CONTRAINDICATIONS
This drug is contraindicated in individuals with a history of sensitivity reactions to any of
its components. It should be discontinued if hypersensitivity to any of its ingredients is
noted.
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 show
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.