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Update on Topical Acne Treatments

J. Tan, MD, FRCP
Windsor, Ontario, Canada

ABSTRACT

Topical acne treatment can positively benefit patients with acne. This review summarizes clinical and prescribing information on currently available topical agents. The efficacy of the medications included in this report is supported by properly designed randomized clinical trials2-8,14.

Key Words: acne, tretinoin, adapalene, isotretinoin, tazarotene, clindamycin, erythromycin, azelaic acid, benzoyl peroxide

Topical acne medications are indicated for treatment of comedonal and mild inflammatory acne, or as adjuncts to systemic therapy in moderate acne1. The newer, more frequently prescribed drugs are summarized herein.

Drug Mechanism of Action

Tretinoin
Retin-A (Janssen-Ortho)
Stieva-A Retisol-A (Stiefel)
Vitamin A Acid (Dermik)
Vitinoin (Penederm)

  • Facilitates removal of existing comedones and inhibits formation of new ones
  • Believed to suppress keratin synthesis
  • (Inhibition of P. acnes)

Adapalene
Differin (Galderma)

  • Prevents microcomedone formation
  • Enhances keratinocyte differentiation
  • (Inhibition of P. acnes)
  • (Anti-inflammatory)

Isotretinoin
Isotrex (Stiefel)

  • Comedolytic and anti-inflammatory
  • (Inhibition of P. acnes)

Tazarotene
Tazorac (Allergan)

  • Comedolytic and believed to inhibit cross-linked envelope formation in human keratocyte cultures

Clindamycin
Dalacin T (Upjohn Pharmacia)

  • Inhibition of P. acnes
  • Anti-inflammatory

Erythromycin
Staticin, T-stat (Westwood-Squibb)
Sans-Acne (Galderma)
Erysol (Stiefel)

  • Inhibition of P. acnes

Azelaic Acid
Azelex (Allergan)

  • Inhibition of P. acnes
  • Slowly releases active oxygen
  • Some keratolytic effect

Benzoyl Peroxide
Benzac, Benzac AC (Galderma)
Solugel, Panoxyl, Acetoxyl (Stiefel)
Desquam-X (Westwood-Squibb)
Benzagel (Dermik)

  • Inhibition of P. acnes
  • Anti-inflammatory
  • (Comedolytic)

Benzoyl Peroxide and Erythromycin
Benzamycin (Dermik)

  • Inhibition of P. acnes
  • (Comedolytic)
  • Anti-inflammatory

Tretinoin and Erythromycin
Stievamycin, Stievamycin mild,
Stievamycin Forte (Stiefel)

  • Comedolytic
  • Inhibition of P. acnes

Table 1: Mechanism of action for topical acne medications9
Any mechanism that is enclosed in parentheses denotes a minimal effect.

Pathogenesis

Some of the factors responsible for acne include heredity and the role of hormones. Exposure to ultraviolet light and the use of certain drugs can also affect acne13. Acne is multifactorial, involving (1) sebaceous hypersecretion due to increased levels of circulating androgens and/or sebaceous gland hypersensitivity, and (2) follicular hyperkeratinization leading to pore occlusion. Inflammatory acne includes (3) the proliferation of Propionibacterium acnes (P. acnes) within the comedone and (4) the generation of chemotactic and proinflammatory factors1.

Treatment Options

The presence of multiple comedones suggests the use of agents directed at follicular hyperkeratinization. Inflammatory lesions may warrant the use of agents with antimicrobial and/or antiinflammatory effects. Other factors that should be considered in therapeutic selection are side effect profile, cost, and individual patient preference.

In a recent survey, acne patients who were referred to a dermatologist’s office were asked, “Which form of treatment would you prefer: topical or systemic?” Female patients were five times more likely than males to prefer topical treatments, as were those with lesser grades of acne severity (see Table 2).

Generally, topical acne agents require a trial period of at least 8– 12 weeks to determine therapeutic benefit. During this time, the patient should be given appropriate advice to minimize the potential for adverse effects. Maintenance of improvement thereafter requires ongoing treatment with periodic tapering to establish ongoing need.

When prescribing for female patients the clinician should be aware of possible teratogenicity. For example, the potential link between topical tretinoin and the fetal malformation is not clear. The USP Drug Information for the Health Care Professional (1999) carries the Pregnancy category C for tretinoin. To be safe, topical tretinoin should not be used during pregnancy.

A multicenter, single-blind, randomized 12 week study in Europe compared clindamycin with a clindamycin phosphate/tretinoin gel formulation (Velac) which is approved for use in France. Velac was found to reduce overall acne scores and was faster acting14. A new drug application for this drug for acne treatment is currently awaiting approval by the US FDA.

Overall group (n=78) Males (n=29) Females (n=49) Acne Grade I and II(n= 39) Acne Grade III and IV(n=39)

Topical

26%

7%

37%

38%

13%

Systemic

21%

32%

14%

10%

32%

No Preference

53%

61%

49%

51%

55%

Table 2: Acne survey results (in percent of responses) when patients were asked, “Which form of treatment would you prefer: topical or systemic?”15

Generic Name Dosage Forms Frequency FDA Pregnancy Category*

Tretinoin

Cream: 0.01%, 0.025%, 0.05%, 0.1%, 0.4%17
Gel: 0.01%, 0.025%, 0.05%
Microsponge: 0.1%
Solution: 0.025%, 0.05%, 0.1%17, 0.2%17

Before retiring

C

Adapalene

Cream: 0.1%
Gel: 0.1%

Before retiring

C

Isotretinoin

Gel: 0.05%

Two times per day

C

Tazarotene

Gel: 0.05%, 0.1%

Once per day

X

Clindamycin

Solution: 1%

Two times per day

B

Erythromycin

Solution: 1.5% Erythromycin, 2% Erythromycin

Two times per day

B

Azelaic Acid

Cream: 20.0%

Two times per day

B

Benzoyl Peroxide

Cleansing Lotion: 2.5%, 4%, 5%, 8%, 10%
Cream: 5%, 10%
Gel: 2.5%, 4%, 5%, 6%, 8%, 10%, 15%, 20%
Lotion: 2.5%, 5%, 5.5%, 10%, 20%

One or two times per day

C

Benzoyl Peroxide and Erythromycin

Benzoyl Peroxide 5%, Erythromycin 3%

Two times per day

C

Tretinoin and Erythromycin

Tretinoin: Regular – 0.025%
Mild – 0.01%
Forte – 0.05%
All contain Erythromycin 4%

Before retiring

C

Table 3: Topical acne preparations.
*FDA Pregnancy categories are A: Controlled studies show no risk, B: No evidence of risk in humans, C: Risk cannot be ruled out, D: Positive evidence of risk, X: Contraindicated in pregnancy11,12.

Adverse Effects

The most common adverse effect of topical acne therapy is mild irritation. Aqueous-based gels may be less irritating than their alcohol-based counterparts, and creams tend to be less irritating and drying than gels. Irritation can be minimized by advising shorter initial application times. These can then be progressively titrated upwards, with less frequent application, and the use of appropriate nonacneigenic moisturizers.

Generic Name Erythema Scaling Burning Initial Flare Photo-Sensitivity Other

Tretinoin

3+

3+

2+

2+

2+

Photodegraded, apply only at night.

Adapalene

1+

1+

1+

1+

0

Photostable.

Isotretinoin

2+

2+

1+

1+

0

Photoisomerizes with light exposure. Plasma levels not detectable with topical application.

Tazarotene

3+

3+

3+

1+

0

Photostable.

Clindamycin

1+

1+

1+

1+

0

Allergic contact dermatitis (rare). May lead to P. acnes resistance with prolonged use.

Erythromycin

1+

1+

1+

1+

0

Irritation somewhat more frequent than for clindamycin. Allergic contact dermatitis (rare). May lead to P. acnes resistance with prolonged use.

Azelaic Acid

1+

1+

1+

1+

0

Less irritating than tretinoin cream and 5% benzoyl peroxide gel.

Benzoyl Peroxide

2+

2+

1+

1+

1+

May bleach clothing. Allergic contact dermatitis (rare).

Benzoyl Peroxide and Erythromycin

2+

2+

2+

2+

2+

Less irritating than benzoyl peroxide alone.

Tretinoin and Erythromycin

3+

3+

3+

2+

2+

Photodegraded, apply only at night.

Table 4: Adverse effects of topical acne medications9.
Legend: 3+ very strong, 2+ strong, 1+ moderate

Summary

Mild acne can be effectively managed by topical medications based on lesional morphology. Appropriate counselling on the use of these medications can minimize adverse effects and enhance compliance.

References

  1. Leyden JJ. Therapy for Acne Vulgaris. N Engl J Med 336(16):1156-62 (1997 Apr).
  2. Lucky AW, Cullen SI, Jarratt MT, Quigley JW. Comparative efficacy and safety of two 0.025% tretinoin gels: Results from a multicenter, double-blind, parallel study. J Am Acad Dermatol 38(4):S17-23 (1998 Apr).
  3. Cunlif fe WJ, Caputo R, Dreno B, et al. Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and US multicenter trials. J Am Acad Dermatol 36:S126-34 (1997 Jun).
  4. Cunlif fe WJ, Caputo R, Dreno B, et al. Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and US multicenter trials. J Am Acad Dermatol 36:S126-34 (1997 Jun).
  5. Eady EA, Cove JH, Joanes DN, Cunliffe, WJ. Topical antibiotics for the treatment of acne vulgaris: a critical evaluation of the literature on their clinical benefit and comparative efficacy. J Dermatol Treat 1:215-226 (1990).
  6. Cunlif fe WJ. The Clinical Efficacy of Azelaic Acid in the Treatment of Acne. Rev Contemp Pharmacother 4: 433-39 (1993).
  7. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: Combined results of two double-blind investigations. J Am Acad Dermatol 37(4):590-5 (1997 Oct).
  8. Shalita AR, Chalker DK, Ellis CN, Parish LC, Smith JG. A multicenter, doubleblind, controlled study of the combination of erythromycin/benzoyl peroxide, erythromycin alone, and benzoyl peroxide alone in the treatment of acne vulgaris. Cutis 49(6A):1-4 (1992).
  9. modified from Gollnick H, Schramm M. Topical Drug Treatment in Acne. Dermatology 196(1):119-25 (1998).
  10. Leyden JJ: Topical treatment of acne vulgaris: Retinoids and cutaneous irritation. J Am Acad Dermatol 38(4):S1-4 (1998 Apr).
  11. Stockton D, Paller A. Drug administration to the pregnant or lactating woman: A reference guide for dermatologists. J Am Acad Dermatol 23(1):87-103 (1990 Jul).
  12. Reed BR. Dermatologic drugs, pregnancy and lactation. Arch Dermatol 133(7):894-898 (1997 Jul).
  13. Zouboulis C, Orfanos CE. Retinoids. In Millikan L (ed) Drug Therapy in Dermatology. Marcel Dekker, New York, in press.
  14. Zouboulis C, Derumeaux L, Decroix L, Maciejewska-Udziela B, Cambazard F, Stuhlert A. A multicentre, single-blind, randomised comparison of a fixed clindamycin phosphate/tretinoin gel formulation (Velac) applied once daily and a clinidamycin lotion formuation (Dalacin T) applied twice daily in the topical treatment of acne vulgaris. Br J Dermatol, in press.
  15. Tan J, Vasey K. Perceptions and Attitudes of Acne Patients. Manuscript in preparation for publication (1999).

News about Photodynamic Therapy

On November 5 1999, the US FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee considered certain issues related to Dusa Pharmaceuticals’ New Drug Application (NDA) for Levulan Photodynamic Therapy (5-aminolevulinic acid). Following presentations by Dusa and the FDA, the agency asked the panel for feedback with respect to proposed product labelling and postmarketing studies.

Earlier this year the US FDA issued an approvable letter for this device for the treatment of actinic keratoses of the face and scalp. The letter said that certain items had to be completed before final FDA marketing approval would be granted. These included:

  • Compliance with the FDA’s Good Manufacturing Practices (GMPs) by all Dusa’s manufacturers
  • Agreement on revised labelling for the product.

Dusa recently submitted revised labelling to the FDA, and reported that re-inspection of its drug manufacturer had taken place.

Because the FDA had already designated Dusa’s NDA as approvable, the agency did not ask for a panel vote on approvability. The FDA is now expected to take these suggestions into consideration when developing final labelling and postmarketing study recommendations. Though nothing is cast in stone, it is possible that this device and associated technologies might be given approval sometime during December 1999.


In this issue:

  1. Current Treatments for Scabies and Pediculosis
  2. Update on Topical Acne Treatments
  3. Update on Drugs and Drug News - Number 1 1999