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Topical Tazarotene Therapy for Psoriasis,
Acne Vulgaris, and Photoaging
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
EDITOR-IN-CHIEF: Stuart Maddin ASSOCIATE EDITOR (International): Hugo Degreef, Catholic University, Leuven: ASSOCIATE EDITOR (Canada): Jason Rivers
INTERNET EDITOR: Harvey Lui PUBLICATIONS EDITOR: Penelope Gray-Allan EDITORIAL ADVISORY BOARD: Kenneth A. Arndt, Beth Israel Hospital & Harvard Medical School, Boston;
Wilma Fowler Bergfeld, Cleveland Clinic, Cleveland; Jan D. Bos, University of Amsterdam, Amsterdam; Enno Christophers, Universitäts-Hautklinik, Kiel; Richard L. Dobson, Medical University
of South Carolina, Charleston; Jeffrey S. Dover, Harvard Medical School, Boston; Boni E. Elewski, University of Alabama, Birmingham; Barbara A. Gilchrest, Boston University School of
Medicine, Boston; W. Andrew D. Griffiths, St. Johns Institute of Dermatology, London; Aditya K. Gupta, University of Toronto, Toronto;Vincent C.Y. Ho, University of British Columbia, Vancouver;
Mark Lebwohl, Mount Sinai Medical Center, New York; James J. Leyden, University of Pennsylvania, Philadelphia; Howard I. Maibach, University of California Hospital, San Francisco;
Larry E. Millikan, Tulane University Medical Center, New Orleans; Takeji Nishikawa, Keio University School of Medicine, Tokyo; Constantin E. Orfanos, Freie Universitäts Berlin,
Universitätsklinikum Benjamin Franklin, Berlin; Stephen L. Sacks, Viridae Clinic Sciences, Vancouver; Alan R. Shalita, SUNY Health Sciences Center, Brooklyn; Richard Thomas, Vancouver
General Hospital, Vancouver; Stephen K. Tyring, University of Texas Medical Branch, Galveston; John Voorhees, University of Michigan, Ann Arbor; Klaus Wolff, University of Vienna, Vienna
Comparators
Results
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.6
There 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.7
The 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% improvement8
At 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.
Phototherapy
Results
UVB broad band12
To 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 band5
There 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 band13
There 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 PUVA14
There 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
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.
2
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
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 7 No. 3 • March 2002
Comparators
Results
®
15
Tazarotene 0.1% gel q.d. vs. Retin A gel q.d. 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.16
There 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.17
There 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.18
There 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.19
There 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
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.
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.
Comparators
Results
Tazarotene 0.1% gel q.d. vs. vehicle q.d.20
Tazarotene 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.21
Tazarotene 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
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 7 No. 3 • March 2002
3
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.
Conclusions
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. A comparison 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.
8.
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.
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.
4
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 7 No. 3 • March 2002
Common Sense Dermatological Drug Suggestions
For Women Who Are Breast-feeding
C. Zip, MD, FRCPC
Department of Medicine, University of Calgary, Calgary, Alberta, Canada
ABSTRACT
Use of medications by breast-feeding mothers is not uncommon. When prescribing a medication to a nursing mother, the physician
must weigh the potential risk of exposing the infant to the medication or the risks of not breast-feeding against the benefits of the
medication to the mother. Information regarding the safety of common dermatological medications during lactation will be
reviewed. Based on this information, treatment recommendations will be made.
Key Words: breast-feeding, antimicrobials, antihistimines, immunomodulators, antipsoriatics, steriods, scabicides, anti-acne agents
Breast-feeding provides optimal nutrition in the first 6 months of
life. Well documented benefits of breast-feeding include a
decreased incidence of infantile diarrhea1 and infection.2 Other
studies show a possible protective affect against sudden infant
death syndrome,3 insulin dependent diabetes mellitus,4 Crohn’s
disease,5 ulcerative colitis,5 lymphoma,6 and allergic disorders.7
The American Academy of Pediatrics (AAP) recommends
exclusive breastfeeding for the first six months of life, continuing
to a year or beyond with the addition of solid food at 6 months of
age.8 In Canada, approximately 80% of new mothers initiate
breast-feeding,9 while 30-40% are still nursing 6 months
postpartum.10 Corresponding US figures are 64% and 29%,
respectively.11
breastfeeding by the AAP. Caution may be in order in when
prescribing erythromycin to lactating mothers of newborns
however, because of recent reports of pyloric stenosis in neonates
treated with erythromycin.17,18 It has been reported that the
calcium present in breast milk may inhibit absorption of the small
amount of tetracycline, however, use of tetracycline while breastfeeding is not advised, because the threshold for its affect on teeth
and bone is unknown.14 Topical clindamycin is partially absorbed
through the skin and small amounts may pass into breast milk. No
problems have been reported in nursing infants with maternal use
of topical clindamycin,19 although bloody diarrhea was reported
in an infant of a mother on intravenous clindamycin.20 No
adverse effects on the infant have been reported with use of
topical metronidazole during lactation, however the manufacturer
advises against its use while breast-feeding.21
The use of prescription and over-the-counter (OTC) medications
is common for nursing mothers. In one study of 14,000 pregnant
or breastfeeding women, 79% of them took at least one
medication, while on average, 3.3 drugs were taken while
breastfeeding.12 Fortunately, severe adverse effects resulting
from the presence of common medications in breast milk are
uncommon. Of 838 infants exposed to medications through
breast milk, 11% experienced minor reactions, and no serious
reactions requiring medical attention or cessation of
breastfeeding occurred.13 The adverse reactions that did occur
were consistent with the known pharmacological affects of the
causative agent.
Terbinafine and itraconazole are both excreted in breast milk, and
the safety of their use during lactation is unknown. Parenteral
fluconazole has been safely used in neonates with candidiasis,
and based on this, Briggs states that its use is probably safe
during breast-feeding.16 The manufacturers of these three
antifungals do not recommend their use while breast-feeding and
the AAP has no rating.22,23,24
Transfer of Medications into Breast Milk
Antihistamines
A number of factors determine the passage of a drug into breast
milk. These include characteristics of the mother, the infant and
the drug itself. In general, drugs given to a nursing mother reach
the infant in much lower concentrations than those given to a
pregnant woman reach the fetus.14
Small amounts of antihistamines are excreted in breast milk.
Their use is not recommended during breast-feeding because
infants may be more susceptible to their adverse effects,
particularly drowsiness and irritability.19,25 Antihistamines may
also reduce milk production in some women.
Antimicrobials
Immunomodulators
Penicillins and cephalosporins are present only in trace amounts
in breast milk, and are compatible with breast-feeding.15 Their
use is associated with a remote risk of alterations in
gastrointestinal flora causing diarrhea and allergic sensitization of
the infant.16 Erythromycin is excreted into breast milk, but no
adverse effects in infants exposed to this drug in breast milk have
been reported,16 and it is considered compatible with
Both cyclosporine and methotrexate are excreted into breast milk,
and considered contraindicated during breast-feeding by the AAP
because of the possibility of immunosuppression, neutropenia,
carcinogenesis and unknown affects on growth.15
Hydroxychloroquine is excreted in small amounts in breast milk
and because of its slow elimination rate and potential to
accumulate to toxic levels in infants, caution is advised with daily
Acyclovir is considered safe during breast-feeding.15,16
Experience with the use of valacyclovir and famciclovir during
human lactation is lacking.16
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 7 No. 3 • March 2002
5
dosing.26 The AAP, however, considers hydroxychloroquine to be
compatible with breast-feeding.15 Tacrolimus is excreted in human
milk. Topical tacrolimus is not recommended by the manufacturer
during breastfeeding, because of the potential for systemic
absorption with topical use.27 The AAP does not rate tacrolimus.
Antipsoriatics
It is not known whether calcipotriol is excreted into breast milk.
The manufacturer recommends its use only if the anticipated
benefits outweigh the potential risks.28 Methoxsalen excretion in
human milk is also unknown and although there are no reports of
adverse effects with its use during lactation, the manufacturer
recommends use only when the probable benefits outweigh the
potential risks.29 Briggs recommends that breast-feeding be
interrupted for at least 24 hours after administration of the drug
because of its photosensitizing affect.16
Steroids
Trace amounts of prednisone and its metabolite prednisolone are
excreted in breast milk.16 The AAP considers prednisone to be
compatible with breastfeeding.15 Hypertension was reported in
the infant of a woman who used a corticosteroid on the nipples.30
Use of topical corticosteroids on the breasts prior to nursing
should be avoided.
Because estrogen decreases the quantity and protein content of
breast milk, the use of combination oral contraceptive pills
should be avoided whenever possible in lactating mothers,
especially in the first two months postpartum.31
Scabicides
It is not known if permethrin is excreted in human milk. Citing
evidence of teratogenicity in animals, the manufacturer
recommends temporary discontinuation of nursing or avoidance
during lactation.32 Anderson considers its use to be safe during
lactation.33
Analgesics
Significant salicylate levels have been found in breast-fed neonates
of mothers taking salicylates, raising concerns about metabolic
acidosis, bleeding, altered pulmonary circulation and Reye’s
syndrome.26 There is one report of salicylate intoxication in an
infant exposed through her mother’s milk.34 The AAP
recommends that it be used with caution in nursing mothers.15
Widespread use of topical salicylic acid should be avoided because
of the potential for significant systemic absorption. Of the
nonsteroidal anti-inflammatories, ibuprofen and flurbiprofen have
the best documentation of safety during lactation because they do
not enter breast milk in significant quantities.14 The AAP
considers ibuprofen, indomethacin, and naprosyn to be compatible
with breast-feeding.15 There is one case report of seizures in an
infant exposed to indomethacin through breast milk.35
Antiacne Agents
There have been no reports of adverse effects from use of topical
benzoyl peroxide and topical tretinoin during lactation.19 It is not
known whether adapalene or tazarotene pass into breast milk.
The manufacturers recommend caution with their use during
Class of
Medication
Choices Compatible
with Breast-Feeding
Comment
Antibiotics
Penicillins, Cephalosporins,
Erythromycin (caution with neonates),
Topical clindamycin, Topical
metronidazole
Possibility of diarrhea, thrush and allergic sensitization of the
infant
Antivirals
Acyclovir
Considered safe during breastfeeding
Antifungals
Fluconazole
Manufacturer does not recommend its use during lactation.
Antihistamines
None
Infants may be more susceptible to their adverse effects
Immunomodulators
Hydroxychloroquine
Methotrexate and cyclosporine are not recommended
Antipsoriatics
Calcipotriol
No reports of adverse effects
Steroids
Prednisone
Topical corticosteroids
Combination oral contraceptives
Trace amounts of prednisone are present in breast milk.
Avoid use of topical corticosteroids on breasts prior to nursing.
Delay use until milk production established; may reduce milk
production.
Scabicides
Permethrin
Probably safe; consider temporary discontinuation of
breastfeeding.
Analgesics
Ibuprofen
Acetaminophen15
Ibuprofen does not enter breast milk in significant amounts.
Antiacne
Benzoyl peroxide
Topical tretinoin
No reports of adverse effects
Table 1: Compatibility of some dermatologic drugs during breastfeeding.
6
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 7 No. 3 • March 2002
lactation.36,37 Spironolactone may pass into breast milk, but has
not been reported to cause problems in nursing babies.19 The
AAP considered spironolactone to be compatible with breastfeeding,15 although its use during lactation is not recommended
by the manufacturer.38
14. Howard CR, Lawrence RA. Drugs and breastfeeding. Clin Perinatology 1999;
26: 447-478.
15. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and
other chemicals into human milk. Pediatrics 1994; 93:137-150.
16. Briggs GG, Freeman RK, Yaffee SL. Drugs in pregnancy and lactation, Fifth
Edition, Baltimore: Williams and Wilkins, 1998.
17. Anonymous. Erythromycin – induced pyloric stenosis in infants. Prescrire
International 2001; 10:16.
Conclusion
When considering a medication for a lactating mother, the
benefits of breast-feeding need to be weighed against the
potential risk of exposure of the infant to the drug in question.
For the majority of dermatological conditions, alternatives that
are compatible with breast-feeding are available, or treatment can
be safely postponed until lactation is completed.
18. Honein MA, Paulozzi LJ, Himelright IM, et al. Infantile hypertrophic pyloric
stenosis after pertussis prophylaxis with erythromycin: A case review and cohort
study. Lancet 1999; 354: 2101-2105.
References
22. Terbinafine product monograph, Novartis Pharmaceuticals Canada Inc., Dorval,
QC, Canada, 2002.
19. USP- DI. Drug Information for the Health Care Professional, Vol. 1, Nineteenth
Edition, Taunton, MA: Rand McNally, 1999.
20. Mann CF. Clindamycin and breast-feeding. Pediatrics 1980; 66:1030-1031.
21. Metronidazole product monograph, Galderma Canada Inc., Thornhill, ON,
Canada, 1996.
1.
Popkin BM, Adair L, Akin JS, et al. Breast-feeding and diarrheal morbidity.
Pediatrics 1990; 86: 874-882.
2.
Beaudry M., Dufour R, Marcoux S. Relation between infant feeding and
infections during the first six months of life. J Pediatr 1995; 126: 191-197.
3.
Ford RPK, Taylor BJ, Mitchell EA, et al. Breastfeeding and the risk of sudden
infant death syndrome. Int J Epidermiol 1993; 22: 885-890.
4.
Mayer EJ, Hamman RF, Gay EC, et al. Reduced risk of IDDM among breast-fed
children. Diabetes 1988; 37:1625-1632.
5.
Rigas A, Rigas B, Glassman M, et al. Breast-feeding and maternal smoking in
the etiology of Crohn’s disease and ulcerative colitis in childhood. Ann
Epidemiol 1993; 3:387-392.
27. Tacrolimus product monograph, Fujisawa Canada Inc., Markham, ON,
Canada, 2001.
6.
Davis MK, Savitz DA, Graubard BI. Infant feeding and childhood cancer. Lancet
1988; 2:365-368.
29. Methoxsalen product monograph, ICN Canada Ltd. Montreal, QC, Canada, 1992.
7.
Gdalevich M, Mimouni D, David M, Mimouni M. Breast-feeding and the onset
of atopic dermatitis in childhood: A systematic review and meta-analysis of
prospective studies. J Am Acad Dermatol 2001; 45: 520-527.
8.
American Academy of Pediatrics, Work Group on Breastfeeding. Breastfeeding
and the use of human milk. Pediatrics 1997; 100: 1035-1039.
9.
Barber CM, Abernathy T, Steinmetz B, Charlebois J. Using a breastfeeding
prevalence survey to identify a population for targeted programs. Can J Public
Health 1997; 88:242-245.
23. Itraconazole product monograph, Janssen-Ortho Inc., Toronto, ON, Canada, 2002.
24. Fluconazole product monograph, Pfizer Canada Inc., Kirkland, QC, Canada, 2001.
25. Reed BR, Dermatologic drug use during pregnancy and lactation. Dermatol
Clinics 1997; 15:197-202.
26. Janssen NM, Genta MS. The effects of immunosuppressive and antiinflammatory medications on fertility, pregnancy and lactation. Arch Intern Med
2000; 160:610-619.
28. Calcipotriol product monograph, Leo Pharma Inc., Thornhill, ON, Canada, 2001.
30. DeStefano P, Bongo C, Borgna – Pignatti C, et al. Factitious hypertension with
mineralocorticoid excess in infants. Helv Paediatr Acta 1983; 38:185-189.
31. Spencer JP,Gonzalez LS, Barnhart DJ.
mother. Am Fam Phys 2001; 64:119-126.
Medications in the breast-feeding
32. Permethin product monograph, Glaxo Smith Kline,Mississauga, ON, Canada, 2002.
33. Anderson PO. Drug use during breast-feeding. Clin Pharm 1991; 10:594-624.
34. Clark JH, Wilson WG. A 16-day-old breast-fed infant with metabolic acidosis
caused by salicylate. Clin Pediatr 1981; 20:53-54.
10. Bourgoin G, Lahaie N, Rheaume B, et al. Factors influencing the duration of
breastfeeding in the Sudbury region. Can J Public Health 1997; 88: 238-241.
35. Eeg-Olofsson O,Malmros I, Elwin CE, Steen B. Convulsions in a breast-fed
infant after maternal indomethacin. Lancet 1978; 2:215.
11. Ryan AS. The resurgence of breastfeeding in the United States. Pediatrics
1997; 99:E12.
36. Adapalene product monograph, Galderma Canada Inc., Thornhill, ON,
Canada, 2002.
12. Collaborative Group on Drug Use in Pregnancy. Medication during pregnancy:
An intercontinental cooperative study. Int J Gynecol Obstet 1992; 39:185–196.
37. Tazarotene product monograph, Allergan, Markham, ON, Canada, 2001.
13. Ito S, Blajchman A, Stephenson M, et al. Prospective follow-up of adverse
reactions in breastfed infants exposed to maternal medication. Am J Obstet
Gynecol 1993; 168:1393-1399.
38. Spironolactone product monograph, Pharmacia Canada Inc., Mississauga, ON,
Canada, 2001.
WE ’RE ON THE NET! www.skincareguide.com
————— INDUSTRY NEWS —————
Schering-Plough Recalls Specific Lots of Claritin-D 12-hour Tablets
In February 2002, Shering-Plough announced a voluntary recall of specific lots of Claritin-D® 12-hour (5mg loratidine/120mg pseudoephedrine sulfate)
tablets directed to wholesale accounts and retail pharmacies. These products were manufactured between August 1999, and June 2001. They are indicated
for the relief of symptoms of seasonal allergic rhinitis.
Schering-Plough as part of its standard quality-control procedures conducted stability testing of specific lots of this product including dissolution tests to
determine the rate that tablets dissolve and the amount of active ingredients released. Test results indicated that some tablets in these lots did not demonstrate
full release of pseudoephedrine at the 5th hour per specification, although be 25 minutes later all tested samples met specifications for releasing the
decongestant component. The company believes that this short delay poses no medical risk to patients.
This recall is being conducted with the knowledge of the US FDA.
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 7 No. 3 • March 2002
7
Update on Drugs
Class
Name/Company
Approval Dates and Comments
Antiviral Agent
Naturally-Derived Alpha
Interferon
Viragen
The Swedish Regulatory Authorities approved expanded use in January
2002, to include the treatment of patients afflicted with any and all
diseases in which patients were or became resistant to treatments using
recombinant (synthetic) interferon. Recombinant interferons usually
contain only one subtype of interferon as compared to multiple
subtypes in naturally derived interferon, which is produced by human
white blood cells.
HIV/AIDS
Efavirenz
Sustiva®
Bristol-Myers Squibb
The US FDA approved a new one-tablet 600mg. formulation in
February 2002, of this non-nucleoside reverse transcriptase inhibitor
used in combination treatment for HIV. The new formulation will
provide doctors with the option of prescribing one 600mg. tablet once
daily instead of three 200mg. capsules once daily.
Oral
Contraceptive
Estradiol/Levonorgestrel
Alesse®
Wyeth-Ayerst Canada
TPP – Canada approved this birth control pill in January 2002, for the
treatment of moderate acne in women.
Oncologic
Agent
HSPPC-96
Oncophage®
Antigenics
The US FDA granted fast-track designation in February 2002, for this
cancer vaccine for the treatment of metastatic melanoma.
HIV/AIDS
Tenofovir Disoproxil Fumerate
Viread®
Gilead Sciences
The EMEA granted marketing approval in all 15 member states of the
European Union in February 2002, for use in combination with other
antiretroviral agents for the treatment of HIV infection in patients who
are experiencing early virological failure.
Antihistamine
Desloratidine
Clarinex® 5mg. Tablets
Schering-Plough
The US FDA approved additional indications for this antihistamine
in February 2002, to treat chronic idiopathic urticaria and
symptoms of allergies caused by indoor and outdoor allergens in
adults and children >12 years of age.
Drug News
HIV/AIDS
Many scientists have believed that HIV acts to deplete its primary target, CD4+ T-cells by blocking new Tcell production. According to a report from the US National Institutes of Health, two independent studies
demonstrated that HIV does not block such production, but acts to accelerate the division of existing Tcells. Consequently, the increases in CD4+ T-cell counts seen following highly active antiretroviral therapy
(HAART) are not due to a boost in the production of new T-cells. Instead, they are caused by a slowdown
in the loss of existing T-cells.
Sunscreens
According to an article published in the Journal of the American Academy of Dermatology* sunscreen
should be reapplied 15-30 minutes after sun exposure begins for maximum benefit. An individual who
does this will have 15-40% less exposure to ultraviolet rays than someone who waits for 2 hours before
reapplying sunscreen.
*J Amer Acad Dermatol 45:882-5 (2001).
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the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and
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