image of silk fabric and dry skin


L.C. Guenther, MD, FRCPC

Division of Dermatology, University of Western Ontario, London, Ontario, Canada

ABSTRACT

Psoriasis, acne vulgaris and photoaging are common conditions. Tazarotene is a pro-drug of tazarotenic acid, a receptor-selective retinoid, which has shown efficacy in the treatment of these disorders. In the treatment of acne vulgaris, it has greater comedolytic activity than the currently available topical retinoids. In psoriasis, tazarotene normalizes keratinocyte differentiation, reverses keratinocyte hyperproliferation and has better anti-inflammatory effects than any of the currently available topical retinoids. It is most commonly used as combination therapy with a topical corticosteroid or phototherapy in psoriasis, or with an antibiotic in acne.

Key Words:
tazarotene, retinoid, psoriasis, acne vulgaris, photoaging

Mechanism of Action

Tazarotene is a pro-drug of the more water soluble tazarotenic acid, a receptor-selective acetylenic retinoid which binds to RARβ and RARγ and weakly to RARα.1 Tazarotenic acid does not interconvert to any other retinoids that could potentially activate other retinoid receptors. In psoriasis, tazarotene normalizes keratinocyte differentiation, reverses keratinocyte hyperproliferation and has anti-inflammatory effects. In acne vulgaris, the abnormal desquamation of the follicular epithelium is normalized.2 In October 2001, the US FDA approved Tazorac® cream 0.1% (tazarotene, Allergan) for the treatment of acne vulgaris. Since 1997, Tazorac® gel (0.05% and 0.1%) has been available for the treatment of stable plaque psoriasis and the 0.1% gel is also indicated for the treatment of mild-to-moderately severe facial acne vulgaris. Tazorac® cream (0.05% and 0.1%) was approved by the US FDA in 2000 for the treatment of plaque psoriasis. Approval by the US FDA and TPP – Canada is expected for the indication of photoaging sometime in 2002.

Psoriasis

Psoriasis affects approximately 2% of the population.3 Plaque psoriasis, the most common variant, is characterized by welldefined erythematous scaly plaques, with or without associated nail disease and arthritis. In most patients, the disease is localized and amenable to topical therapy.

Tazarotene is efficacious as monotherapy,4 but is more commonly used in combination with phototherapy or with a topical corticosteroid in order to enhance efficacy and tolerability.5 Adjunctive use of a mid or high-potency steroid results in greater reductions of overall disease severity, plaque elevation and adverse events (see Table 1).

Rebound does not appear to be a problem. Epidermal atrophy induced by steroids can also be minimized by tazarotene. The reduction of epidermal thickness was only 28% when tazarotene was used in conjunction with diflorasone diacetate 0.05% compared to 43% when the steroid was used alone.5 Use of the 0.1% gel once daily in combination with mometasone furoate 0.1% cream once daily is more efficacious than twice daily calcipotriol ointment6 or twice daily mometasone furoate 0.1% cream.7 Superior maintenance of remission was seen with thrice weekly tazarotene 0.1% gel used in conjunction with twice weekly clobetasol propionate 0.05% ointment than when the vehicle was used alone.8

Acne vulgaris

Approximately 95% of the population suffers at some point in their lifetime from acne vulgaris.9 Papules, pustules, closed and open comedones, cysts and scarring may be seen. Although more common in teenage years, it may persist into the fourth and fifth decades. Comparative clinical trials have shown that once daily 0.1% tazarotene gel is more efficacious than Retin A® 0.025% gel, Retin A Micro® 0.1% and Differin® gel and that alternate day use was as efficacious as once daily Differin® gel (see Table 3). Greater global improvement was noted when tazarotene 0.1% gel was used once daily in combination with 1% clindamycin phosphate once daily. This combination and the combination of tazarotene 0.1% gel + erythromycin/benzoyl peroxide gel once daily were significantly more efficacious than twice daily 1% clindamycin phosphate lotion.

ComparatorsResults
Tazarotene 0.1% gel +:

  • Fluocinolone acetonide 0.01% cream (LOW) vs.
  • Mometasone furoate 0.1% cream (MID) vs.
  • Fluocinonide 0.05% cream (HIGH) vs.
  • Placebo cream10
  • There was a lower median time to reach 50% improvement with (2 weeks) or HIGH (3 weeks) vs. placebo (4 weeks) (p<0.05).
  • More patients showed 50% improvement at 12 weeks with MID (91%) or HIGH (95%) vs. placebo (80%) (p<0.05).
  • There were fewer adverse events with MID or HIGH.
  • No differences were seen between LOW and placebo.
Tazarotene 0.1% gel +:

  • Fluocinonide 0.05% vs.
  • Mometasone furoate 0.1% vs.
  • Diflorasone diacetate 0.05% vs.
  • Betmethasone dipropionate 0.05% cream vs.
  • Fluticasone propionate 0.005% vs.
  • Diflorasone diacetate 0.05% cream11
There was a statistically significant greater global improvement and reduction of plaque elevation, scaling and erythema with betamethasone dipropionate 0.05% cream, mometasone furoate 0.1% ointment and diflorasone diacetate 0.05% ointment compared to tazarotene monotherapy
Tazarotene 0.1% gel q.d. + Mometasone furoate cream q.d. vs. Calcipotriol 0.005% ointment b.i.d.6There was a statistically greater reduction in trunk area, plaque elevation, 0.1% scaling and erythema (p<0.05), and at 8 weeks (end of treatment), a greater reduction in upper extremity area (p<0.05). At week 2, 45% on Tazarotene + mometasone vs. 26% on calcipotriol achieved >75% improvement (p<0.05).
Tazarotene 0.1% gel q.d. + Mometasone furoate 0.1% cream q.d. vs. Mometasone furoate cream b.i.d.7The tazarotene + mometasone furoate group had significantly greater and more rapid efficacy, and a more prolonged effect post-treatment.
Tazarotene 0.1% gel thrice weekly vs. Tazarotene 0.1% gel thrice weekly + clobetasol propionate 0.05% ointment twice weekly vs. vehicle after achieving at least 50% improvement8At 5 months, 73% on tazarotene/clobetasol, 47% on tazarotene and 19% on vehicle had retained at least a 50% improvement relative to baseline (p<0.05).

Table 1: Topical corticosteroid combination trials with tazarotene 0.1% gel.

Results of the phototherapy trials are shown in Table 2. In all studies, enhanced efficacy and a lowered incidence of irritation without additional phototoxicity were noted when tazarotene was used.

PhototherapyResults
UVB broad band12To obtain 50% improvement: median cumulative UVB was reduced (390 mJ/cm2 vs. 1644 mJ/cm2 ) (p≤0.001) and less time was needed (25 days vs. 53 days) with tazarotene 0.1% gel once daily for 2 weeks, followed by thrice weekly UVB + tazarotene 0.1% gel compared to UVB monotherapy.
311 UVB narrow band5There was a significantly greater reduction in psoriasis area and severity index (PASI) in 1/2 body treated with tazarotene 0.1% gel vs. 5% salicylic acid ointment 1 week before and during 3 weeks of 311 UVB.
311 UVB narrow band13There was a greater reduction in PASI in the 1/2 body treated with tazarotene 0.1% gel (64%) vs. emollient (48%) (p<0.05).
Bath PUVA14There was a 76% decrease in PASI after 3 weeks in tazarotene 0.05% gel treated 1/2 body vs. 58% with vehicle (p<0.05).

Table 2: Phototherapy trials with topical tazarotene

Photoaging

Clinical studies have shown that topical tazarotene 0.1% gel, 0.05% cream and 0.1% cream are more efficacious than the vehicle in reducing fine wrinkling (see Table 4). In a 24-week study involving 349 individuals, mottled hyperpigmentation and overall integrated assessment (OIA) of photodamage were improved with both cream formulations and 0.05% tretinoin cream when compared to the vehicle. There was a trend towards a faster response with 0.1% tazarotene cream when compared to the 0.05% formulation. The 0.05% tazarotene and tretinoin groups had a similar proportion with at least 50% improvement, but at weeks 12 and 20, the 0.1% tazarotene group had a significantly greater proportion compared to the tretinoin group.

ComparatorsResults
Tazarotene 0.1% gel q.d. vs. Retin A® gel q.d.15 0.025%Tazarotene was more efficacious in reducing open comedo count (65% vs. 44%, p=0.03), total noninflammatory lesion count (55% vs. 42% p=0.04) and total inflammatory lesion count (54% vs. 44% NS)
Tazarotene 0.1% gel q.d. vs. Retin A Micro® 0.1% q.d.16There were statistically significant reductions in overall disease severity (36% vs. 26%, p=0.02), global response scores (2.80 vs. 3.35, p=0.02), and noninflammatory lesions (60% vs. 38%, p=0.02) with tazarotene.
Tazarotene 0.1% gel q.d. vs. Differin® Gel q.d.17There was a greater reduction with tazarotene when compared to adapalene in mean global response score (2.38 vs. 3.41 at 12 weeks, p<0.0001), overall disease severity (44% vs. 24%, p<0.0001), noninflammatory lesions (71% vs. 48%, p<0.0001), inflammatory lesions (70% vs. 55%, p=0.0002) and those with at least 50% improvement (78% vs. 52%, p=0.002).
Tazarotene 0.1% gel q.2d. vs. Differin® Gel q.d.18There were no significant differences in efficacy.
Tazarotene 0.1% gel q.d. vs. Tazarotene 0.1% gel q.d. + 1% clindamycin phosphate q.d. vs. Tazarotene 0.1% gel q.d. + benzoyl peroxide gel q.d. vs 1% clindamycin phosphate lotion. Tazarotene 0.1% gel + Erythromycin 3%/ Benzoyl Peroxide 5% gel q.d. vs. Clindamycin Phosphate 1% q.d.19There was significantly greater global improvement with tazarotene 0.1% gel + 1% clindamycin phosphate than with tazarotene monotherapy or clindamycin monotherapy. Tazarotene 0.1% gel + erythromycin/benzoyl peroxide gel once daily was significantly more efficacious than twice daily

Table 3: Acne vulgaris comparative trials

Side effects

Local cutaneous irritation including burning, itching, erythema, peeling or dryness occurs in approximately one-quarter of patients. In clinical trials, the severity was usually mild-to-moderate.

Drug interactions

Additional dryness might occur with other dermatologic medications or cosmetics with a strong drying effect.

How to use

Patient education is important in order to minimize the potential for irritation. A small amount of tazarotene should be applied to dry skin, typically at night. However, since the product is photostable, it can be used in the morning. The cream and gel do not stain clothing and rub in well. In the treatment of psoriasis, only the areas affected with psoriasis are treated since use on uninvolved skin may be associated with irritation. Use of a cotton-tipped applicator and protection of the surrounding skin with petrolatum may help minimize use on unaffected skin. In acne, the entire affected area (not just lesions) is treated in the hope of preventing microcomedo formation.

In order to minimize irritation, treatment can be initiated with the 0.05% cream and stepped up as tolerated. Scalp and nail psoriasis are preferentially treated with the gel formulation. Alternate day and short contact treatment (30 seconds-5 minutes)2 can also be considered. With time, most patients are able to tolerate once daily treatment, but may occasionally need to skip an application. In the winter and in dry climates, emollients may reduce dryness and enhance tolerance. They can be applied immediately after washing with a mild cleanser prior to application of tazarotene, or at another time of day. Application immediately after applying tazarotene might result in inadvertent spread of tazarotene. In the treatment of psoriasis and acne vulgaris, combination therapy should be considered as a means of increasing efficacy and tolerability.

ComparatorsResults
Tazarotene 0.1% gel q.d. vs. vehicle q.d.20Tazarotene 0.1% gel was more efficacious than vehicle after 12 weeks in reduction of fine wrinkling and skin roughness on forearm skin (p=0.008).
Tazarotene 0.05% cream q.d. vs. Tazarotene 0.1% cream q.d. vs. tretinoin 0.05% cream q.d. vs. vehicle q.d.21Tazarotene 0.05%, tazarotene 0.1% and tretinoin 0.05% creams significantly improved mottled hyperpigmentation, fine wrinkles and OIA compared to vehicle (67% on 0.1% tazarotene, 52% on 0.05% tazarotene and 55% on tretinoin 0.05% cream had at least 50% improvement at week 24).

Table 4: Photoaging studies

Contraceptive counseling should be given to women of childbearing potential before topical tazarotene is used. Although absorption is minimal, it should not be used by pregnant women since systemic tazarotene is teratogenic.

Conclusion

Topical tazarotene is very efficacious in the treatment of psoriasis, acne and photoaging. It is the most potent comedolytic topical retinoid currently available. Combination therapy with corticosteroids or phototherapy in psoriasis, or antibiotics in acne vulgaris, can enhance efficacy and tolerance. Irritation can be minimized with patient education, and use of the 0.05% cream, on alternate day and short-contact regimens.

References

  1. Chandraratna RA. Tazarotene—first of a new generation of receptor-selective retinoids. Br J Dermatol 135(Suppl 49):18-25 (1996 Oct).
  2. Bershad S, Poulin YP, Berson DS, et al. Topical retinoids in the treatment of acne vulgaris. Cutis 64(2 Suppl):8-20 (1999 Aug).
  3. Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol Clin 14(3):485-96 (1996 Jul).
  4. Weinstein GD, Krueger GG, Lowe NJ, et al. Tazarotene gel, a new retinoid for topical therapy of psoriasis: vehicle-controlled study of safety, efficacy and duration of therapeutic effect. J Am Acad Dermatol 37(1):85-92 (1997 Jul).
  5. Guenther L. Tazarotene combination treatments in psoriasis. J Am Acad Dermatol 43(2 Pt 3):S36-42 (2000 Aug).
  6. Guenther LC, Poulin YP, Pariser DM. Acomparison of tazarotene 0.1% gel once daily plus mometasone furoate 0.1% cream once daily versus calcipotriene 0.005% ointment twice daily in the treatment of plaque psoriasis. Clin Ther 22(10):1225-38 (2000 Oct).
  7. Koo J, Martin D. Double-blind comparison of tazarotene gel q.d. plus mometasone furoate cream q.d. versus mometasone furoate cream b.i.d. Poster presentation at: American Academy of Dermatology annual meeting, (1999 July 28-August 1), New York, NY.
  8. Lebwohl M, Lombardi K, Tan MH. Duration of improvement in psoriasis after treatment with tazarotene 0.1% gel plus clobetasol propionate 0.05% ointment: comparison of maintenance treatments. Int J Dermatol 40(1):64-6 (2001 Jan).
  9. Ho V, Schacter D, Miller R, et al. Acne management for the 90s: current treatment guidelines. Can J Diagnosis 12(suppl):1-25 (1995).
  10. Lebwohl MG, Breneman DL, Goffe BS, et al. Tazarotene 0.1% gel plus corticosteroid cream in the treatment of plaque psoriasis. J Am Acad Dermatol 39(4 Pt 1):590-6 (1998 Oct).
  11. Green L, Sadoff W, and the Tazarotene Plus High-Potency or Mid-Potency Steroid Study Group. A clinical evaluation of tazarotene 0.1% gel, with and without a high- or mid-high-potency corticosteroid, in patients with stable plaque psoriasis. J Cut Med Surg. In Press 2002.
  12. Koo JY, Lowe NJ, Lew-Kaya DA, et al. Tazarotene plus UVB phototherapy in the treatment of psoriasis. J Am Acad Dermatol 43(5 Pt 1):821-8 (2000 Nov).
  13. Behrens S, Grundmann-Kollmann M, Schiener R, Peter RU, Kerscher M. Combination phototherapy of psoriasis with narrow-band UVB irradiation and topical tazarotene gel. J Am Acad Dermatol 42(3):493-5 (2000 Mar).
  14. Behrens S. Combination treatment of psoriasis with photochemotherapy and tazarotene gel, a receptor-selective topical retinoid. (Letter to Ed.) Br J Dermatol 141:154-179 (1999).
  15. Webster GF, Berson D, Stein LF, Fivenson DP, Tanghetti EA, Ling M. Efficacy and tolerability of once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a randomized trial. Cutis 67(6 Suppl):4-9 (2001 Jun).
  16. Leyden JJ, Tanghetti EA, Miller B, et al. Once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.1% microsponge gel for the treatment of facial acne vulgaris: a double-blind randomized trial. Cutis 69(suppl 2):12-19 (2002).
  17. Webster GF, Guenther L, Poulin YP, et al. A multicenter, double-blind, randomized comparison study of the efficacy and tolerability of once-daily tazarotene 0.1% gel and adapalene 0.1% gel for the treatment of facial acne vulgaris. Cutis 69(suppl 2):4-11 (2002).
  18. Leyden J, Lowe N, Kakita L, Draelos Z. Comparison of treatment of acne vulgaris with alternate-day applications of tazarotene 0.1% gel and once-daily applications of adapalene 0.1% gel: a randomized trial. Cutis 67(6 suppl):10-6 (2001 Jun).
  19. Draelos ZD, Tanghetti EA, and the Tazarotene Combination Leads to Efficacious Acne Results (CLEAR) Trial Study Group. Cutis 69(suppl 2):20-29 (2002).
  20. Sefton J, Kigman AM, Kopper SC, Lue JC, Gibson JR. Photodamage pilot study: a double-blind, vehicle-controlled study to assess the efficacy and safety of tazarotene 0.1% gel. J Am Acad Dermatol 43(4):656-63 (2000 Oct).
  21. Kang S, Leydon JJ, Lowe NJ, et al. Tazarotene cream for the treatment of facial photodamage: a multicenter, investigator-masked, randomized, vehiclecontrolled, parallel comparison of 0.01%, 0.025%, 0.05%, and 0.1% tazarotene creams with 0.05% tretinoin emollient cream applied once daily for 24 weeks. Arch Dermatol 137(12):1597-604 (2001 Dec).

Industry News

 

Roche Initiates an Enhanced Pregnancy Prevention Program to Prevent Accutane – Exposed Pregnancies

In January 2002, Hoffmann-LaRoche, working closely with the US FDA distributed an enhanced version of their Pregnancy Prevention Program for Women on Accutane® to more than 375,000 dermatologists, primary care prescribers and pharmacists in the US. The program is called S.M.A.R.T. (System to Manage Accutane® Related Teratogenicity). It involves the prescriber, pharmacist and patient to ensure that female patients are not pregnant when they begin taking Accutane® and that they do not become pregnant while taking the medication and for one month after stopping treatment. An innovative component of the program is the use of yellow self-adhesive Accutane® Qualifications Stickers, which prescribers will apply to all Accutane® prescriptions.

To receive the first Accutane® prescription, the female patient will be required to meet four qualifications:

  1. Have two negative pregnancy tests – the first as a screening test and the second as a confirmation test that will be administered during the first 5 days of her next menstrual period.
  2. Select and commit to using two effective forms of birth control simultaneously one month prior to treatment, during treatment and for one month after stopping treatment.
  3. Read and sign an informed consent agreement explaining the risk of potential birth defects associated with Accutane®.
  4. Learn about and be encouraged to enroll in the Accutane® Survey, a system to track female Accutane® patients, learn about their experiences with pregnancy prevention efforts and determine their pregnancy status.

Each month the patient must have a negative pregnancy test and receive contraception counseling from the prescriber before receiving a new prescription. If the patient meets these qualifications, or is male, the prescriber will then write a prescription for a 1-month supply, affix one of the yellow Accutane® Qualification Stickers and date it. Prescriptions must be filled within 7 days of the qualification date on the sticker.

This program is being phased in and the deadline for compliance is April 10, 2002.

The S.M.A.R.T. program is only applicable for treating patients in the US. For other countries, including Canada, Roche has created uniquely tailored programs to address their distinctive health care needs.

STL Volume 7 Number 3

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