WARNINGS
Pregnancy Category X. See CONTRAINDICATIONS section. Women of child-bearing
potential should be warned of the potential risk and use adequate birth-control
measures when TAZORAC® Gel is used. The possibility that
a woman of childbearing potential is pregnant at the time of institution of
therapy should be considered. A negative result for pregnancy test having a
sensitivity down to at least 50 mIU/mL for hCG should be obtained within 2 weeks
prior to TAZORAC® Gel therapy, which should begin during
a normal menstrual period.
PRECAUTIONS
General:
TAZORAC® Gel should be applied only to the
affected areas. For external use only. Avoid contact with eyes, eyelids, and
mouth. If contact with eyes occurs, rinse thoroughly with water. The safety of
use of TAZORAC® Gel over more than 20% of body surface
area has not been established in psoriasis or acne.
Retinoids should not be used on eczematous skin, as they may cause severe
irritation.
Because of heightened burning susceptibility, exposure to sunlight (including
sunlamps) should be avoided unless deemed medically necessary, and in such
cases, exposure should be minimized during the use of TAZORAC® Gel. Patients must be warned to use sunscreens (minimum SPF
of 15) and protective clothing when using TAZORAC® Gel.
Patients with sunburn should be advised not to use TAZORAC® Gel until fully recovered. Patients who may have considerable
sun exposure due to their occupation and those patients with inherent
sensitivity to sunlight should exercise particular caution when using
TAZORAC® Gel and ensure that the precautions outlined in
the Information for Patients subsection are observed.
TAZORAC® Gel should be administered with caution if
the patient is also taking drugs known to be photosensitizers (e.g., thiazides,
tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the
increased possibility of augmented photosensitivity.
Some individuals may experience excessive pruritus, burning, skin redness or
peeling. If these effects occur, the medication should either be discontinued
until the integrity of the skin is restored, or the dosing should be reduced to
an interval the patient can tolerate. However, efficacy at reduced frequency of
application has not been established. Alternatively, patients with psoriasis who
are being treated with the 0.1% concentration can be switched to the lower
concentration.
Weather extremes, such as wind or cold, may be more irritating to patients
using TAZORAC® Gel.
Information for Patients:
See attached Patient Package
Insert.
Drug Interactions:
Concomitant dermatologic medications and cosmetics that have a
strong drying effect should be avoided. It is also advisable to "rest" a
patient's skin until the effects of such preparations subside before use of
TAZORAC® Gel is begun.
Carcinogenesis, Mutagenesis, Impairment of
Fertility:
A long-term study of tazarotene following oral administration of
0.025, 0.050, and 0.125 mg/kg/day to rats showed no indications of increased
carcinogenic risks. Based on pharmacokinetic data from a shorter-term study in
rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic
exposure (AUCde) in the rat equivalent to 0.32 times the
AUC0-24h observed in psoriatic patients treated with 2
mg/cm2 of tazarotene gel 0.1% (extrapolated for topical
application over 20% body surface area), and 0.38 times the maximum AUC0-24h in acne patients treated with 2 mg/cm2 of tazarotene gel 0.1% over 15% (targeted) body surface
area.
In evaluation of photo co-carcinogenicity, median time to onset of tumors was
decreased, and the number of tumors increased in hairless mice following chronic
topical dosing with intercurrent exposure to ultraviolet radiation at tazarotene
concentrations of 0.001%, 0.005%, and 0.01% in a gel formulation for up to 40
weeks.
A long-term topical application study of up to 0.1% tazarotene in a gel
formulation in mice terminated at 88 weeks showed that dose levels of 0.05,
0.125, 0.25, and 1.0 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41
weeks due to severe dermal irritation) revealed no apparent carcinogenic effects
when compared to vehicle control animals; untreated control animals were not
completely evaluated. Systemic exposure (AUC0-12h) at the
highest dose was 2.0 times the AUC0-24h observed in
psoriatic patients treated with 2 mg/cm2 of tazarotene
gel 0.1% (extrapolated for topical application over 20% body surface area), and
2.5 times the maximum AUC0-24h in acne patients treated
with 2 mg/cm 2 of tazarotene gel 0.1% over 15 %
(targeted) body surface area.
Tazarotene was found to be non-mutagenic in the Ames assay using Salmonella
and E. coli and did not produce structural
chromosomal aberrations in a human lymphocyte assay. Tazarotene was also
non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and
was non-clastogenic in the in vivo mouse micronucleus
test.
No impairment of fertility occurred in rats when male animals were treated
for 70 days prior to mating and female animals were treated for 14 days prior to
mating and continuing through gestation and lactation with topical doses of
tazarotene gel up to 0.125 mg/kg/day. Based on data from another study, the
systemic drug exposure (AUCde) in the rat would be
equivalent to 0.31 times the AUC0-24h observed in
psoriatic patients treated with 2 mg/cm2 of tazarotene
gel 0.1% (extrapolated for topical application over 20% body surface area), and
0.38 times the maximum AUC0-24h in acne patients treated
with 2 mg/cm2 of tazarotene gel 0.1% over 15 % (targeted)
body surface area.
No impairment of mating performance or fertility was observed in male rats
treated for 70 days prior to mating with oral doses of up to 1.0 mg/kg/day
tazarotene, which produced an AUCde that was 0.95 times
the AUC0-24h observed in psoriatic patients treated with
2 mg/cm2 of tazarotene gel 0.1% (extrapolated for topical
application over 20% body surface area), and 1.2 times the maximum AUC0-24h in acne patients treated with 2 mg/cm2 of tazarotene gel 0.1% over 15 % (targeted) body surface
area.
No effect on parameters of mating performance or fertility was observed in
female rats treated for 15 days prior to mating and continuing through day 7 of
gestation with oral doses of tazarotene up to 2.0 mg/kg/day. However, there was
a significant decrease in the number of estrous stages and an increase in
developmental effects at 2.0 mg/kg/day (see CONTRAINDICATIONS). This dose produced an AUC0-24h which was 1.7 times that observed in psoriatic patients
treated with 2 mg/cm2 of tazarotene gel 0.1%
(extrapolated for topical application over 20% body surface area), and 2.1 times
the maximum AUC0-24h in acne patients treated with 2
mg/cm2 of tazarotene gel 0.1% over 15% (targeted) body
surface area.
Reproductive capabilities of F1 animals, including F2 survival and
development, were not affected by topical administration of tazarotene gel to
female F0 parental rats from gestation day 16 through lactation day 20 at the
maximum tolerated dose of 0.125 mg/kg/day. Based on data from another study, the
systemic drug exposure (AUCde) in the rat would be
equivalent to 0.31 times the AUC0-24h observed in
psoriatic patients treated with 2 mg/cm2 of tazarotene
gel 0.1% (extrapolated for topical application over 20% body surface area), and
0.38 times the maximum AUC0-24h in acne patients treated
with 2 mg/cm2 of tazarotene gel 0.1% over 15% (targeted)
body surface area.
Pregnancy:
Teratogenic Effects: Pregnancy Category
X: See CONTRAINDICATIONS section. Women of
child-bearing potential should use adequate birth-control measures when
TAZORAC® Gel is used. The possibility that a woman of
childbearing potential is pregnant at the time of institution of therapy should
be considered. A negative result for pregnancy test having a sensitivity down to
at least 50 mIU/mL for hCG should be obtained within 2 weeks prior to
TAZORAC® Gel therapy, which should begin during a normal
menstrual period. There are no adequate, well-controlled studies in pregnant
women. Although there may be less systemic exposure in the treatment of acne of
the face alone due to less surface area for application, tazarotene is a
teratogenic substance, and it is not known what level of exposure is required
for teratogenicity in humans (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Nursing mothers:
After single topical doses of 14C-tazarotene to the skin of lactating rats, radioactivity was
detected in milk, suggesting that there would be transfer of drug-related
material to the offspring via milk. It is not known whether this drug is
excreted in human milk. Caution should be exercised when tazarotene is
administered to a nursing woman.
Pediatric Use:
The safety and efficacy of tazarotene have not been established
in pediatric patients under the age of 12 years.
Geriatric Use:
Of the total number of subjects in clinical studies of tazarotene
gels, 0.05% and 0.1% for plaque psoriasis, 163 were over the age of 65. Subjects
over 65 years of age experienced more adverse events and lower treatment success
rates after 12 weeks of use of TAZORAC® Gel compared with
those 65 years of age and younger. Currently there is no other reliable clinical
experience on the differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals can not be ruled
out. Tazarotene gel for the treatment of acne has not been clinically evaluated
in persons over the age of 65.
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