A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Retin A Warnings, Precautions, Pregnancy, Nursing, Abuse - Tretinoin (topical)
Retin A Warnings, Precautions, Pregnancy, Nursing, Abuse - Tretinoin (topical)
WARNINGS
Gel
Gels are flammable. Keep away from heat
and flame. Keep tube tightly closed.
Emollient Cream
- Tretinoin emollient
cream is a dermal irritant,
and the results of continued irritation
of the skin for greater
than 48 weeks in chronic, long term
use are not known. There is evidence
of atypical changes
in melanocytes and keratinocytes, and of increased dermal elastosis
in some patients treated with tretinoin
emollient cream
for longer than 48 weeks. The significance of these findings is
unknown.
- Safety and effectiveness
of tretinoin emollient
cream in individuals
with moderately or heavily pigmented
skin have not been established.
- Tretinoin emollient
cream should not be
administered if the patient is also taking drugs known to be photosensitizers
(e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines,
sulfonamides) because of the possibility of augmented phototoxicity.
Because of heightened burning susceptibility, exposure
to sunlight (including sunlamps) should be avoided or minimized
during use of tretinoin
emollient cream. Patients must be warned to use sunscreens (minimum
SPF of 15) and protective clothing
when using tretinoin
emollient cream. Patients
with sunburn should be advised not to use tretinoin
emollient cream
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 tretinoin emollient
cream and assure that
the precautions outlined in the PATIENT PACKAGE INSERT, Emollient
Cream are observed.
Tretinoin emollient
cream should be kept out
of the eyes, mouth, angles of the nose, and mucous
membranes. Topical use may cause
severe local erythema,
pruritus, burning, stinging, and peeling
at the site of application.
If the degree of local
irritation warrants,
patients should be directed to use less medication, decrease the
frequency of application, discontinue use temporarily, or discontinue
use altogether.
Tretinoin has been reported to cause
severe irritation
on eczematous skin and should be used only with utmost caution in
patients with this condition.
Application of larger amounts of medication
than recommended will not
lead to more rapid or better results, and marked redness, peeling,
or discomfort may occur.
PRECAUTIONS
General
Cream, Gel, Liquid, and Gel with Microspheres: If
a reaction suggesting sensitivity or chemical
irritation occurs,
use of the medication should be discontinued. Tretinoin acne
treatment should be
kept away from the eyes, the mouth, the paranasal
creases, and mucous membranes.
Topical use may induce severe local
erythema and peeling
at the site of application.
The skin of certain individuals
may become excessively dry, red, swollen, or blistered. If the degree
of local irritation
warrants, patients should be directed to temporarily use the medication
less frequently, discontinue use temporarily, or discontinue use
altogether. Tretinoin has been reported to cause
severe irritation
on eczematous skin
and should be used with utmost caution in patients with this condition.
Efficacy at reduced frequencies of application has not been established.
Exposure to sunlight, including sunlamps, should be minimized during
the use of tretinoin, and patients with sunburn
should be advised not to use the product
until fully recovered because of heightened susceptibility to sunlight
as a result of the use of tretinoin. Patients who may be required
to have considerable sun exposure due to occupation
and those with inherent
sensitivity to the sun should exercise particular caution. Use of
sunscreen products
(SPF 15) and protective clothing over treated areas is recommended
when exposure cannot
be avoided. Weather extremes, such as wind or cold, also may be
irritating to patients under treatment
with tretinoin.
Emollient Cream: Tretinoin emollient
cream should only be used
as an adjunct to a comprehensive
skin care and sun avoidance
program. (See INDICATIONS AND
USAGE).
If a drug sensitivity,
chemical irritation,
or a systemic adverse
reaction develops, use of tretinoin
emollient cream
should be discontinued.
Weather extremes, such as wind or cold, may be more irritating
to patients using tretinoin
emollient cream.
Information for the Patient
See PATIENT PACKAGE INSERT,
Cream, Gel, Liquid and Gel with Microspheres and PATIENT
PACKAGE INSERT, Emollient Cream.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Cream, Gel, Liquid, and Emollient Cream: In
a lifetime dermal study in CD-1 mice, at 100 and 200 times the average
recommended human topical
clinical dose, a few
skin tumors in the female
mice and liver tumors in male
mice were observed. The biological
significance of these findings is not clear because they occurred
at doses that exceeded the dermal maximally tolerated dose
(MTD) of tretinoin
and because they were within the background natural
occurrence rate for these
tumors in this strain of mice. There was no evidence
of carcinogenic
potential when tretinoin
was administered topically at a dose
5 times the average
recommended human topical clinical
dose. For purposes of comparisons of the animal
exposure to human exposure,
the “recommended human
topical clinical
dose” is defined as 500 mg
of 0.05% tretinoin
cream and 1.0 g of 0.025%
tretinoin cream or
gel applied daily to a 50
kg person.
In a chronic, two-year bioassay of Vitamin A acid
in mice performed by Tsubura and Yamamoto, generalized amyloid
deposition was reported
in all groups in the basal
layer of the Vitamin A
treated skin. In CD-1 mice,
a similar study reported hyalinization
at the treated skin sites
and the incidence of this finding was 0/50, 3/50, 3/50 and 2/50
in male mice and 1/50,
0/50, 4/50, and 2/50 in female
mice from the vehicle
control, 0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg groups, respectively.
Studies in hairless albino
mice suggest that tretinoin
may enhance the tumorigenic potential
of carcinogenic
doses of UVB and UVA light
from a solar simulator. In
other studies, when lightly pigmented
hairless mice treated with tretinoin
were exposed to carcinogenic
doses of UVA/UVB light, the incidence
and rate of development
of skin tumors were either
reduced or no effect
was seen. Due to significantly different experimental conditions,
no strict comparison of these disparate
data is possible at this time. Although the significance of these
studies to humans is not clear, patients should minimize exposure
to sun.
The mutagenic potential
of tretinoin was evaluated
in the Ames assay and in the in vivo mouse
micronucleus assay,
both of which were negative.
Dermal Segment I and III studies with tretinoin
have not been performed in any species. In
oral Segment I and Segment
III studies in rats with tretinoin, decreased survival
of neonates and growth
retardation were
observed at doses in excess of 2 mg/kg/day (>400 times the average
recommended human topical
clinical dose).
Gel with Microspheres: In
a lifetime dermal study in CD-1 mice, there was no evidence
of carcinogenic
potential when tretinoin
was administered topically at a dose
of 1.25 times the recommended clinical dose. For purposes of comparisons
of animal exposure
to human exposure, the
“recommended human clinical
dose” is defined as 1.0 g of 0.1% gel
with microspheres applied to a 50 kg
person. In the same study,
at 25 and 50 times the recommended human
clinical dose, the
dermal maximum tolerated
dose (MTD) of tretinoin
was exceeded, yet there were no biologically significant findings.
Dermal carcinogenicity testing has not been performed with the
microspheres or gel with
microspheres. The components of the microspheres have not demonstrated
carcinogenic potential
when evaluated individually. The components of the microspheres
have shown mutagenic and teratogenic
potential with chronic
exposure at doses several orders of magnitude
higher than the human
clinical dose. The very low levels of these components in microsponge
polymer (<25 ppm),
used in the drug formulation,
indicate an insignificant human
risk under usage conditions.
Studies in hairless albino
mice suggest that tretinoin
may enhance the tumorigenic potential
of ultraviolet (UV)
light from a solar
simulator. In other studies, when lightly pigmented
hairless mice treated with tretinoin were exposed to carcinogenic
doses of UVA/UVB light, the incidence
and rate of development
of skin tumors were either
reduced or no effect
was seen. Due to significantly different experimental conditions,
no strict comparison of these disparate
data is possible. Although the significance of these studies to
humans is not clear, patients should avoid or minimize exposure
to sun.
Tretinoin had no mutagenic potential
when evaluated in the Ames assay and the in vivo mouse
micronucleus assay.
The microspheres had no mutagenic potential
when evaluated in the Ames assay.
Dermal fertility and perinatal
development studies
with gel with microspheres
have not been performed in any species. In
oral fertility and perinatal
development studies in rats with tretinoin, decreased survival
of neonates and growth
retardation were
observed at doses in excess of 2 mg/kg/day (>100 times the recommended
human clinical
dose which is 1.0 g/50
kg adult).
Pregnancy, Teratogenic Effects, Pregnancy Category C
Oral: Oral tretinoin
has been shown to be teratogenic in rats, mice, rabbits, hamsters,
and subhuman primates. It was teratogenic and fetotoxic
in rats when given orally in doses 1000 times the average recommended
human topical
clinic dose. However,
variations in teratogenic doses among various strains of rats have
been reported. In the cynomolgus
monkey, which metabolically is closer to humans for tretinoin
than other species examined, fetal
malformations were reported at oral
doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day
(1000 times the average
recommended human topical
clinical dose), although
increased skeletal variations were observed at all doses. Dose-related
increased embryolethality and abortion
were reported. Similar results have also been reported in pigtail
macaques.
Topical: Topical tretinoin
in animal teratogenicity
tests has generated equivocal results. There is evidence
for teratogenicity (shortened or kinked tail) of topical
tretinoin in Wistar
rats at doses greater than 1 mg/kg/day (200 times the recommended
human topical
clinical dose). Anomalies
(humerus: short 13%, bent 6%; os
parietal incompletely
ossified 14%) have also been reported in rats when 10 mg/kg/day
was dermally applied.
Tretinoin has not been shown to be teratogenic
in rats and rabbits when given in doses of 100 and 320 times the
topical human
dose, respectively (assuming a 50 kg
adult applies 250 mg
of 0.1% cream topically).
However, at these topical
doses, delayed ossification
of a number of bones
occurred in both species. These changes may be considered variants
of normal development
and are usually corrected after weaning.
Topical Tretinoin Gel 0.025%: Tretinoin gel
has been shown to be teratogenic
in rabbits when given in doses 364 times the topical human dose
for gel (assuming a 50 kg
adult applies 1.0 g of
0.025% gel topically). In
this study, increased incidence
of left palate
and hydrocephaly was reported in the tretinoin-treated animals.
In one study in New Zealand
White rabbits treated with gel
where doses of 0.2, 0.5 and 1.0 mg/kg/day of tretinoin
were administered topically for 24 hours a day to pregnant rabbits,
there appeared to be an association
of the dosages with increased incidences of domed head
and hydrocephaly in some of the fetuses, typical of retinoid-induced
fetal malformations in
this species.
There are other reports, in New Zealand White rabbits with doses
of approximately 80 times the recommended human
topical clinical
dose, of an increased incidence
of domed head and hydrocephaly,
typical of retinoid-induced
fetal malformations in this species. No abnormalities were observed
at 0.2 mg/kg/day, 10 times the normal
human topical
dose of tretinoin. In a
repeat study of the highest topical
dose (1.0 mg/kg/day) in
pregnant rabbits, these effects were not seen. Other pregnant
rabbits exposed to six hours of 0.5 or 1.0 mg/kg/day tretinoin
with proper controls to prevent oral ingestion, did not wshow
any teratogenic
effects up to 50 times (1.0 mg/kg/day) the human
topical dose. In
addition, topical tretinoin
in non gel with microspheres formulations was not teratogenic
in rats and rabbits when given in doses of 250 and 80 times the
recommended human clinical
topical dose, respectively, (assuming a 50 kg
adult applied a daily
dose of 1.0 g of 0.1% gel
topically). At these topical
doses, however, delayed ossification of several bones occurred in
rabbits. In rats, a dose-dependent
increase of supernumerary ribs was observed.
When given subcutaneously to rabbits, tretinoin
was teratogenic
at 2 mg/kg/day but not at 1 mg/kg/day. These doses are approximately
400 and 200 times, respectively, the human
topical dose
of tretinoin gel,
0.025% (assuming a 50 kg
adult applies 1.0 g of
0.025% gel or cream
topically).
In contrast, several well-controlled animal
studies have shown that dermally applied tretinoin
was not teratogenic
at doses of 100 and 200 times the recommended human
topical clinical
dose, in rats and rabbits, respectively.
Preclinical Toxicity Studies: In
male mice treated topically
with gel with microspheres
at 0.5, 2.0 or 5.0 mg/kg/day tretinoin
(25, 100 or 250 times the recommended human
dose) for 90 days, a reduction
in testicular weight, but with no pathological changes, was observed
at 100 and 250 times the human
topical dose. Similarly,
in female mice, there
was a reduction in
ovarian weights, but
without any underlying pathological changes, at 5.0 mg/kg/day (250
times the recommended human
dose). In this study there
was a dose-related increase in the plasma
concentration
of tretinoin 4 hours after the first dose. A separate toxicokinetic
study in mice indicates that systemic
exposure is greater
after topical application
to unrestrained animals than to restrained animals, suggesting that
the systemic toxicity observed is probably related to oral
ingestion. Male and female
dogs treated with gel with
microspheres at 0.2, 0.5 or 1.0 mg/kg/day tretinoin (10, 25 or 50
times the human dose,
respectively) for 90 days showed no evidence
of reduced testicular
or ovarian weights or
pathological changes.
There are no adequate and well-controlled studies in pregnant
women. Tretinoin should be used during pregnancy only if the potential
benefit justifies the potential
risk to the fetus.
There have been isolated reports of birth
defects among babies born to women exposed to topical
tretinoin during pregnancy.
To date, there have been no adequate and well-controlled studies
performed in pregnant women, and the teratogenic
blood level of tretinoin
is not known. However, a well-conducted retrospective cohort
study of babies born to women exposed to topical
tretinoin during the
first trimester of
pregnancy found no excess birth defects among these babies when
compared to babies born to women in the same cohort
who were not similarly exposed. Nevertheless, topical tretinoin
should be used during pregnancy only if the potential
benefit justifies the potential
risk to the fetus.
With widespread use of any drug, a small number
of birth defect
reports associated temporally with the administration
of the drug would be expected
by chance alone. Thirty
cases of temporally-associated congenital
malformations have been reported during two decades of clinical
use of another formulation of topical
tretinoin (cream,
gel and liquid). Although
no definite pattern of teratogenicity and no causal association
has been established from these cases, 5 of the reports describe
the rare birth defect
category holoprosencephaly (defects associated with incomplete midline
development of the
forebrain). The significance of these spontaneous
reports in terms of risk
to the fetus is not known.
Nonteratogenic Effects: Dermal tretinoin
has been shown to be fetotoxic
in rabbits when administered in doses 100 times the recommended
topical human clinical
dose. Oral tretinoin
has been shown to be fetotoxic in rats when administered in doses
500 times the recommended topical
human clinical dose. There are, however, no adequate and well-controlled
studies in pregnnt women. Tretinoin should not be used during pregnancy.
Nursing Mothers
It is not known whether this drug
is excreted in human milk.
Because many drugs are excreted in human
milk, caution should be exercised when tretinoin is administered
to a nursing woman.
Pediatric Use
Gel with Microspheres: Safety and effectiveness
in children below the age
of 12 have not been established.
Emollient Cream: Safety and effectiveness
in patients less than 18 years of age
have not been established.
Geriatric Use
Gel with Microspheres and Emollient Cream: Safety
and effectiveness in a geriatric population
(older than 50 years) have not been established.
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