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If Solagé is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, discomfort, or discoloration, including hypopigmentation, may occur. Oral ingestion of the drug may lead to the same adverse effects as those associated with excessive oral intake of vitamin A (hypervitaminosis A). If oral ingestion occurs, the patient should be monitored, and appropriate supportive measures should be administered as necessary. The maximal no-effect level for oral administration of Solagé in rats was 5.0 mL/kg (30 mg/m2). Clinical signs observed were attributed to the high alcohol content (77%) of the drug formulation.
No adequate or well-controlled trials have been conducted with Solagé in pregnant women. The combination of mequinol and tretinoin may cause fetal harm when administered to a pregnant woman. Due to the known effects of these active ingredients, Solagé should not be used in women of childbearing potential.
In a dermal teratology study in New Zealand White rabbits, there were no statistically significant differences among treatment groups in fetal malformation data; however, marked hydrocephaly with visible doming of the head was observed in one mid-dose litter (12 and 0.06 mg/kg or 132 and 0.66 mg/m2 of mequinol and tretinoin, respectively) and two fetuses in one high dose litter (40 and 0.2 mg/kg or 440 and 2.2 mg/m2 of mequinol and tretinoin, respectively) of Solagé, and two high-dose tretinoin (0.2 mg/kg, 2.2 mg/m2) treated litters. These malformations were considered to be treatment related and due to the known effects of tretinoin. This was further supported by coincident appearance of other malformations associated with tretinoin, such as cleft palate and appendicular skeletal defects. No effects attributed to treatment were observed in rabbits in that study treated topically with mequinol alone (dose 40 mg/kg, 440 mg/m2). A no-observed-effect level (NOEL) for teratogenicity in rabbits was established at 4 and 0.02 mg/kg (44 and 0.22 mg/m2 mequinol and tretinoin, respectively) for Solagé which is approximately the maximum possible human daily dose, based on clinical application to 5% of total body surface area. Plasma tretinoin concentrations were not raised above endogenous levels, even at teratogenic doses. Plasma mequinol concentrations in rabbits at the NOEL at one hour after application were 124 ng/mL or approximately twelve times the mean peak plasma concentrations of that substance seen in human subjects in a clinical pharmacokinetic study.
In a repeated study in pregnant rabbits administered the same dose levels as the study described above, additional precautionary measures were taken to prevent ingestion, although there is no evidence to confirm that ingestion occurred in the initial study. Precautionary measures additionally limited transdermal absorption to a six hour exposure period, or approximately one-fourth of the human clinical daily continuous exposure time. This study did not show any significant teratogenic effects at doses up to approximately 13 times the human dose on a mg/m2 basis. However, a concurrent tretinoin dose group (0.2 mg/kg/day) did include two litters with limb malformations.
In a published study in albino rats (J. Am. Coll. Toxicology 4(5):31–63, 1985), topical application of 5% of mequinol in a cream vehicle during gestation was embryotoxic and embryolethal. Embryonic loss prior to implantation was noted in that study where animals were treated throughout gestation. Coincidentally, mean preimplantation embryonic loss was increased in the first rabbit study in all mequinol treated groups, relative to control, and in the high dose mequinol/tretinoin and tretinoin only treated groups in the second study. In those studies, dosing began at gestation day 6, when implantation is purported to occur. Increased preimplantation loss was also noted at the high combination dose in a study of early embryonic effects in rats, as was decreased body weight in male pups; these findings are consistent with the published study.
Solagé was not teratogenic in Sprague-Dawley rats when given in topical doses of 80 and 0.4 mg/kg mequinol and tretinoin, respectively (480 and 2.4 mg/m2 or 11 times the maximum human daily dose). The maximum human dose is defined as the amount of solution applied daily to 5% of the total body surface area.
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. Although no definite pattern of teratogenicity and no casual association has been established from these cases, 6 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.
Last reviewed on RxList: 1/19/2010
This monograph has been modified to include the generic and brand name in many instances.
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