TRI-LUMA® Cream contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people.
The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.
TRI-LUMA® Cream contains hydroquinone, which may produce exogenous ochronosis, a gradual blue-black darkening of the skin, whose occurrence should prompt discontinuation of therapy. The majority of patients developing this condition are Black, but it may also occur in Caucasians and Hispanics.
Cutaneous hypersensitivity to the active ingredients of TRI-LUMA® Cream has been reported in the literature. In a patch test study to determine sensitization potential in 221 healthy volunteers, three volunteers developed sensitivity reactions to TRI-LUMA® Cream or its components.
TRI-LUMA® Cream contains hydroquinone and tretinoin that may cause mild to moderate irritation. Local irritation, such as skin reddening, peeling, mild burning sensation, dryness, and pruritus may be expected at the site of application. Transient skin reddening or mild burning sensation does not preclude treatment. If a reaction suggests hypersensitivity or chemical irritation, the use of the medication should be discontinued.
TRI-LUMA® Cream also contains the corticosteroid fluocinolone acetonide. Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced by systemic absorption of topical corticosteroid while on treatment. If HPA axis suppression is noted, the use of TRI-LUMA® Cream should be discontinued. Recovery of HPA axis function generally occurs upon discontinuation of topical corticosteroids.
Information for Patients
Exposure to sunlight, sunlamp, or ultraviolet light should be avoided. Patients who are consistently exposed to sunlight or skin irritants either through their work environment or habits should exercise particular caution. Sunscreen and protective covering (such as the use of a hat) over the treated areas should be used. Sunscreen use is an essential aspect of melasma therapy, as even minimal sunlight sustains melanocytic activity.
Weather extremes, such as heat or cold, may be irritating to patients treated with TRI-LUMA® Cream. Because of the drying effect of this medication, a moisturizer may be applied to the face in the morning after washing.
Application of TRI-LUMA® Cream should be kept away from the eyes, nose, or angles of the mouth, because the mucosa is much more sensitive than the skin to the irritant effect. If local irritation persists or becomes severe, application of the medication should be discontinued, and the health care provider consulted. Allergic contact dermatitis, blistering, crusting, and severe burning or swelling of the skin and irritation of the mucous membranes of the eyes, nose, and mouth require medical attention.
If the medication is applied excessively, marked redness, peeling, or discomfort may occur.
This medication is to be used as directed by the health care provider and should not be used for any disorder other than that for which it is prescribed.
The following tests may be helpful in evaluating patients for HPA axis suppression:
ACTH or cosyntropin stimulation test
A.M. plasma cortisol test
Urinary free cortisol test
Patients should avoid medicated or abrasive soaps and cleansers, soaps and cosmetics with drying effects, products with high concentration of alcohol and astringent, and other irritants or keratolytic drugs while on TRI-LUMA® Cream treatment. Patients are cautioned on concomitant use of medications that are known to be photosensitizing.
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.
Corticosteroids, when systemically administered, appear in human milk. It is not known whether topical application of TRI-LUMA® Cream could result in sufficient systemic absorption to produce detectable quantities of fluocinolone acetonide, hydroquinone, or tretinoin in human milk. Because many drugs are secreted in human milk, caution should be exercised when TRI-LUMA® Cream is administered to a nursing woman. Care should be taken to avoid contact between the infant being nursed and TRI-LUMA® Cream.
Safety and effectiveness of TRI-LUMA® Cream in pediatric patients have not been established.
Clinical studies of TRI-LUMA® Cream did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.