). Studies evaluating the efficacy of nontraditional therapies are growing. For acne treatment, patients may choose to use nontraditional therapies in addition to traditional therapies. A few of the more popular options include: Tannins (17). Witch hazel (Hamamelis virginiana) bark extract is the most common source for tannins, and is used topically for its astringent properties. Since the tannins are lost in commercial distillation, the extract is prepared fresh by steeping 5-10 grams of herb in 1 cup of boiling water, then straining it. Similar extracts are made using white oak or English walnut tree barks. These extracts are safe and are used 2-3 times daily. 11

12 Fruit Acids (17). Acidic preparations from various fruits are used topically for their exfoliative effects. Some of the acids include: citric, gluconic, gluconolactone, glycolic, malic, and tartaric. The potency of the fruit acid preparations depends upon both the concentration of the acid and ph of the product. The lower the ph, the more active the acid will be on skin, increasing its irritation potential. Hence a low concentration product at a ph of 3 can be more irritating than a higher concentration product at a ph of 7. A study showed one preparation containing gluconolactone was equivalent to 5% BP for clearing inflamed and noninflamed acne lesions, but other studies have shown that exfoliants alone do not heal most acne conditions. Additional studies are needed. The main counseling point to patients wanting to continue fruit acid therapy in parallel to traditional therapy is that fruit acids will add to the skin irritation caused by tested traditional therapies, so they should be applied as tolerated after the traditional therapy has been used as directed. Tea Tree Oil (17). Tea tree oil is a very safe topical extract from the tea tree (Melaleuca alternifolia). It contains about 100 compounds consisting of primarily plant terpenes and alcohols. It is poisonous when taken internally. Studies indicate that it statistically improves acne after about 3 months of multiple daily applications with less irritation than BP. In some patients it can cause contact dermatitis. Vitex (17). Vitex agnus-castus is an oral whole-fruit extract taken to treat premenstrual acne. It is believed to act on follicle stimulating and leuteinizing hormones to increase endogenous progesterone and decrease endogenous estrogen. The German Commission E monographs state the dose is 40mg/day. It should not be taken if pregnant or nursing, and can cause gastrointestinal upset and rash. Patients using this herb must inform their physicians before starting on traditional hormonal treatments. Other alternative therapies (17,18). Despite less clinical information, the following substances may be used as acne therapy: Topical bitter nightshade (Solanum dulcamara) and oral brewer s yeast (Saccharomyces cerevisiae) are said to impart antimicrobial effects that may improve acne conditions. Topical duckweed (Lemma minor) is used in China. Oral gamma-linolenic acid replacement from primrose or borage oils may help individuals who have altered sebum content that contributes to abnormal follicular keratinization. CONCLUSION Acne patients can look to pharmacists to gain an overall perspective about what to expect from non-drug and drug therapies. Patients should understand that skin cleansing and diet do not cause acne, but may make an acne condition worse. Successful treatment requires both the proper medication and patient compliance. Clearing acne lesions is a long process, hence patient education and support are needed to 12