PLANNING COMMITTEE - cdn.dal.ca · 0.025%-0.05% are most useful, higher strengths are often not tolerated). • Starting with every 2nd or 3rd night. • Applying 30-45 minutes after

1

PLANNING COMMITTEE

1. Content Experts • Clinical expert

• Peter Green MD FRCPC, Assistant Professor, Department of Medicine, Division of Dermatology, Dalhousie University

• Drug evaluation pharmacist • Kim Kelly, BScPharm, Drug Evaluation Unit, Capital Health • Cait O’Sullivan, BA, BScPharm, PharmD, University of Washington

Internship 2. Family Physician Advisory Panel

• Bernie Buffett MD, Neils Harbour, Nova Scotia • Ken Cameron BSc MD CCFP FCFP, Dartmouth, Nova Scotia • Heather Robertson MD, Bridgewater, Nova Scotia

3. Dalhousie CME • Michael Allen MD, Family Physician, Director Academic Detailing Service • Michael Fleming MD CCFP FCFP, Family Physician, Director Family Physician

Programs in CME 4. Academic Detailers

• Lillian Berry BScPharm • Isobel Fleming BScPharm ACPR • Cathy Ross RN BScNursing

Disclosure statements The Academic Detailing Service is operated by Dalhousie Continuing Medical Education and funded by the Nova Scotia Department of Health. Dalhousie University Office of Continuing Medical Education has full control over content.

Dr Peter Green has received honoraria from Leo Pharma, Canadian Pharmacists Association and Dalhousie CME.

Dr Michael Allen has received funding from the Nova Scotia Department of Health for research projects and to develop CME programs.

Kim Kelly provides drug evaluation support to the Nova Scotia Department of Health.

Cite this document as: Acne Review 2008 Dalhousie CME Academic Detailing Service September 2008 http://cme.medicine.dal.ca/ad_resources.htm

Please direct correspondence to: Dr Michael Allen [email protected] You may leave comments on this document at http://cme.medicine.dal.ca/ad_resources.htm

The information contained in this document, and related presentations made by representatives of the Academic Detailing Service, are based on current literature and recommendations. Although care has been taken in preparing this material, Dalhousie University does not and cannot guarantee its accuracy. Physicians must use their own discretion in applying this information to individual patient care. Anyone using the information does so at their own risk and shall be deemed to indemnify Dalhousie University and individual representatives of the Academic Detailing Service from any and all injury or damage arising from such use.

September 2008 “Seek simplicity, and mistrust it.” Alfred North Whitehead

AAcademic DDetailing SService

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CONTENTS SUMMARY STATEMENTS AND CLINICAL TIPS.................................................3

WHOLESALE COST OF ACNE THERAPIES .......................................................8

OBJECTIVES ..........................................................................................10

INTRODUCTION.......................................................................................11

Sources of information ........................................................................11

Limitations of evidence .......................................................................11

Pathophysiology.................................................................................12

Classification of acne ..........................................................................14

TREATMENT

Goals of therapy.................................................................................15

General principles...............................................................................15

Benzoyl peroxide ...............................................................................18

Topical retinoids.................................................................................20

Antibiotics, topical and oral..................................................................23

Evidence ....................................................................................24

Suggestions for prescribing ............................................................26

Hormonal therapy: oral contraceptives ..................................................30

Hormonal therapy: spironolactone ........................................................33

Oral isotretinoin .................................................................................34

APPENDIX 1 Details of studies comparing oral contraceptives.........................38

REFERENCES ..........................................................................................39

Tables and Figures Table 1 Classification of acne severity.........................................................14

Table 2 Suggestions for treatment .............................................................17

Table 3 COCs approved for acne in women..................................................30

Table 4 Androgenic effects of progestins in COCs used to treat acne ...............31

Table 5 Results of studies of COCs with anti-androgenic progestins.................32

Figure 1. Pilosebaceous unit .....................................................................12

Figure 2. Development of acne lesions .......................................................13


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Summary statements and Clinical tips

General Care Considerations • The goals of therapy are:

• Reduce acne lesions: It may not be possible to eliminate lesions completely. In mild to moderate acne, it is reasonable to expect about a 50% reduction in the number of lesions, though some patients will obtain more or less than this.

• Prevent scarring: Begin treatment early and encourage patients not to pick their lesions. Acne that is not responding and leading to scarring should be referred to a dermatologist.

• Address psychological stress: Some patients may perceive their acne to be worse than it appears objectively. This psychological impact should be taken seriously.

• Topical treatments may make acne worse for the first 2 weeks.

• It is necessary to wait 8 to 12 weeks before changing therapy. It takes that long for most therapies to show noticeable effectiveness and for the patient to adjust to irritation from topical agents.

Do • Wash face only once daily with mild soap if using acne therapies. Patients may rinse their face

without soap more frequently if desired.

• Use oil-free makeup.

• Shave areas lightly, only once and follow grain of hair growth.

• Use moisturizers in dry seasons.

• Apply topical therapies to whole affected area, not just individual lesions.

• Start with 1 topical preparation at a time and apply initially only at bedtime. Increase to twice daily if tolerated. It is reasonable to follow patients after 4 to 6 weeks to check for tolerability.

• If using 2 therapies, apply 1 in the morning and 1 in the evening.

• Consider vehicles as well as active agents: • Creams for dry or sensitive skin • Gels for oily skin. Some patients may experience burning and irritation. • Lotions for any skin type. They spread well over hair-bearing skin, however may contain

propylene glycol and cause burning and drying. • Solutions Mainly used for topical antibiotics. May work best with oily skin.

Don’t • Don’t use soaps that are associated with erythema, dryness, and itching. Dove and Cetaphil are

examples of mild cleansers.

• Don’t pick at lesions or use comedo extractors.


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Benzoyl Peroxide page 18 Considerations • Has been shown to give comparable results in terms of efficacy and tolerability to the topical

retinoids tretinoin and adapalene.

• Antibacterial action has not been shown to lead to resistance.

• Can be used in combination with topical retinoids, topical and oral antibiotics, spironolactone, and combination oral contraceptives.

• Oxidizing action may inactivate topical antibiotics or topical retinoids. Separate the application of benzoyl peroxide products from other topical products by applying one in the morning and the other in the evening. You may also use pre-mixed combination products but these are more expensive.

• May bleach hair, clothing, towels, sheets, and bedding.

• Most cost-effective versus other antimicrobial agents in mild-moderate facial acne; has not been assessed in more extensive acne (e.g. truncal).

Do • Consider first line for mild to moderate acne.

• Start with 2.5%.

• Suggested initiation routine:

• Apply q 2-3 nights, or

• Apply 15 mins day 1, 30 mins day 2, doubling time each night until 4 hours reached then leave on all night, or

• Apply 2 hours X 4 nights, 4 hours X 4 nights then all night.

• Once tolerance is achieved can increase to 5% and use BID except when used in combination with other agents.

• When used with topical retinoids reduce to once daily, may also need to reduce strength if too drying.

• For large areas can use washes, instead of "leave on" products, to reduce irritation.

Don’t • Don’t use strengths > 5% as they are no more effective and more likely to cause adverse effects.

• Don’t use more irritating formulations such as acetone and alcohol-based gels. Water-based preparations are preferred unless skin is oily.


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Topical retinoids page 20 Considerations • There is uncertainty about the relative tolerance or efficacy of currently available retinoids

(tretinoin, adapalene, tazarotene).

• Adapalene may be less irritating.

• Tazarotene may be more irritating and more efficacious. Irritation may be decreased by applying every second day.

Do • Consider first line for mild to moderate acne.

• Minimize irritation from retinoids by:

• Starting with lower strength formulations (tretinoin 0.01%, adapalene 0.1%, tazarotene 0.05%).

• When tolerated, increase to once daily application, increase strength if needed (tretinoin 0.025%-0.05% are most useful, higher strengths are often not tolerated).

• Starting with every 2nd or 3rd night.

• Applying 30-45 minutes after washing. (Prescribing information for Differin and Retin-A Micro say that they can be applied immediately after washing).

• Applying moisturizers.

• Use sunscreens since retinoids are photosensitizing. Combination products with sunscreens are likely insufficient to protect skin given the limited skin area the product is applied to, the frequency of application (once daily), and the generally small amount applied.

Don’t • Don’t use topical retinoids in pregnant women. Topical retinoids should be used in women of

childbearing years only after contraceptive counselling. • Don’t apply too much. Creams and gels should become invisible within a minute of gently rubbing. • Don’t use retinoids + antibiotics (e.g. Stievamycin) without benzoyl peroxide to minimize risk of

developing antibiotic resistance.


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Topical and Oral Antibiotics page 23 Considerations • Considered more effective for inflammatory lesions than non-inflammatory lesions.

• Resistance to antibiotics is a major concern and may be minimized by:

• Using topical and oral antibiotics for the shortest time possible.

• Using benzoyl peroxide with topical and oral antibiotics.

• Separate formulations of benzoyl peroxide plus topical antibiotic may be more cost-effective than the combination formulations but the oxidizing effect of benzoyl peroxide on other topical agents may limit the ability to apply it twice daily. See Benzoyl Peroxide above.

• According to a 2003 Cochrane review, there is no reliable RCT evidence that minocycline is more efficacious than other oral antibiotics. It is more expensive and may on rare occasions cause lupus-like syndrome.

• If there is a poor response, check compliance, correct use of therapy, and rule out other diagnoses. If none of these apply, the following strategies:

• Are unlikely to be helpful:

• Switching between topical clindamycin and topical erythromycin.

• Stepping down from an oral tetracycline to topical antibiotic.

• Using 2 chemically dissimilar antibiotics together.

• Combining a topical antibiotic and an oral antibiotic.

• May be helpful • Stepping up from a topical product to an oral tetracycline.

• Switching to a tetracycline with a simpler dosage regimen if non-compliance is a concern.

Do • Always prescribe benzoyl peroxide when prescribing a topical or an oral antibiotic as it may

reduce the risk of developing resistant strains of P. acnes.

• This also applies when using a topical antibiotic plus a retinoid i.e., add benzoyl peroxide to a topical antibiotic plus a retinoid such as Stievamycin.

• Consider oral antibiotic therapy in patients with numerous or widespread lesions, truncal involvement, or large and deep inflammatory lesions that do not respond to topical therapy. Use only to gain a measure of control over inflammatory lesions.

• Benzoyl peroxide washes or soap can be added if lesions are too extensive for gels or lotions.

• The optimal duration of oral antibiotic therapy is uncertain:

• A suggestion is to use antibiotics for 2 to 3 months and not longer than 6 months. Shorter courses may decrease the risk of developing of resistance.

• Stop antibiotic therapy when you and the patient agree there is no further improvement or the improvement is only slight.

• Re-use the same antibiotic for subsequent courses if patients relapse, assuming the initial course was effective.

Don’t • Don’t prescribe topical or oral antibiotics without benzoyl peroxide.

• Don’t switch antibiotics without adequate justification e.g., drug allergy, intolerance, or inadequate response.

• Don’t use concomitant topical and oral antibiotics.


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Combined Oral Contraceptives (COCs) page 30 Considerations • COCs prescribed for acne contain 20-35 ug of ethinyl estradiol and a progestin.

• Yasmin, Diane-35, and CyEstra-35 contain anti-androgenic progestins. (Diane-35 and CyEstra-35 contain identical agents.)

• Limited evidence suggests that Yasmin and Diane-35 may be more efficacious than other combinations. RCTs have not shown a difference in efficacy between Yasmin and Diane-35.

• Diane-35 and CyEstra-35 are indicated by Health Canada for acne but not contraception.

• Yasmin is indicated by Health Canada for contraception and acne and is cheaper.

• Concomitant use of oral antibiotics and COCs:

• Rifampin and griseofulvin have been shown to impair the contraceptive action of COCs, but it is uncertain if other antibiotics have this effect. There is disagreement around whether a back up method of contraception should be recommended if oral antibiotics and COCs are taken together.

Do • In most cases, hormonal therapy is combined with other therapies including benzoyl peroxide,

topical antibiotics, or topical retinoids.

Spironolactone page 33 Considerations • Spironolactone is an anti-androgen. • Spironolactone may be most useful in women who do not need contraception and for whom

menstrual disturbances are no longer an issue. Spironolactone may also be useful in women with hirsutism and in late-onset acne in woman.

• There is a risk of feminization of a male fetus if spironolactone is taken by a pregnant woman.

Isotretinoin page 34 Considerations • Recommended for moderate to severe acne that has not responded to other regimens.

• Use requires careful monitoring by the physician and compliance by the patient. Please consult the handout for more details and the CPS for a complete monograph.

• Consider use of a consent form.

• Low dose (20 mg daily X 6 months) can be considered in adult onset acne.


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Wholesale costs of acne therapies, not including dispensing fee - June 2008

Preparations Concentration Pack size Cost1 Cost / g or mlBenzoyl Peroxide Water based gel Panoxyl Aquagel 2.5% 5% 60 g 7.69 0.13 Benzac AC or W 5% 60 g 8.48 0.14 Adasept 5% 50 ml 8.48 0.17 Solugel 4% 45 g 9.65 0.21 Alcohol based gel Panoxyl 5% 60 g 7.69 0.13 Benzagel 5% 60 g 9.24 0.15 Acetone based gel Acetoxyl 2.5% 5% 60 g 7.74 0.13 Lotion Benoxyl 5% 60 ml 8.24 0.14 Oxy 2.5 / Oxy 5 2.5% 5% 28 g 4.86 0.17 Benzagel 5% 15 ml 3.28 0.22 Wash Benzac W 5% 225 g 12.72 0.06 Benzagel wash 5% 85 ml 5.26 0.06 Panoxyl wash 5% 175 ml 11.3 0.06 Panoxyl bar 5% 100 g 6.79 0.07 Retinoids Cream Tretinoin Vitamin A Acid 0.01% 0.025% 0.05% 0.1% 25 g 7.55 0.30 Stieva-A 0.01% 0.025% 0.05% 0.1%Forte 25 g 7.55 0.30 Retin-A 0.01% 0.025% 0.05% 0.1% 30 g 11.92 0.40 Retisol A SPF15 0.01% 0.025% 0.05% 0.1%Forte 45 g 31.89 0.71 Adapalene Differin 0.1% 45 g 41.79 0.93 Tazarotene Tazorac 0.05% 0.1%Forte 30 g 42.14 1.40 Gel Tretinoin Vitamin A Acid 0.01% 0.025% 0.05% 25 g 7.55 0.30 Stieva-A 0.01% 0.025% 0.05% 25 g 7.55 0.30 Retin-A 0.01% 0.025% 30 g 11.92 0.40 Retin-A Micro 0.04% 0.1% 20 g / 45 g 13.42 / 30.12 0.67 Adapalene Differin 0.1% 45 g 41.79 0.93 Differin XP 0.3% 45 g 58.57 1.30 Tazarotene Tazorac 0.05% 0.1% 30 g 42.14 1.40 Solution Stieva-A 0.025% 50 ml 9.46 0.19 1 - costs of different concentrations are the same for each preparation

Combination BP/topical antibiotic preparations Clindoxyl (BP 5%/Clin 1%) is given a 4 month expiry date after dispensing. Stored at room temperature by the patient.

BenzaClin (BP 5%/Clin 1%) is given a 3 month expiry date after dispensing. Stored at room temperature by the patient. Benzamymcin (BP 5%/Ery 3%) is given a 3 month expiry date after dispensing. Requires refrigeration by the patient.


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Topical antibiotics Preparations Concentration Pack size Cost Cost / g or mlClindamycin Clinda T 1% 60 ml 13.29 0.22 Taro-clindamycin 1% 30 ml / 60 ml 6.64 / 13.29 0.22 Dalacin T 1% 30 ml / 60 ml 10.49 / 20.98 0.35 Clindets pledgets 1% 60 ml 40.04 0.67 Clindasol +SPF 15 1% 25 g 20.20 0.81 Erythromycin Erysol+SPF 15 2% 25 g 18.08 0.72 Combination products BP + clindamycin BenzaClin 5% / 1% 25 g / 50 g 22.70/45.40 0.91 Clindoxyl 5% / 1% 30 g / 45 g 27.49/41.24 0.92 BP + erythro Benzamycin 5% / 3% 46.6 g 44.44 0.96 Tretinoin + erythro Stievamycin 4.0% / 0.01Mild 4.0 / 0.025Reg 25 g 13.82 0.55 Stievamycin Forte 4.0 / 0.05Forte 25 g 15.90 0.64 Oral antibiotics Strength Dose Cost / unit 90 day cost Tetracyclines Apo-Tetracycline 250 mg 500 bid 0.05 18.70 Doxycyclinegeneric 100 mg 100 od 0.57 51.68 Minocin 100 mg 100 od 1.22 109.86 Minocyclinegeneric 100 mg 100 od 1.01 91.13 Erythromycins Base Apo-erythrobase 250 mg 500 bid 0.18 63.00 Eryc 250 mg 500 bid 0.23 84.24 333 mg 333 bid 0.49 88.00 Apo-erythro EC 250 mg 500 bid 0.37 134.39 333 mg 333 bid 0.42 74.65 Stearate Apo-Erythro S 250 mg 500 bid 0.20 72.97 500 mg 500 bid 0.52 93.49 Combined oral contraceptives Trade name Contents Cost / monthYasmin EE 30 ug / Drosperinone 3 mg 12.33 Tri-Cyclen EE 35 ug / Norgestimate 180-250 ug 14.03 Alesse EE 20 ug / Levonorgestrel 100 ug 14.48 Aviane EE 20 ug / Levonorgestrel 100 ug 9.74 CyEstra EE 35 ug / Cyproterone 2 mg 22.87 Diane-35 EE 35 ug / Cyproterone 2 mg 31.03 Oral isotretinoin Trade name Regimen Cost: 5 mos for

60 kg person Accutane 40 mg once daily for 1 month

Then alternate 40 mg on day 1 and 80 mg on day 2 for 4 months 420

Accutane 40 mg once daily for 1 month Then 60 mg once daily (40 mg plus 2 x 10 mg) for 4 months 540

Clarus 40 mg once daily for 1 month Then alternate 40 mg on day 1 and 80 mg on day 2 for 4 months 390

Clarus 40 mg once daily for 1 month Then 60 mg once daily (40 mg plus 2 x 10 mg) for 4 months 497

Dalhousie Academic Detailing Service. Source McKesson Canada Maritimes, Wholesale Distributor. June 2008


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Objectives and Key Messages • The objectives of this academic detailing document are to address the following

key messages:

1. Benzoyl peroxide or a topical retinoid can be used as first line therapy in mild to moderate acne. Clinical trial evidence does not confirm that one agent is superior to the other in terms of efficacy or tolerability. • Benzoyl peroxide is less expensive. • Topical retinoids should be used in women of childbearing years only after

contraceptive counselling. They should not be used in pregnant women.

2. If the goal is to minimize antibiotic use, it is reasonable to consider

benzoyl peroxide in combination with a topical retinoid as second line therapy. • Evidence for the effect of benzoyl peroxide plus a topical retinoid versus

either agent alone is inconsistent.

3. Resistance of Propionibacterium acnes (P. acnes) is a concern when prescribing topical and oral antibiotics. • P. acnes has not been shown to develop resistance to benzoyl peroxide. • Topical antibiotics should be used with benzoyl peroxide to decrease the

risk of resistance developing. • There is evidence that

• A topical antibiotic (clindamycin) + benzoyl peroxide is superior to benzoyl peroxide alone.

• Topical retinoids + topical antibiotics are superior to either agent alone. However this combination does not minimize the development of resistance as benzoyl peroxide is believed to do.

• Oral antibiotics (tetracyclines, erythromycin) should be used judiciously in inflammatory acne. • Studies have generally shown no difference in efficacy between oral

antibiotics. The choice of therapy should be based on cost and safety. • Minocycline has not been shown to be more efficacious than other oral

antibiotics and on rare occasions may cause lupus-like reactions. It is more expensive than other commonly used antibiotics.


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Introduction Sources of information • In researching material for this topic we have reviewed

• Recent guidelines and systematic reviews • Cochrane reviews • Health technology assessment reports • Primary publications • Academic detailing documents prepared by the Rx Files Academic Detailing

Program in Saskatchewan http://www.rxfiles.ca/. Limitations of evidence • A 2002 comprehensive methodologic review of the acne literature concluded

that only 14 of 250 comparisons had a high level of evidence.1 This review and others outline the limitations that make it difficult to interpret studies about efficacy and adverse effects of acne preparations.

• Studies have differing inclusion and exclusion criteria (e.g., acne severity, acne duration, previous therapy, P. acnes colonization).

• Different methods of assessing acne are used in the studies.2 Methods used are: • Counting lesions • Comparing to a photographic standard • Using terminology such as mild, moderate, severe • Numerical grades • Physician-reported change • Patient-reported change

• Vehicles used may not have the same composition in comparison groups and vehicles may affect the response to therapy.3

• Overestimation of treatment effects may arise because: • Many studies are not analyzed by intention-to-treat.

• Results are often presented as total improvement rather than the net improvement over vehicle.4

• Underestimation of treatment effects may arise because some studies analyzed by intention to treat may use “last observation carried forward”.

• Studies are of differing duration and few extend beyond 12 weeks, therefore giving limited evidence about long-term treatment.

• Not all therapies are compared to topical benzoyl peroxide which is considered by some to be the mainstay of treatment.5,6

• There is little evidence about the optimal sequence of therapy (e.g., 1st line, 2nd line, etc.)


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Pathophysiology

• The information in this section comes from the 2003 Report on the Management of Acne from the Global Alliance to Improve Outcomes in Acne.7

• The target organ for acne is the pilosebaceous unit, which consists of the hair follicle, hair shaft, and sebaceous glands. (Figure 1).

Figure 1. Pilosebaceous unit

• Androgens lead to enlargement of the sebaceous glands resulting in increased sebum production and the formation of microcomedones.

• The microcomedo, a microscopic lesion not visible to the naked eye, is the primary lesion of acne and is produced by • Follicular growth and desquamation • Sebaceous gland hyperplasia.

• With time, the hair follicle fills with lipids, bacteria, and cell fragments.

• Ultimately, a clinically apparent lesion occurs, either • A noninflammatory lesion (open or closed comedo) or • An inflammatory lesion, (papule, pustule, or nodule) if P. acnes proliferate

and generate inflammatory mediators. • The exact role of P. acnes in the pathogenesis of acne and response to

therapy is controversial6 and fully establishing its place in the development of acne is difficult.8,9

• Microbiology studies have not found P. acnes to be present in all acne lesions 8 and population size was not shown to correlate with disease

http://en.wikipedia.org/wiki/Sebaceous_gland


13

severity.10 Similarly, a reduction in P. acnes does not always correlate with clinical improvement.11

• However, the presence of resistant strains has been shown to negatively affect outcomes of topical12 and systemic13,14,15 antimicrobial therapy.

• Figure 2 summarizes development of acne lesions.

Figure 2. Development of acne lesions • Various treatments have been reported to affect different processes in the

development of acne although there is some inconsistency:

Normalization of follicular keratinization Anti-inflammatory

• Benzoyl peroxide16

• Topical retinoids7,16

• Oral isotretinoin7

• Hormonal therapy7

• Benzoyl peroxide

• Topical retinoids7

• Some antibiotics (tetracyclines)16

• Oral Isotretinoin7

Antibacterial Decreased sebum production

• Benzoyl peroxide

• Antibiotics

• Hormonal therapy7

• Oral isotretinoin7

Papules Pustules Cysts Nodules

Inflammatory lesions

Microcomedo

Pilosebaceous unit

Follicular hyperkeratinization Excessive sebum production

Androgen

Non-inflammatory lesions Closed comedones Open comedones

Sebum accumulation Follicular enlargement Keratin buildup

P. acnes Immune reactions


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Classification of acne

• The 2007 US Guidelines17 state: • Clinicians may find it helpful to use a consistent classification/grading scale

(encompassing the numbers and types of acne lesions as well as disease severity) to facilitate therapeutic decisions and assess response to treatment.

• Several grading systems exist. However, there is no consensus on a single or best grading or classification system.

• We suggest the approach in Table 1 which has features from 3 grading systems2,18,19 and includes scarring as recommended by our content expert. Lesion counts are included as a guide to help classification in case of uncertainty due to appearance alone. It is not recommended to try to count lesions in every patient.

• Two important points are: • Palpate as well as inspect affected areas to determine the presence of cysts

or nodules. • Examine the back, chest, and shoulders. Patients with truncal acne may not

volunteer that they have acne in these areas.

• In this document: • Non-inflammatory lesions refer to comedones. • Inflammatory lesions refer to papules, pustules, nodules, and/or cysts.

Table 1 Classification of acne severity Classification Description Lesion count

Mild Mainly comedones with occasional small inflamed papule or pustule.

No scarring.

< 20 comedones or

<15 inflammatory lesions or

< 30 total lesion count

Moderate Comedones and more numerous papules and pustules (mainly facial).

Mild scarring.

20-100 comedones or

15-50 inflammatory lesions or

30-125 total lesion count

Severe* Numerous comedones, papules, and pustules which may have spread to the trunk and/or nodulocystic lesions.

Moderate acne that has not settled with 6 months treatment.

Moderate to severe scarring.

> 100 comedones or

> 50 inflammatory lesions or

>125 total lesion count or

> 5 cysts

*Acne fulminans is a rare form of extremely severe cystic acne occurring primarily in teenage boys, characterized by the presence of highly inflammatory nodules and plaques that undergo suppurative degeneration leaving ulcerations, fever, weight loss, anemia, leukocytosis, elevated erythrocyte sedimentation rate, and polyarthritis. (Dorland’s Illustrated Medical Dictionary 27th edition). This requires urgent referral to a dermatologist.


15

Treatment • This section will provide general information for therapy and review some of the

features of the various treatments and the evidence for their efficacy and tolerability.

• For each class of therapy we will present: • Availability • Mechanism of action • Evidence for efficacy and tolerability • Suggestions for prescribing including precautions

We have also provided a summary of suggested treatments in Table 2, page 17. It is important to remember that the optimal sequence of therapy is uncertain. Goals of therapy • When starting therapy it is important to consider the goals of therapy:

1. Reduction of acne lesions • It may not be possible to eliminate lesions completely. In mild to

moderate acne, it is reasonable to expect about a 50% reduction in the number of lesions, though some patients will obtain more or less than this.4

2. Prevention of scarring • Treatment should begin early and patients encouraged not to pick their

lesions. Acne that is not responding and leading to scarring should be referred to a dermatologist.

3. Addressing psychological stress resulting from acne.20 • Some patients may perceive their acne to be worse than it appears

objectively. This psychological impact should be taken seriously.16 General principles • Use oil-free makeup.

• Shaving: shave area lightly, only once and follow grain of hair growth.

• Face washing: Some patients may tend to wash their face too frequently while on acne therapies, leading to dryness. • Our content expert advises that washing once daily with mild soap is

sufficient.

• Patients may rinse their face without soap more frequently if they wish.

• Examples of mild soaps and cleansers are Dove and Cetaphil.21

• Use moisturizers in dry seasons.

• Diet: The association between diet and acne is uncertain and not sufficient to recommend changes in diet. Limited epidemiological studies have found a


16

weak association (relative risk ~ 1.2) between intake of milk and acne in adolescent girls and boys.22,23 However milk intake and acne severity were self-reported. There was no association with self-reported intake of pizza and chocolate.

• We found one RCT that found that a low glycemic load diet led to a greater decrease in acne lesions than a regular diet. However this study was small (N = 27 per group) and not analyzed by intention-to-treat. The authors stated that larger studies are needed to confirm the effect of diet on acne.24

• Discourage patients from picking at lesions to minimize scarring. There is contradictory advice about comedo removal with a comedo extractor. Some publications state it can be a useful adjunct to topical therapy in patients with resistant comedones.16,18 However, our local expert does not advise this approach.

• Patient education is essential to encourage compliance:

• Advise the patient that topical treatments may make acne worse for the first 2 weeks. It is necessary to wait 8 to 12 weeks before changing therapy. It takes that long for most therapies to show noticeable effectiveness and for the patient to adjust to irritation from topical agents.

• Optimizing therapy may take several months.

• Topical therapies

• Should be applied to the whole affected area, not just individual lesions.

• May cause irritation around mucous membranes and irritation that may be aggravated by sun exposure.25

• Start with one topical preparation at a time and apply initially only at bedtime. Increase to BID if tolerated.25

• If using 2 therapies, apply 1 in the morning and 1 in the evening.

• Lower concentrations and cream formulations of benzoyl peroxide and retinoids are usually less irritating than higher concentrations and gels.25

• It is important to consider vehicles as well as active agents:5 • Creams: for dry or sensitive skin • Gels: for oily skin. Some patients may experience burning and irritation.

• Acetone and alcohol based gels can be especially irritating. • Lotions: for any skin type. They spread well over hair-bearing skin,

however may contain propylene glycol and have burning and drying effects.

• Solutions: Mainly used for topical antibiotics. May work best with oily skin.


17

Table 2 Suggestions for treatment

Treatment Options1

Acne Severity

1st line • Benzoyl peroxide (BP) • Topical retinoid

2nd line options

• Topical retinoid + BP2 • Topical antibiotic3,4 + BP • Topical antibiotic3,4 +

retinoid +BP5

3rd line options • Oral antibiotic4 + BP

(avoid monotherapy) • Oral antibiotic4 + BP +

topical retinoid • Oral isotretinoin6 (Accutane,

Claris) Combined oral contraceptives Spironolactone or low dose6,8 oral isotretinoin

Mild to moderate

Moderate to severe

(not responding to topical treatment*)

*Severe presentations (e.g. nodulocystic acne or acne fulminans) may require initiation of therapy with 3rd line

options.

Used in women for mild, moderate or severe acne (1st, 2nd or 3rd line)7 often in combination with other options

Adult onset acne in women

1 – Wait 8 to 12 weeks before changing from one therapy to another.

2 – It is reasonable to consider topical retinoids with BP as second line therapy, especially if the goal is to minimize antibiotic use. Evidence for the effect of benzoyl peroxide plus a topical retinoid versus either agent alone is inconsistent. (There is consistent evidence that topical clindamycin + BP is superior to BP alone).

3 – Do not switch from one topical antibiotic to another. Change to oral agent if antibiotic treatment desired (inflammation present).

4 – Long term therapy with topical or oral antibiotics is not recommended due to concerns of developing resistance. • Topical or oral antibiotics are used only to gain a measure of control over inflammatory lesions and should

be stopped when there is no further inflammation.

• Response to topical or oral antibiotics usually occurs within 3 months. Once patients respond (no further inflammation) consider “stepping down” to benzoyl peroxide or a topical retinoid to maintain response.

5 – The addition of benzoyl peroxide may address resistance concerns and may lead to better outcomes. Separate the application of benzoyl peroxide products from other topical products by applying one in the morning and the other in the evening.

6 – When starting oral isotretinoin discontinue other therapies.

7 – 1st line in women also wanting birth control or add on treatment to 1st and 2nd line therapies in women with no contraindications. Some suggest use ahead of oral antibiotics.

8 – Expert opinion suggests 20 mg oral isotretinoin daily X 6 months as treatment option for adult onset acne.


18

Specific therapies – topical agents Benzoyl peroxide

Availability • Available as

• Water-based gels • Alcohol-based gels • Acetone-based gels • Lotions

• Available in concentrations between 2.5% and 10% but concentrations >5% are no more efficacious and may produce more irritation than those of ≤ 5%.

Mechanism of action • Benzoyl peroxide is the most widely used topical agent and has comedolytic,

antibacterial, and anti-inflammatory actions.16,26

• Has been shown to reduce comedones and inflammatory lesions.19

• Antibacterial action does not lead to bacterial resistance.26

Evidence

Evidence for monotherapy

• Evidence comes from comparisons to other therapies. Outcomes are reported in more detail in sections in this handout about these therapies. Keeping in mind the limitations of acne trials, benzoyl peroxide has shown comparable results in terms of efficacy and tolerability versus:

• Tretinoin27,28

• Adapalene29,30,31

• Benzoyl peroxide has also shown comparable results in terms of efficacy vs oral antibiotics and topical antibiotics but patients experienced more skin irritation.15,32,33,34,

• Benzoyl peroxide has been shown to be more cost-effective than other anti-microbial agents.15


19

Evidence for combination therapy

• Benzoyl peroxide is used in combination with other topical therapies (retinoids, antibiotics) for the treatment of moderate to severe acne.

• Combined with topical retinoids: Evidence for the effect of benzoyl peroxide plus topical retinoid versus either agent alone is inconsistent.

• One study found no statistically significant difference between the combination and either agent alone. Benzoyl peroxide 5% was applied only once daily.30

• To the contrary, another study found a statistically significant benefit for the combination compared to either agent alone. However benzoyl peroxide was administered at only 2.5% once daily, which is not an optimal regimen.31

• Another study found no statistically significant difference between the combination and the topical retinoid alone.35 • The benzoyl peroxide preparation used in combination was 4% gel applied

BID. The topical retinoid was tazarotene 0.1% gel applied once daily. • Yet another study36 found the combination to be superior to a retinoid

alone in reducing inflammatory lesions only, reductions in comedones were not significantly different. • The benzoyl peroxide preparation used in combination was a 6% wash

once daily. The topical retinoid was 0.1% tretinoin microsphere gel (Retina-A Micro).

• Combined with topical antibiotics: Evidence for the effect of benzoyl peroxide in combination with topical antibiotics plus or minus topical retinoids can be found in the antibiotic section (see page 25).

Suggestions for prescribing

• BMJ Clinical Evidence recommends benzoyl peroxide as first line monotherapy in mild acne.19

• Start with 2.5% and increase gradually to 5%. Don’t use strengths greater than 5% as they are no more effective and likely to cause adverse effects.

• Apply twice daily if possible before trying other therapies.

• Benzoyl peroxide washes can be used for large areas and are less irritating than “leave on” preparations37 but may be less effective.

• Benzoyl peroxide is used in combination with other therapies (i.e. topical retinoids, topical and oral antibiotics, combination oral contraceptives, and spironolactone) when monotherapy is not effective. • When used with topical retinoids reduce benzoyl peroxide to once daily, and

reduce strength if too drying.

• Combining benzoyl peroxide with topical or oral antibiotics reduces the risk of developing resistant strains.7


20

• Common adverse effects are dryness, peeling, erythema, burning, and pruritus which may subside with continued use.

• A less common but more serious adverse effect is contact sensitization dermatitis.

• May bleach hair, clothing, towels, sheets, and bedding.

• Benzoyl peroxide is a strong oxidizer and may affect the action of other products when used concurrently. Separate the application of benzoyl peroxide products from other topical products by applying one in the morning and the other in the evening.

Topical retinoids

Availability • The three main retinoids available in Canada are

• Tretinoin (e.g. Vitamin A Acid, Stieva-A, Retin-A, Retisol A) • Adapalene (Differin) • Tazarotene (Tazorac)

• Tretinoin has been in use for many years while adapalene and tazarotene are newer agents.

Mechanism of action

• Topical retinoids are reported to inhibit the formation of the microcomedo, the precursor to mature comedones and inflammatory lesions, and have anti-inflammatory actions.7

Evidence


• Guidelines often suggest topical retinoids as first line therapy,7 especially for comedonal acne. However these recommendations do not provide references comparing topical retinoids to benzoyl peroxide. The Global Alliance Guidelines state that the first-line use of topical retinoids is consensus (not solely based on evidence).

• BMJ Clinical Evidence recommends topical retinoids be used in mild acne that does not respond to benzoyl peroxide.19

• Clinical studies have not consistently shown topical retinoids to be superior to benzoyl peroxide in reducing lesions.

• We found 2 eight-week trials that reported that tretinoin showed no statistically significant difference compared to benzoyl peroxide 5% BID in terms of efficacy or adverse events.27,28 However neither trial was blinded.

• A 12-week study found that tretinoin 0.025% was superior to benzoyl peroxide 5% in efficacy and there was no difference in adverse effects.38


21

• We also found 2 trials comparing adapalene 0.1% to benzoyl peroxide 4%29 or 5%.30 • There was no statistically significant difference between benzoyl

peroxide and adapalene in adverse effects or decrease in inflammatory or non-inflammatory lesions. In one of these trials, benzoyl peroxide provided more rapid response than adapalene.29

• We found no trials comparing benzoyl peroxide to tazarotene.

• The Global Alliance Guidelines state “There is a need to perform very well controlled clinical trials comparing benzoyl peroxide with the newer retinoids.”7

• There is no consensus about the relative efficacy of currently available topical retinoids (tretinoin, adapalene, and tazarotene).17

• There is uncertainty about the relative tolerance of currently available topical retinoids.

• A facial tolerability study concluded that it is difficult to clearly determine the relative tolerance between topical retinoids since multiple factors (i.e. concentration, vehicle, skin vulnerability [sensitive skin vs normal skin]) seem to influence tolerability. “The tolerance of topical retinoid therapy involves multiple factors and it is not appropriate to categorize the potential for irritation as an inherent property of a given retinoid”.39

• On the other hand, two review articles concluded that adapalene 0.1% is or may be better tolerated than tretinoin or tazarotene.40,20 • Some trials suggest adapalene 0.1% may have fewer adverse effects

than other topical retinoids.41,42, 43

• Other trials suggest tazarotene may have more adverse effects than other topical retinoids. 45

• Tolerability results of a trial comparing tazarotene 0.05% cream and adapalene 0.3% gel showed they were statistically similar throughout the study.46

• Tazarotene 0.1% gel applied every other day was compared to adapalene 0.1% gel applied daily. There were no clinically significant differences in tolerability.47

• The concentration and/or vehicle of any particular topical retinoid may affect tolerability.17

• It is important to note that with all topical retinoids adverse effects usually subside within the first 4 weeks of treatment. Some trials note differences in tolerance early, but find no difference in tolerance at study endpoint.43,48,49,36

Evidence for combination therapy

• Topical retinoids can be used in combination with benzoyl peroxide, topical or oral antibiotics (see benzoyl peroxide and antibiotic sections for evidence), combined oral contraceptives, and spironolactone.


22


• Topical retinoids should be used in women of childbearing years only after contraceptive counselling. They should not be used by pregnant women.50

• May take several months to achieve optimal response.

• Creams and lower concentrations are less irritating but may take longer for a response than gels and higher concentrations.40

• Alternate-day tazarotene 0.1% gel may be as effective as daily adapalene 0.1% gel.47

• Tazarotene may be effective with short contact therapy (5 mins or less).51

• Adverse effects are local irritation, erythema, dryness, soreness, peeling, burning, and pruritus.

• A less common serious adverse effect is true contact allergy.52

• Avoid in severe acne that affects large areas, broken or peeling skin, and mucous membranes; avoid UV light exposure.53

• Sunscreens are recommended as topical retinoids are photosensitizing.20 Our content expert considers that combination products with sunscreens are likely insufficient to protect skin given the limited skin area the product is applied to, the frequency of application (once daily), and the generally small amount applied.

• Minimize irritation from topical retinoids by:

• Starting with lower strength formulations (tretinoin 0.01%, adapalene 0.1%, tazarotene 0.05%). • When tolerated, increase strength if needed (tretinoin 0.025% - 0.05%

are most useful, higher strengths may not be tolerated). • Starting with every 2nd or 3rd night. • Applying 30-45 minutes after washing. (Prescribing information for Differin

and Retin-A Micro say that they can be applied immediately after washing). • Applying moisturizers.

• Not applying too much. Creams and gels should become invisible within a minute of gently rubbing.


23

Antibiotics

Availability of topical antibiotics

• The two most frequently used topical antibiotics are

• Erythromycin available as: • 2% gel with SPF 15% sunscreen

• 3% gel with benzoyl peroxide 5%

• 4% gel with tretinoin 0.01%, 0.025%, and 0.05%

• Clindamycin available as: • 1% solution

• 1% solution in pledgets • a small pellet of absorbent cotton used for accurately controlled placement of medication

or base, each pledget = 1ml of 1% solution

• 1% cream with SPF 15% sunscreen

• 1% gel with benzoyl peroxide 5%

Availability of oral antibiotics

• The most frequently used oral antibiotics are • Tetracycline 500 mg BID (It is not necessary to use 250 mg QID.)

• Doxycycline 100 mg once daily

• Minocycline 100 mg once daily. (Our content expert suggests increasing to twice daily if needed.)

• Erythromycin 333 to 500 mg BID (Generally reserved for when tetracyclines cannot be used.)

Mechanism of action

• Antibiotics are reported to have bactericidal action against P. acnes and anti-inflammatory effects.7,54

Resistance

• When prescribing topical or oral antibiotics, it is important to consider that P. acnes may develop resistance.

• Oral antibiotics used to treat acne promote resistance not only in P. acnes but in many other organisms, including respiratory tract colonizers (e.g., group A streptococcus) that may become pathogens in the future.55

• Strains of P. acnes less sensitive to antibiotics were reported in clinical trials in the early 1980s shortly after the arrival of topical antibiotics.


24

• Data from 6 European centres found that patterns of local antibiotic use influenced the distribution of resistant strains of P. acnes.56

• Although we found no studies regarding the development of P. acnes resistance in Canada there is no reason to think the Canadian situation would be any different than other countries.

• The clinical significance of increasing antibiotic resistance is uncertain. The following evidence supports that increasing resistance to P. acnes is associated with reduced clinical response.

• Some patients with resistant strains of P. acnes have higher bacterial counts and may have poorer response to topical12 and oral 13,14,15 antibiotics than those with sensitive strains.57

• A study comparing oral tetracyclines, benzoyl peroxide, and combined topical erythromycin + benzoyl peroxide found: • Patients treated with oral tetracyclines who had P. acnes resistant to

tetracycline had a poorer response than those with P. acnes not resistant to tetracycline.

• The same poorer response was not found in patients with erythromycin-resistant P. acnes treated with topical erythromycin and topical benzoyl peroxide.15

• Factors that increase the likelihood of resistance developing are:16,26 • Antibiotic treatment longer than 12 weeks (most common reason).

• Poor compliance.

• History of multiple courses of antibiotics.

• Close contact with others colonized with resistant P. acnes (siblings, relatives).

Evidence


• There is evidence showing that monotherapy with topical and oral antibiotics does improve acne. However, we have not reviewed this evidence as it is now generally recommended that monotherapy with antibiotics for the treatment of acne be avoided. 7,26,57,58


25

Evidence for topical antibiotic plus benzoyl peroxide and/or topical retinoid • Effect of benzoyl peroxide in combination with topical antibiotics.

• Combining benzoyl peroxide with topical antibiotics appears to improve efficacy and reduce the risk of developing resistant strains of P. acnes. • P. acnes has not been found to develop resistance to benzoyl

peroxide.7,59 • Combinations of benzoyl peroxide and topical clindamycin have been

found to be superior to benzoyl peroxide alone 60,33, 32or clindamycin alone.12,33,60,32

• There is some inconsistency in the studies of benzoyl peroxide/topical erythromycin combinations vs benzoyl peroxide alone: • One study found the combination superior to benzoyl peroxide alone 61

while another showed no statistically significant difference.15

• One study found no statistically significant difference between combinations of benzoyl peroxide/clindamycin and benzoyl peroxide/erythromycin.61

• Effect of topical retinoids in combination with topical antibiotics. • The combination of topical retinoids and topical antibiotics lead to better

response than either agent alone.62,63,64,65 • However this does not consider the development of resistance which benzoyl

peroxide is believed to address.57 • Therefore, triple therapy (adding benzoyl peroxide to topical retinoids and

topical antibiotics) may address resistance concerns and may lead to better outcomes.66,67

Evidence for oral antibiotic plus benzoyl peroxide and/or topical retinoid

• We found no studies comparing oral antibiotics alone to oral antibiotics plus benzoyl peroxide.

• There is evidence that oral doxycycline is more efficacious when combined with topical adapalene 0.1% gel.68

Evidence for comparative efficacy of oral antibiotics (tetracyclines, erythromycin)

• We did not completely review primary publications for evidence about the comparative efficacy of the different oral antibiotics as monotherapy or in combination.

• A comprehensive review of oral antibiotics states: • Due to wide differences between published acne studies with respect to

disease definitions, end-points, doses used, duration of treatments etc., as well as the many unanswered questions that require further investigation, it is not currently possible to derive definitive treatment guidelines backed up by high quality evidence.26


26

• The Global Alliance guidelines states • Comparative studies of oral antibiotics have generally shown no significant

differences between the available alternatives.7

• Minocycline has been promoted by some as the preferred oral antibiotic for the treatment of acne but little evidence exists to justify this recommendation.

• A 2003 Cochrane review concluded that minocycline is likely to be an effective treatment for moderate acne vulgaris, but found no reliable RCT evidence to justify its use first-line, especially given the price differential and the concerns about its safety.69

• Its efficacy relative to other acne therapies could not be reliably determined due to the poor methodological quality of the trials and lack of consistent choice of outcome measures.

• Similarly the relative risk of adverse drug reactions could not be ascertained reliably and no recommendations can be made concerning the appropriate dose that should be used. However, physicians should be aware that the risk of lupus-like syndrome and pigmentation increases with cumulative dose.

• A large 18 week double-blind RCT found minocycline was:15 • The antimicrobial regimen most compromised by bacterial resistance. • The least cost-effective of the five antimicrobial regimens studied.

• No more effective than • Oral oxytetracycline 500 mg BID (a first generation tetracycline), or • Benzoyl peroxide alone, or • Benzoyl peroxide with topical erythromycin.

• A 2008 review found no significant differences between tetracyclines in terms of efficacy and concluded that the choice of therapy should be based on cost and safety criteria.70


• Our content expert considers that antibiotics are generally effective for inflammatory lesions and should not be used for strictly non-inflammatory (comedonal) acne.

• Many suggestions for prescribing are based on concerns about drug resistance in P. acnes and other bacteria (antibiotic stewardship). • “Some reduction in antibiotic usage is advisable and that, as in other areas of

medicine, antibiotics should not be given unnecessarily.”59

• Consider non-antibiotic alternatives first such as benzoyl peroxide and topical retinoids. These 2 agents can be combined by giving 1 in the morning and 1 in the evening.17


27

• Recommendations for combination therapy are based mostly on concerns about resistance.

• Combining benzoyl peroxide with oral antibiotics to improve efficacy and reduce the development of resistance is supported by some.59,7,26,58, 71,57

• Our content expert recommends adding benzoyl peroxide UPFRONT with both ORAL and TOPICAL antibiotics.

• This approach is supported by others because:

• Colonization with resistant bacteria decreases the proportion of patients responding to oral tetracyclines even during short-term (18 weeks) use, 15 and

• The duration of treatment required before resistance emerges varies from patient to patient.26

• Separate formulations of benzoyl peroxide plus topical antibiotic may be more cost-effective than the combination formulations15 but may limit the ability to increase benzoyl peroxide dosing to twice daily.

• Benzoyl peroxide is a strong oxidizer and may affect the action of other products when used concurrently. Separate the application of benzoyl peroxide from other topical products by applying one in the morning and the other in the evening.

• Commercial preparations have been given expiry dates based on chemical stability studies.

• Guidelines recommend combining topical antibiotics with topical retinoids.7 This approach may lead to better response than topical antibiotics or topical retinoids alone.62,63, 64,65 However, it does not consider the development of resistance which benzoyl peroxide addresses.57 • Stievamycin gel (tretinoin/erythromycin) is the only commercially available

combination product that does not contain benzoyl peroxide. When using Stievamycin gel and benzoyl peroxide concurrently, apply one in the morning and the other in the evening.

Combination BP/topical antibiotic preparations

Clindoxyl (BP 5%/Clin 1%) is given a 4 month expiry date after dispensing. Stored at room temperature by the patient.

BenzaClin (BP 5%/Clin 1%) is given a 3 month expiry date after dispensing. Stored at room temperature by the patient.

Benzamymcin (BP 5%/Ery 3%) is given a 3 month expiry date after dispensing. Requires refrigeration by the patient.


28

• Consider oral antibiotic therapy in patients with numerous or widespread lesions, truncal involvement, or large and deep inflammatory lesions that do not respond to topical therapy.53 Our content expert suggests to use only to gain a measure of control over inflammatory lesions. • Benzoyl peroxide washes or soap can be added if lesions are too extensive

for gels or lotions.

• The optimal duration of oral antibiotic therapy is uncertain: • A suggestion is to use for 2 to 3 months and not longer than 6 months.26

Shorter courses decrease the development of resistance.

• Stop antibiotic therapy when you and the patient agree there is no further improvement or the improvement is only slight.26

• Re-use the same antibiotic for subsequent courses if patients relapse, assuming the initial course was effective.

• Do not • Switch antibiotics without adequate justification e.g., drug allergy,

intolerance or inadequate response.

• Use concomitant topical and oral antibiotics.

• Failure to respond • First, check compliance and correct use of therapy.

• Rule out other causes such as folliculitis. Acute folliculitis is caused by a super-infection of follicles (e.g. by staphylococci or pseudomonas) and is generally unresponsive to first-line acne treatments. It may be difficult to differentiate acne and folliculitis. Suggestions from our content expert are:

Acne Folliculitis

Comedones No comedones

Distribution to T-zone, upper back, and chest

Distribution asymmetric or atypical for acne

Varying size and morphologies of lesions with papules, pustules, and nodules

More likely to be monomorphic with pustules

• If there is a poor response to antibiotic therapy, the following strategies: • Are unlikely to be helpful:59,58

• Switching between topical clindamycin and topical erythromycin.

• Stepping down from an oral tetracycline to topical antibiotic.

• Using 2 chemically dissimilar antibiotics together.

• Combining a topical antibiotic and an oral antibiotic.


29

• May be helpful • Stepping up from a topical product to an oral tetracycline.

• Switching to a tetracycline with a simpler dosage regimen if non-compliance is a concern.

• Despite the potential effects of antibiotic resistance, it is not practical to test for it in clinical practice and microbiology testing is considered unnecessary in the routine evaluation and management of patients.17

• Adverse effects

• We have not listed all reported adverse effects. We have reported the more notable adverse effects associated with certain drugs.

• Adverse effects associated with the oral tetracycline family include: • Pseudotumor cerebri (benign intracranial hypertension).72

• Case reports and reviews of tetracycline, minocycline, and doxycycline monotherapy exist with regard to an association with pseudotumor cerebri.

• Symptoms include50 • Headache and tinnitus are frequent complaints • Dizziness, nausea, and vomiting • Visual symptoms (e.g., transient visual obscuration, general

blurriness, and intermittent horizontal diplopia) • Most cases resolve with discontinuation, but permanent

sequelae can occur (i.e. permanent visual deficits).

• Photosensitivity (can occur with the other tetracyclines but is more common with doxycycline).7

• Our content expert considers photosensitivity to be least common with minocycline.

• Dizziness, vertigo, ataxia, drowsiness and fatigue (can occur with the other tetracyclines but is more common with minocycline).7

• Azotemia in patients with significantly impaired renal function.

• On rare occasions, minocycline is associated with • Pigment deposition in the skin, mucous membranes and teeth (blue

skin and teeth), particularly when used long term and/or at higher dosages.

• Auto-immune hepatitis, a systemic lupus erythematosis-like syndrome, and serum sickness-like reaction.7

• Hypersensitivity syndrome50


30

• Erythromycin, particularly the estolate, may cause reversible cholestatic hepatitis.

• Abdominal cramps, nausea and vomiting may precede the onset of biliary colic, fever, anorexia and hepatic enlargement with or without jaundice

• Erythromycin estolate is contraindicated in patients with pre-existing liver disease.

• Hepatotoxicity rarely occurs with the other erythromycin salts.50

Hormonal therapy - oral contraceptives

Availability

• Combined oral contraceptives (COCs) prescribed for acne contain 20-35ug of ethinyl estradiol (EE) and a progestin (Table 3).

Table 3: COCs approved for acne in women Trade name Company

Generic Components

Indication

Covered by Nova Scotia Pharmacare?

Cost/

Month2 ($)

Yasmin Bayer

EE 30ug Drospirenone 3mg

Acne Contraception

Yes 12.33

Diane-35 Bayer

EE 35ug Cyproterone acetate 2mg

Acne1

No 31.03

CyEstra-35 Pharma Science

EE 35ug Cyproterone acetate 2mg

Acne1

No 23.34

Tri-Cyclen Ortho-McNeil

EE 35ug Norgestimate 180-250ug

Acne Contraception

Yes 14.03

Alesse Wyeth

EE 20ug Levonorgestrel 100ug

Acne Contraception

Yes 14.48

Aviane Apotex

EE 20ug Levonorgestrel 100ug

Acne Contraception

Yes 9.74

EE – ethinyl estradiol

1 – Diane-35 and CyEstra-35 have official indication for acne but not contraception. The manufacturers of CyEstra-35 and Diane-35 both state that either agent “should not be prescribed for the purpose of contraception alone. However, when taken as recommended, it will provide reliable contraception in patients treated for acne.” Diane-35 does have the indication for contraception in other countries such as Australia.

2 – Drug costs from McKesson Canada Maritimes, Wholesale Distributor

Mechanism of action

• Estrogens suppress ovarian androgen production and reduce free testosterone blood levels by increasing sex hormone globulin serum levels, thereby decreasing the androgenic influence on the pilo-sebaceous unit.16 Estrogen is a potent anti-androgen.


31

• Progestins exert varying androgenic effects at the androgen receptor. • Some progestins have pro-androgenic effects and may counter the anti-

androgenic effects of estrogen whereas others exert anti-androgenic effects. • Table 4 lists the androgenic properties of the various preparations listed in

order of increasing androgenic effects.

• In theory, COCs containing progestins with minimal to anti-androgenic effects should treat acne more effectively than those containing progestins with pro-androgenic effects.

Table 4: Androgenic effects of progestins in COCs used to treat acne Trade name

Progestin Derived from Effects on androgen

Yasmin Drospirenone1

Spironolactone Anti-androgenic

Diane-35 CyEstra-35

Cyproterone Hydroxyprogesterone Anti-androgenic

Tri-Cyclen

Norgestimate 19-nortestosterone (3rd gen) Minimally androgenic

Alesse Aviane

Levonorgestrel

19-nortestosterone (2nd gen) Pro-androgenic

1 – Comparable to a 25 mg dose of oral spironolactone

Evidence • A 2007 Cochrane report reviewed the evidence for oral contraceptives. The

following section reports findings from preparations available in Canada. We do not give references for the individual studies. The interested reader can find these studies in the Cochrane review.73

• For ease of reading we refer to preparations by brand name.

• COCs were found to reduce the number of acne lesions compared to placebo.

• Four studies compared Diane-35 to other COCs • 2 trials vs Combiphasic

• 1 vs Yasmin

• 1 vs Min-Ovral

• One study compared Yasmin to Tri-Cyclen.

• Table 5 briefly presents the results of these trials. More details of the studies are in Appendix 1.

• Diane-35 was not compared to Tri-Cyclen.

• Alesse was not compared to Diane-35/CyEstra-35, Yasmin, or Tri-Cyclen.


32

Table 5: Results of studies of COCs with anti-androgenic progestins73

Progestin androgenic properties

Anti - androgenic

Minimally androgenic Pro - androgenic

COCs Yasmin Tri-Cyclen Combiphasic1 Min-Ovral2

Diane-35 (anti-androgenic)

No difference

Mixed results Diane-35 better

Yasmin Mixed results

1 – Combiphasic (EE 40-30ug + biphasic desogestrel 25-125) is not available in Canada 2 – Min-Ovral (EE 30ug + levonorgestrel 150 ug) is indicated for contraception but not acne

• Messages from the Cochrane review include:

• Since COCs reduce acne lesion count, severity grades and self assessed acne versus placebo, they should be considered for women with acne who also want an oral contraceptive.

• The comparative efficacy of COCs is less clear. • COCs containing cyproterone (e.g., Diane-35) were comparable to

drospirenone (Yasmin).

• COCs containing cyproterone acetate (e.g., Diane-35) seem to improve acne better than levonorgestrel 150 ug (Min-Ovral); however this finding is based on limited evidence.

• [Alesse/Aviane, the formulation indicated for acne, contains the same estrogen and progestin as Min-Ovral but at lower doses • Ethinyl estradiol 20 ug rather than 30ug

• Levonorgestrel 100 ug rather than 150ug

• Therefore, the efficacy of Diane-35 compared to Alesse/Aviane is uncertain.

• Alesse was not directly compared to Diane-35, CyEstra-35, Yasmin, or Tri-Cyclen.]

• Comparisons between other COCs were conflicting, found no [clear] difference in their ability to reduce acne [or involved preparations not available in Canada.]


• It takes 3 months (3 cycles) for a COC to improve acne.74

• Our content expert suggests that it may take 6 months or longer for improvement.


33

• Eady et al suggest that oral contraceptives be considered over antibiotics for females with acne due to concerns over resistance as long as there are no contraindications that preclude the use of a COC.59

• The risk of venous thromboembolism with Diane-35/CyEstra-35 does not differ significantly from that associated with the use of conventional COCs.75

• There is uncertainty about whether the concomitant prescribing of oral antibiotics and oral contraceptives decreases the effectiveness of the contraceptive.

• “There is a lack of good quality, robust evidence on the effects of drugs on hormonal contraception. Most data have been obtained from case reports, which provide limited evidence.” 76

• The Society of Obstetricians and Gynecologists of Canada 2004 Guidelines say:77 • “Whether or not antibiotic use has an effect on the efficacy of COCs has

been a matter of controversy.

• A significant pharmacokinetic interaction between COCs and antibiotics (except rifampin and griseofulvin) has not been proven.

• It is not possible at this time to predict who is at risk for potential interaction.”

• There is disagreement around whether a back up method of contraception should be recommended.

• Hormonal therapy is rarely used alone in the treatment of acne. In most cases, hormonal therapy is combined with other therapies including benzoyl peroxide, topical retinoids, or topical antibiotics.7

• Diane-35 and Yasmin were shown to be comparable for the treatment of acne. Yasmin is cheaper.

• Yasmin, Alesse, Aviane and Tri-Cyclen are covered by Nova Scotia Pharmacare.

• Diane-35 and CyEstra-35 are not covered by Nova Scotia Pharmacare.

Hormonal therapy – spironolactone

Availability

• Available as a 25 mg and 100 mg tablet.

Mechanism of action

• Spironolactone is an anti-androgen that exerts its effects by blocking androgen receptors and inhibiting 5α-reductase which blocks the conversion of testosterone to dihydrotestosterone.7


34

Evidence

• We have not reviewed the primary evidence about spironolactone.

• A 2003 Cochrane review found that, due to small study sizes, the effectiveness of spironolactone in the treatment of acne could not be elucidated.78


• Response may take as long as three months.

• Spironolactone may be most useful in women who do not need contraception and for whom menstrual disturbances are no longer an issue. Spironolactone may also be useful in women with hirsutism.74

• Our local expert considers spironolactone to be a treatment option in late-onset acne in woman.

• Spironolactone may cause hyperkalemia, particularly when higher doses are prescribed, when there is cardiac or renal compromise, or when combined with a COC.7,74

• Treatment with spironolactone can occasionally cause menstrual disturbances. Coadministration with a COC can lesson this adverse effect.

• If spironolactone is prescribed with Yasmin it should be noted that the drospirenone component of Yasmin is comparable to a 25 mg dose of spironolactone.74

• There is a risk of feminization of a male fetus if spironolactone is taken by a pregnant woman.

• Side effects can be minimized if therapy is initiated with a low dose (25-50 mg daily). Maintenance doses are in the range of 25 to 100 mg per day.

Oral isotretinoin

Availability

• Available as 10 mg and 40 mg capsules (Accutane and Clarus).

Mechanism of action

• Oral isotretinoin affects all pathogenic factors of acne:

• Decreases the size and secretion of the sebaceous glands.

• Normalizes follicular keratinization.

• Prevents the formation of new comedones.

• Indirectly inhibits P. acnes growth via changes of the follicular milieu.

• Exerts an anti-inflammatory effect.7


35

Evidence

• Oral isotretinoin is the accepted standard of care in severe acne or acne that has not responded to other treatments. Therefore, we have not reviewed the evidence for its efficacy.

Suggestions for prescribing7

• Isotretinoin is recommended for

• Severe nodulocystic acne

• Acne associated with scarring

• Treatment in patients failing to respond to or unable to tolerate systemic antibiotics and/or hormonal therapy

• Acne associated with significant psychological stress.52

• Although oral isotretinoin doses range from 0.1 to 2.0 mg/kg, doses >1.0 mg/kg/day are rarely used.

• In general, treatment continues until a cumulative dose of 120 to 150 mg/kg is achieved.

• Start at a lower dose to minimize potential side effects, particularly flare. A commonly recommended treatment regimen is

• 0.5 mg/kg/day (given once daily or BID) for 1 month followed by • 1.0 mg/kg/day for the rest of a 16 to 20-week course of therapy.

• If the patient has a severe flare up in the first two months, consider discontinuing isotretinoin and consulting with a dermatologist.

• It is cheaper to prescribe 40 mg capsules than 10 mg capsules, for example the costs of Accutane for a 60 kg person are: • 40 mg daily X 1 month, then alternating 40 mg on days 1 and 80 mg on

day 2 X 4 months costs ~ $420 (drug cost only).

• 40 mg daily X 1 month, then 60 mg daily (40 mg + 2 X 10 mg) X 4 months costs ~ $540 (drug cost only).

• Resolution of acne may take longer and relapse may be more likely with lower doses. In some cases with severe acne involving deep nodules, a longer treatment period (24-32 weeks) may be needed. Rarely, an even longer period is required.

• If relapse occurs, wait at least 8 weeks before retreatment with oral isotretinoin.52

• After a course of oral isotretinoin our content expert recommends: • Wait ~ 2 to 4 weeks before starting benzoyl peroxide or topical retinoid

follow-up treatment to give time for dryness and sensitivity to subside.

• To decrease risk of scarring

• Wait 12 months before dermabrasion or cutaneous laser treatments

• Wait 6 to 12 months before electrolysis or wax epilation50


36

• Adverse effects: • Teratogenic effects are the most serious. Isotretinoin is contraindicated in

pregnancy. • Two reliable forms of birth control should be used. • Test for pregnancy

• Twice before initiating treatment (at initial assessment and 11 days before starting treatment)

• Monthly during treatment • One month after finishing treatment

• Consider obtaining signed consent before starting isotretinoin.

• Visual disturbances such as a sudden decrease in night vision can occur. Discontinue isotretinoin and refer to an ophthalmologist for follow-up.50

• There are case reports of depression and suicide but a systematic review,79 and cohort studies,80,81 found no conclusive evidence of increased risk. • The American Academy of Dermatology concluded there are no known

absolute or relative psychiatric contraindications to isotretinoin therapy in a patient who is carefully monitored.82

• A Health Canada panel concluded that the ideal data defining the relationship between isotretinoin and suicide is not available but currently there is no definitive data providing a cause and effect relationship. In view of the number of case reports and conflicting opinions the panel felt “it was prudent to be cautious in this regard.”83

• The Compendium of Pharmaceutical and Specialties (CPS) 2008 states, “If symptoms of depression develop or worsen during treatment with oral isotretinoin, the drug should be discontinued promptly and the patient referred for appropriate psychiatric treatment as necessary.”50

• Common side effects are dryness of lips, mouth, eyes, nose, peeling of fingertips, dry skin, itching, thirst, redness, sun sensitivity, headache, myalgias, and back ache.

• Side effects from drying are worse in the first 8 weeks and can be treated with lip balm, eye lubricants, nasal moisturizers, and temporary removal of contact lenses.

• Sunscreens should be used for sun sensitivity.

• Myalgias are dose-related and are less likely with lower doses and slow titration. Can be treated with acetaminophen or NSAIDs.

• Oral isotretinoin has been associated with a number of cases of pseudotumor cerebri (a benign intracranial hypertension), many with concomitant use of tetracyclines. There are, however, case reports of isotretinoin producing pseudotumor cerebri as monotherapy.72 See page 29 for symptoms of pseudotumor cerebri.


37

• Accutane 10 mg contains refined peanut oil which may be a concern for patients allergic to peanuts. Clarus does not contain peanut oil.50

• Other anti-acne medications are usually not prescribed with isotretinoin, for example: • Topical agents aggravate dryness52

• Vitamin A supplements increased toxicity52

• Tetracyclines increased risk of pseudotumor cerebri72

• Liver function tests and lipids, especially triglycerides should also be monitored. A monitoring flow chart, titled “Isotretinoin (Accutane, Clarus) Monitoring Form”, is available on the RxFiles home page www.rxfiles.ca.

• For a complete review of adverse effects and precautions of oral isotretinoin, prescribers should consult the product monograph in the CPS.


38

Appendix 1. Details of studies comparing oral contraceptives73

• Four studies compared Diane-35 to other COCs:

• Diane-35 vs Yasmin

• No statistically significant difference between COCs in total lesion count over 9 menstrual cycles

• Diane-35 vs Combiphasic (EE 40-30ug + biphasic desogestrel 25-125ug)

• Two studies showed inconsistent results:

• Both studies showed no significant differences in acne grades or mean counts of pustules, nodules, or papules. One found a higher mean comedo count with Combiphasic while the other found no difference.

• Combiphasic is not available in Canada.

• Diane-35 vs Min Ovral (EE 30ug + levonorgestrel 150ug)

• Diane-35 resulted in a significantly lower mean pustule and papule count and more women in the Diane-35 group had a “good” outcome.

• Diane-35 has not been compared to Tri-Cyclen or Alesse. The closest to these comparisons would be Combiphasic and Min Ovral, respectively. Combiphasic contains desogestrel, a 3rd generation progestin with minimal androgenic effects like norgestrel contained in Tri-Cyclen. Min Ovral contains the same progestin as Alesse but in a higher dose, levonorgestrel 150 ug rather than 100ug.

• One study has compared Yasmin to Tri-Cyclen:

• Yasmin was superior to Tri-Cyclen for reduction in total lesion count (WMD -3.30; 95% CI -6.45 to -0.15)

• More women in the Yasmin group had improvement in facial acne as assessed by the investigator and the women themselves.

• the investigator (0R 1.85; 95% CI 1.14 to 3.01) and

• the women themselves (OR 1.64; 95% CI 1.09 to 2.47)

• Yasmin and Tri-Cyclen were comparable in their decreases in:

• inflammatory lesion count

• sex hormone-binding globulin levels

• androgen levels

• Yasmin has not been compared to Alesse.


39

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PLANNING COMMITTEE - cdn.dal.ca · 0.025%-0.05% are most useful, higher strengths are often not tolerated). • Starting with every 2nd or 3rd night. • Applying 30-45 minutes after