Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies to determine the carcinogenic potential of TRI-LUMA® Cream have not been conducted.
Studies of hydroquinone in animals have demonstrated some evidence of carcinogenicity. The carcinogenic potential of hydroquinone in humans is unknown.
Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources.
Mutagenicity studies were not conducted with this combination of active ingredients. Published studies have demonstrated that hydroquinone is a mutagen and a clastogen. Treatment with hydroquinone has resulted in positive findings for genetic toxicity in the Ames assay in bacterial strains sensitive to oxidizing mutagens, in in vitro studies in mammalian cells, and in the in vivo mouse micronucleus assay. Tretinoin has been shown to be negative for mutagenesis in the Ames assay. Additional information regarding the genetic toxicity potential of tretinoin and of fluocinolone acetonide is not available.
A dermal reproductive fertility study was conducted in SD rats using a 10-fold dilution of the clinical formulation. No effect was seen on the traditional parameters used to assess fertility, although prolongation of estrus was observed in some females, and there was a trend towards an increase in pre-and post-implantation loss that was not statistically significant. No adequate study of fertility and early embryonic toxicity of the full-strength drug product has been performed. In a six-month study in minipigs, small testes and severe hypospermia were found when males were treated topically with the full strength drug product.
Pregnancy Category C: TRI-LUMA® Cream contains the teratogen, tretinoin, which may cause embryo-fetal death, altered fetal growth, congenital malformations, and potential neurologic deficits. It is difficult to interpret the animal studies on teratogenicity with TRI-LUMA® Cream, because the availability of the dermal applications in these studies cannot be assured, and comparison with clinical dosing is not possible. There are no adequate and well-controlled studies in pregnant women. TRI-LUMA® Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Summary Statement on Teratogenic Risk
TRI-LUMA® Cream contains the teratogen, tretinoin, which may cause embryo-fetal death, altered fetal growth, congenital malformations, and potential neurologic deficits. However, human data have not confirmed an increased risk of these developmental abnormalities when tretinoin is administered by the topical route.
Clinical considerations relevant to actual or potential inadvertent exposure during pregnancy:
In clinical trials involving TRI-LUMA® Cream in the treatment of facial melasma, women of child-bearing potential initiated treatment only after having had a negative pregnancy test and used effective birth control measures during therapy. Thus, safety and efficacy of TRI-LUMA® Cream in pregnancy has not been established. In general, use of drugs should be reduced to a minimum in pregnancy. If a patient has been inadvertently exposed to TRI-LUMA® Cream in pregnancy, she should be counseled on the risk of teratogenesis due to this exposure. The risk of teratogenesis due to topical exposure to TRI-LUMA® Cream may be considered low. However, exposure during the period of organogenesis in the first trimester is theoretically more likely to produce adverse outcome than in later pregnancy.
The prescriber should have the following clinical considerations in making prescribing decisions:
The potential developmental effects of tretinoin are serious but the risk from topical administration is small.
Exposure during the period for organogenesis in the first trimester is theoretically more likely to produce adverse outcome than in later pregnancy.
The risk to the mother for not treating melasma should be determined by the physician with the patient. Mild forms of melasma may not necessarily require drug treatment. TRI-LUMA® Cream is indicated for the treatment of moderate to severe melasma. Melasma may also be managed with other forms of therapy such as topical hydroquinone in the presence of sunlight avoidance, or stopping the use of hormonal birth control methods. If possible, delaying treatment with TRI-LUMA® Cream until after delivery should be considered.
There are no adequate and well-controlled studies in pregnant women. TRI-LUMA® Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Data Discussion: Tretinoin is considered to be highly teratogenic upon systemic administration. Animal reproductive studies are not available with topical hydroquinone. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.
1. Human Data.
In clinical trials involving TRI-LUMA® Cream in the treatment of facial melasma, women of child-bearing potential initiated treatment only after having had a negative pregnancy test, and used effective birth control measures during therapy. However, 15 women became pregnant during treatment with TRI-LUMA® Cream. Of these pregnancies, 6 resulted in healthy babies, 6 outcomes still unknown, 2 were reported as miscarriages, and 1 case was lost to follow-up.
Epidemiologic studies have not confirmed an increase in birth defects associated with the use of topical tretinoin. However, there may be limitations to the sensitivity of epidemiologic studies in the detection of certain forms of fetal injury, such as subtle neurologic or intelligence deficits.
2. Animal Data.
In a dermal application study using TRI-LUMA® Cream in pregnant rabbits, there was an increase in the number of in utero deaths and a decrease in fetal weights in litters from dams treated topically with the drug product.
In a dermal application study in pregnant rats treated with TRI-LUMA® Cream during organogenesis there was evidence of teratogenicity of the type expected with tretinoin. These morphological alterations included cleft palate, protruding tongue, open eyes, umbilical hernia, and retinal folding or dysplasia.
In a dermal application study on the gestational and postnatal effects of a 10-fold dilution of TRI-LUMA® Cream in rats, an increase in the number of stillborn pups, lower pup body weights, and delay in preputial separation were observed. An increase in overall activity was seen in some treated litters at postnatal day 22 and in all treated litters at five weeks, a pattern consistent with effects previously noted in animals exposed in utero with retinoic acids. No adequate study of the late gestational and postnatal effects of the full-strength TRI-LUMA® Cream has been performed.
It is difficult to interpret these animal studies on teratogenicity with TRI-LUMA® Cream, because the availability of the dermal applications in these studies could not be assured, and comparison with clinical dosing is not possible.
All pregnancies have a risk of birth defect, loss, or other adverse event regardless of drug exposure. Typically, estimates of increased fetal risk from drug exposure rely heavily on animal data. However, animal studies do not always predict effects in humans. Even if human data are available, such data may not be sufficient to determine whether there is an increased risk to the fetus. Drug effects on behavior, cognitive function, and fertility in the offspring are particularly difficult to assess.